Breast cancer in women •
Updated 2013 Jul 01 12:23:00 PM: ACR Appropriateness Criteria for palpable breast masses (National Guideline Clearinghouse 2013 Jul 1) view updateShow more updates
Related Summaries: •
Breast cancer (list of topics)
General Information
Description: •
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breast cancer classified as o carcinoma in situ (noninvasive carcinoma, stage 0) if cancer cells contained within duct (ductal carcinoma in situ) or lobule (lobular carcinoma in situ) o invasive breast cancer (infiltrating breast cancer, stages I-IV) if cancer cells spread beyond basement membrane of duct or lobule to adjacent breast parenchyma o Reference - Cleve Clin J Med 2008 Mar;75 Suppl 1:S10 full-text invasive breast cancer classified as(6, 7) o early breast cancer - stages I, IIa, IIb no tumor extension to chest wall or skin can include movable ipsilateral axillary lymph node metastases no distant metastases o locally advanced breast cancer - stages IIIa, IIIb, IIIc - any of the following without distant metastases metastases in ipsilateral axillary lymph nodes that are clinically fixed or matted metastases in clinically detected internal mammary lymph nodes tumor > 5 cm and metastases in movable ipsilateral axillary lymph nodes tumor with direct extension to chest wall or skin o advanced breast cancer - stage IV (distant metastases) see Staging for further details
Types: •
histopathologic types of breast carcinomas(7) o in situ carcinomas ductal carcinoma in situ (DCIS) lobular carcinoma in situ (LCIS) incidental finding of microscopic abnormal tissue growth in lobules of breast(6) does not progress to cancer, but associated with increased risk of subsequent invasive breast cancer in either breast (6) o invasive carcinomas ductal inflammatory clinical diagnosis
associated with diffuse skin edema, skin and breast erythema (peau d'orange), firmness of underlying tissue without palpable mass involving ≥ one-third of breast findings due to tumor embolization to dermal lymphatics and engorgement of superficial capillaries classified as T4d for staging so stage III or IV on presentation associated with poor prognosis does not apply to locally advanced cancer presenting late in course of disease and with skin involvement medullary, not otherwise specified medullary with lymphoid stroma mucinous (colloid) - if < 1 cm, has very low incidence of axillary lymph node metastases, but sentinel lymph node biopsy may be appropriate papillary (predominantly micropapillary pattern) tubular - if < 1 cm, has very low incidence of axillary lymph node metastases, but sentinel lymph node biopsy may be appropriate lobular undifferentiated squamous cell adenoid cystic secretory cribiform microinvasive carcinoma - invasive carcinoma with no focus of tumor cells > 1 mm (7) o typically occurs with DCIS or LCIS with small foci of tumor cells beyond basement membrane o rarely occurs without noninvasive disease Paget's disease(7) o exudate or crust of nipple and areola caused by infiltration of epidermis by noninvasive breast cancer epithelial cells o can occur with noninvasive disease (usually DCIS, rarely LCIS) or with invasive disease (infiltrating) breast sarcomas o account for < 1% of all primary breast malignancies o usually occur in women ages 40-60 years o most common types include angiosarcoma malignant fibrous histiocytoma stromal sarcoma o other types can include cystosarcoma phyllodes (can have epithelial component) fibrosarcoma liposarcoma leiomyosarcoma spindle-cell sarcoma
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rhabdomyosarcoma o Reference - Breast Cancer Res Treat 2010 Aug;122(3):619 case reports of other rare breast cancers o carcinosarcoma of breast (Cases J 2009 Jan 6;2(1):105) o juvenile secretory carcinoma of breast (Pediatric Surgery Update 2006 Jun;26(6):3) o glycogen-rich clear cell carcinoma of breast (World J Surg Oncol 2008 Apr 29;6:44 full-text) o adenoid cystic carcinoma (Int Semin Surg Oncol 2006 Jun 30;3:17 full-text) o primary breast lymphoma (World J Surg Oncol 2007 Nov 26;5:134 full-text) o granulocytic sarcoma (Diagn Pathol 2009 Jan 6;4(1):2) o other cancers (such as cervical, lung, or renal cell carcinoma) metastatic to breast (MEDLINE search for "metastasis to breast")
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Who is most affected: •
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breast cancer incidence and death rates increase with age o 95% of new cases occur in women > 40 years old o 97% of breast cancer deaths occur in women > 40 years old o Reference - American Cancer Society Breast Cancer Facts & Figures 2011-2012 PDF incidence of breast carcinoma among women < 25 years old was 3.2 per million people (4 cases diagnosed from 1935 to 2005) in Olmstead County, Minnesota (Obstet Gynecol 2011 Sep;118(3):529)
Incidence/Prevalence: •
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estimated global breast cancer incidence was 1,643,000 cases in 2010 o based on population-based cancer registries, vital registration data, and verbal autopsy data from 187 countries during 1980 and 2010 o annual rate increased by 3.1% per year from 641,000 cases in 1980 o Reference - Lancet 2011 Oct 22;378(9801):1461, editorial can be found in Lancet 2011 Oct 22;378(9801):1442, commentary can be found in Lancet 2012 Apr 14;379(9824):1391 breast cancer is most common cancer and second most common cause of cancer deaths in women in United States o based on annual report of cancer status in United States with data for 2003 to 2007 o age-adjusted incidence of breast cancer 120.7 per 100,000 women, varied with ethnicity from 82.3 per 100,000 Asian/Pacific Islander women to 123.4 per 100,000 non-Hispanic women o age-adjusted breast cancer death rates 24 per 100,000 women, varied with ethnicity from 12.2 per 100,000 Asian/Pacific Islander women to 32.4 per 100,000 black women o Reference - J Natl Cancer Inst 2011 May 4;103(9):714 full-text incidence of breast cancer increases with age and varies with ethnicity o based on invasive female breast cancer incidence in United States 2005 to 2007 o probability of developing breast cancer in next 10 years of life based on age 0.06% (1 in 1,681) at age 20 years 0.43% (1 in 232) at age 30 years
1.45% (1 in 69) at age 40 years 2.38% (1 in 42) at age 50 years 3.45% (1 in 29) at age 60 years 3.74% (1 in 27) at age 70 years lifetime risk 12.15% (1 in 8)
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Female Breast Cancer Incidence and Mortality Rates in United States: Ethnic Group
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Mortality Rates per 100,000 (2003-2007)
Non-Hispanic white women 125.4
23.9
African American women
116.1
32.4
Hispanic/Latina women
91
15.3
American Indian/Alaska Native women
89.2
17.6
Asian American/Pacific Islander women
84.9
12.2
Reference - American Cancer Society Breast Cancer Facts & Figures 2011-2012 PDF lifetime risk estimates for Australian women o 8.6% for general population o 7.8% for women with no family history of breast cancer o 12.5%-16.7% in women with 1 affected relative o 16.7%-25% in women with 2 affected relatives o Reference - Aust N Z J Surg 2000 Oct;70(10):725 in BMJ 2000 Apr 1;320(7239):906 incidence of pregnancy-associated breast cancer 37.4 per 100,000 deliveries in Sweden o based on population-based cohort from Swedish registers of women aged 15-44 years o 1,161 (7%) cases of pregnancy-associated breast cancer among total of 16,620 breast cancer cases from 1963 to 2002 o increase in pregnancy-associated breast cancer from 16 per 100,000 deliveries in 1963 to 37.4 per 100,000 deliveries in 2002 o Reference - Obstet Gynecol 2009 Sep;114(3):568 incidence of breast cancer with remote metastasis at diagnosis 2.9 per 100,000 women aged 25-39 years in 2009 o based on retrospective cohort analysis of Surveillance, Epidemiology, and End Results (SEER) database from 1976 to 2009 o SEER database included 28% of United States population in 2009 o incidence of breast cancer with remote metastasis at diagnosis significantly increased from 1976 to 2009 in women aged 25-39 years o
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Incidence of Breast Cancer per 100,000 (2004-2008)
2.9 (95% CI 2.31-3.59) per 100,000 women in 2009 1.53 (95% CI 1.01-2.21) per 100,000 women in 1976 o Reference - JAMA 2013 Feb 27;309(8):800, correction can be found in JAMA 2013 Mar 27;309(12):1229 Causes and Risk FactorsComplications and Associated Conditions History and PhysicalDiagnosisStagingTreatment
Treatment overview: Early invasive breast cancer: • initial treatment options include o breast-conserving surgery (lumpectomy) followed by radiation therapy to breast breast-conserving surgery (plus radiation therapy) for early breast cancer
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appears as effective for survival and rate of distant metastases as mastectomy (level 2 [mid-level] evidence), but may be associated with need for re-excision or future mastectomy neoadjuvant (preoperative) chemotherapy may be used for large tumors to improve resectability (NZGG Grade A) adjuvant radiation therapy after breast-conserving surgery may reduce 10year recurrence risk and 15-year breast cancer-related mortality (ESMO Level I, Grade A, level 2 [mid-level] evidence) accelerated fractionation of adjuvant radiation therapy associated with similar recurrence and survival rates as standard radiation therapy regimen but may reduce acute skin toxicity and might increase late skin and subcutaneous toxicity (ESMO Level I, Grade B, level 2 [mid-level] evidence) boost radiation to tumor bed in addition to whole breast radiation therapy reduces local recurrence risk in early breast cancer, especially in younger patients (ESMO Level I, Grade A, level 1 [likely reliable] evidence) o mastectomy indicated for patient preference, or if large or multicentric tumor precludes breast conservation therapy if desired, breast reconstruction can be done immediately or delayed delaying breast reconstruction until after completion of postmastectomy radiation therapy may reduce complications (level 2 [mid-level] evidence) postmastectomy radiation therapy recommended if ≥ 4 positive axillary nodes (ESMO Level II, Grade B) or stage T3-T4 tumor (ESMO Level III, Grade B), and may be considered for other risk factors such as close margin to pectoralis fascia adjuvant radiation therapy after mastectomy associated with reduced 5year local recurrence risk and 15-year mortality (level 2 [mid-level] evidence) o for Paget's disease of breast, central lumpectomy may result in similar 15-year breast cancer-specific survival as mastectomy (level 2 [mid-level] evidence) sentinel lymph node (SLN) biopsy is preferred method of axillary lymph node assessment for staging of early breast cancer with no clinical evidence of lymph node involvement
SLN resection alone is as effective as axillary lymph node dissection (ALND) for survival and regional control in women with invasive breast cancer and clinically negative lymph nodes and negative SLN (level 1 [likely reliable] evidence) o ALND has been recommended for patients with positive SLN (micrometastasis or macrometastasis) ALND no longer routinely required for patients with T1-2 tumors and 1-2 positive SLNs without extracapsular extension who will have adjuvant therapies (radiation therapy plus systemic therapy), based on similar tumor recurrence rates and similar 5-year overall survival comparing SLN dissection alone vs. SLN dissection plus ALND (level 2 [mid-level] evidence) ALND still indicated if T3 tumor, preoperative palpable lymph nodes, > 2 positive lymph nodes, matted axillary nodes, or having neoadjuvant chemotherapy adjuvant systemic therapy o endocrine therapy for hormone receptor-positive tumors tamoxifen (Nolvadex) 20 mg/day for 5 years recommended for premenopausal women and appears to reduce recurrence risk and allcause mortality over 15 years (NZGG Grade A, level 2 [mid-level] evidence) for postmenopausal women options which may reduce recurrence risk compared to tamoxifen alone include (NZGG Grade A, level 2 [mid-level] evidence) tamoxifen for 2-3 years followed by aromatase inhibitors for 2-3 years for total 5 years aromatase inhibitor monotherapy for 5 years o trastuzumab (Herceptin) for human epidermal growth factor receptor type 2 (HER2)-positive tumors may increase overall survival and disease-free survival but may increase risk for heart failure (NZGG Grade A, level 2 [mid-level] evidence) o chemotherapy decision to use chemotherapy should be individualized, especially if favorable prognosis where absolute benefit is small Adjuvant! Online provides individualized estimates of recurrence and survival with and without adjuvant endocrine and/or chemotherapy chemotherapy generally recommended if higher recurrence risk based on combination of factors such as node-positive, tumor > 1 cm, HER2-positive, hormone receptor-negative, high-grade histology, and lymphovascular invasion Oncotype DX may predict whether addition of chemotherapy to tamoxifen will reduce recurrence risk in women with hormone receptor-positive breast cancer who are node-negative (NACB Grade A, Level I/II) or node-positive (level 2 [mid-level] evidence) combination chemotherapy for early breast cancer may reduce 15-year all-cause mortality, breast cancer mortality, and recurrence risk (level 2 [mid-level] evidence) benefits consistent in multiple subgroups regardless of estrogen receptor status and use of tamoxifen (level 2 [mid-level] evidence) o
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taxane-containing regimens (for adjuvant treatment) may improve survival compared to nontaxane-containing regimens in women with early breast cancer (NZGG Grade A, level 2 [mid-level] evidence)
bisphosphonates o bisphosphonates (as a drug class) may not be associated with reduced rates of recurrence or bone metastases in patients with early breast cancer (level 2 [midlevel] evidence); clodronate and zoledronic acid each have mixed results in large randomized trials (level 2 [mid-level] evidence) o bisphosphonates may not decrease fracture rate (level 2 [mid-level] evidence) but may decrease bone loss (level 3 [lacking direct] evidence) so recommended if osteoporosis (NZGG Grade A) along with lifestyle interventions, calcium, and vitamin D to reduce risk for bone loss (NZGG Grade C)
Locally advanced breast cancer: • for locally advanced breast cancer including inflammatory breast cancer - treatment
includes o neoadjuvant chemotherapy (NZGG Grade A) o surgery for noninflammatory disease - mastectomy or breast-conserving therapy for inflammatory disease - mastectomy o radiation therapy o endocrine therapy if hormone receptor-positive, including use in neoadjuvant therapy o addition of HER2 inhibitor (such as trastuzumab) if HER2-positive, including use in neoadjuvant therapy
Advanced breast cancer: • for advanced (metastatic) breast cancer chemotherapy recommended for women with
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triple-negative tumors (HER2, estrogen receptor, and progesterone receptor), symptomatic or rapidly progressive organ metastases, or disease refractory to hormone therapy o combination chemotherapy associated with increased survival and time to progression compared to single-agent chemotherapy, but may increase adverse effects (level 2 [mid-level] evidence) o taxane-containing regimens may improve overall survival, time to progression, and overall response compared to some other chemotherapy regimens (level 2 [mid-level] evidence) o chemotherapy agents which may improve survival or progression-free survival in women with advanced breast cancer which progresses on first-line therapy include eribulin (Halaven), everolimus (Afinitor), and ixabepilone (Ixempra) (level 2 [mid-level] evidence) for HER2-positive advanced breast cancer o trastuzumab (Herceptin) may improve survival but associated with increased risk of cardiac dysfunction (level 2 [mid-level] evidence) o addition of lapatinib (Tykerb) to paclitaxel (or to letrozole) may increase progression-free survival (level 2 [mid-level] evidence)
addition of pertuzumab (Perjeta) to trastuzumab plus docetaxel increases progression-free survival (level 1 [likely reliable] evidence) endocrine therapy for hormone receptor-positive advanced breast cancer o endocrine therapy associated with similar survival rates compared to chemotherapy for initial treatment of hormone receptor-positive metastatic breast cancer (level 2 [mid-level] evidence); endocrine therapy may be preferred due to better tolerability, except in rapidly progressive disease o aromatase inhibitors (anastrozole, letrozole, exemestane) may have survival benefit over other endocrine therapies in postmenopausal women with advanced breast cancer (level 2 [mid-level] evidence) o preferred first-line therapy is anastrozole 1 mg orally once daily or letrozole 2.5 mg orally once daily, alternative is tamoxifen 20-40 mg/day orally o endocrine therapies used for disease progression after first-line therapy include exemestane 25 mg orally once daily or fulvestrant (Faslodex) 250 mg intramuscularly once monthly bisphosphonates (oral or IV) o may reduce risk of skeletal events in women with advanced breast cancer and clinically evident bone metastases (level 2 [mid-level] evidence) o may not reduce risk of skeletal events in women with advanced breast cancer without prior bone metastasis (level 2 [mid-level] evidence) o appear effective for pain relief in painful bone metastases (level 2 [mid-level] evidence) denosumab (Xgeva) may reduce risk for skeletal-related events more than bisphosphonates in women with breast cancer and bone metastases (level 2 [mid-level] evidence) low-molecular-weight heparin (LMWH) reduces symptomatic venous thromboembolism (VTE) (level 1 [likely reliable] evidence) and possibly 2-year mortality (level 2 [mid-level] evidence) in patients with advanced cancer surgical resection of primary tumor associated with increased survival in retrospective studies of patients with advanced breast cancer (level 2 [mid-level] evidence) o
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Recurrent breast cancer: • breast-conserving surgery for recurrent ipsilateral breast cancer may be associated with •
worse survival compared to mastectomy (level 2 [mid-level] evidence) limited evidence regarding adjuvant systemic therapy for women with isolated locoregional recurrence following primary treatment of operable breast cancer
Surveillance after primary cancer treatment: • mammography surveillance might improve overall survival and breast cancer-specific •
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survival (level 2 [mid-level] evidence) breast magnetic resonance imaging (MRI) appears more accurate than clinical exam, mammogram, and ultrasound for detection of breast cancer recurrence (level 2 [mid-level] evidence) more intensive approaches to follow-up (addition of chest x-ray and bone scan) may improve disease-free survival but not overall survival compared with regular physical exams and yearly mammography in women with early breast cancer (level 2 [mid-level] evidence)
Additional considerations:
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increased physical activity associated with reduced mortality (level 2 [mid-level] evidence) and exercise may improve quality of life in breast cancer patients and survivors (level 2 [mid-level] evidence); aspirin associated with reduced risk of breast cancer mortality and distant recurrence in women with early or locally advanced disease (level 2 [mid-level] evidence) medications associated with reduced frequency and severity of hot flashes include antidepressants (level 2 [mid-level] evidence), clonidine (level 2 [mid-level] evidence), megestrol acetate (level 1 [likely reliable] evidence), gabapentin (level 2 [mid-level] evidence) see also Ductal carcinoma in situ or Lobular carcinoma in situ
Diet: •
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dietary modifications do not appear to reduce mortality or progression in cancer patients (level 2 [mid-level] evidence) o based on systematic review of trials with methodologic limitations o systematic review of 25 randomized trials in patients with cancer and 34 randomized trials in patients with preinvasive lesions o only 3 trials had adequate randomization, allocation concealment and blinding o trials examined effect of dietary interventions on cancer at either specific sites including lung, breast, skin, head and neck, or at multiple body sites o dietary interventions included healthy diet - advising ≥ 1 of balanced healthy diet, weight loss in overweight women, general reduction in fat intake as a percentage of total calories, increased intake of fiber or of fruit and vegetables, or optimal calorie or protein diet - in 7 trials of cancer, 6 trials of preinvasive lesions retinol in 4 trials of cancer, 2 trials of preinvasive lesions selenium in 2 trials of cancer vitamin B6 in 2 trials of cancer o researchers analyzed results from dietary interventions across body sites o no significant effects found with healthy diet, dietary supplements, weight loss, exercise, antioxidants, or retinol o Reference - J Natl Cancer Inst 2006 Jul 19;98(14):961 full-text lower fat diet has inconsistent results in 2 randomized trials o lower fat diet with higher intake of vegetables, fruit, and fiber does not appear to reduce mortality or recurrence risk in women with early breast cancer (level 2 [mid-level] evidence) based on randomized trial without attention control 3,088 women aged 18-70 years with early-stage breast cancer randomized to intervention vs. control intervention group had telephone counseling, cooking classes, and newsletters promoting daily targets of 5 vegetable servings, vegetable juice 16 ounces, 3 fruit servings, fiber 30 g, and 15%20% energy intake from fat control group had print materials promoting 5 servings of fruit and vegetables, fiber 20 g, and < 30% energy intake from fat
actual dietary intake was assessed by patient recall and plasma carotenoid concentrations (as marker for vegetable and fruit intake) mean follow-up 7.3 years in dietary assessment at 4 years, intervention associated with (all p < 0.001) increased mean number of vegetable and fruit servings increased mean fiber intake increased plasma carotenoid level decreased energy intake from fat clinical outcomes comparing intervention vs. control invasive breast cancer event in 16.7% vs. 16.9% (not significant) mortality 10.1% vs. 10.3% (not significant) Reference - WHEL trial (JAMA 2007 Jul 18;298(3):289 full-text), editorial can be found in JAMA 2007 Jul 18;298(3):335, commentary can be found in JAMA 2007 Nov 14;298(18):2135, ACP J Club 2008 Jan-Feb;148(1):8 o lower fat diet may reduce risk of breast cancer relapse (level 2 [mid-level] evidence) based on randomized trial without attention control 2,437 postmenopausal women treated for early-stage breast cancer were randomized to low-fat diet (20% of total kcals) vs. usual diet (fat about 40% of total kcals) intervention group had dietary counseling sessions every 2 weeks for 16 weeks then every 3 months control group had dietitian contact at baseline and every 3 months median follow-up 5 years intervention associated with greater reduction in fat intake (p < 0.0001) based on annual follow-up phone interviews breast cancer recurrence in 9.8% low-fat diet group vs. 12.4% control group (NNT 39) comparison was statistically significant using adjusted Cox model analysis (p = 0.034) but not significant using stratified log rank test (p = 0.077) Reference - WINS trial (J Natl Cancer Inst 2006 Dec 20;98(24):1767 fulltext) soy protein intake may benefit breast cancer survivors o soy protein intake > 10 mg/day associated with decreased risk of recurrence but not mortality in breast cancer survivors (level 2 [mid-level] evidence) based on pooled analysis of 3 prospective cohort studies 9,514 breast cancer survivors were followed for mean 7.4 years and evaluated for association between soy isoflavone intake and breast cancer outcomes 14.2% had recurrence, 12.3% died from any cause, and 9.3% died from breast cancer mean soy isoflavone intake 2.6-45.9 mg/day across studies
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compared to soy isoflavone intake < 4 mg/day, intake ≥ 10 mg/day associated with decreased risk of recurrence (hazard ratio 0.75, 95% CI 0.61-0.92) association was significant among women with estrogen receptornegative breast cancer and among tamoxifen users no significant differences in breast cancer-specific or overall mortality Reference - Am J Clin Nutr 2012 Jul;96(1):123 soy protein intake associated with decreased mortality and recurrence (level 2 [mid-level] evidence) based on population-based cohort study in China 5,042 women aged 20-75 years with primary breast cancer diagnosed in previous 6 months and having surgical therapy were assessed at 18, 36, and 60 months median follow-up 3.9 years 9 women died during surgery 444 (8.8%) died and 534 (10.6%) had recurrences or breast cancer-related deaths multivariate-adjusted 4-year rates comparing highest vs. lowest quartile of soy protein intake total mortality 7.4% vs. 10.3% (hazard ratio [HR] 0.71, 95% CI 0.540.92) recurrence rate 8% vs. 11.2% (HR 0.68, 95% CI 0.54-0.87) association observed in women with estrogen receptor-positive or -negative breast cancer and with or without tamoxifen use Reference - JAMA 2009 Dec 9;302(22):2437 full-text increasing dietary intake of soy isoflavone does not appear to increase risk of breast cancer recurrence or death in women with history of estrogen- and/or progesterone-receptor positive breast cancer receiving adjuvant endocrine therapy (level 2 [mid-level] evidence) based on cohort study 524 women aged 29-72 years (47.3% premenopausal) who had surgery for breast cancer and were receiving adjuvant endocrine therapy (tamoxifen or anastrozole) were assessed for dietary intake of soy isoflavones and breast cancer recurrence or death all women had estrogen- and/or progesterone-receptor positive breast cancer median follow-up 5.1 years increasing dietary intake of soy isoflavone associated with reduced risk of recurrence in postmenopausal women (p = 0.02 for trend across quartiles of consumption) no significant difference in risk of death in postmenopausal women no significant differences in risk of breast cancer recurrence or death in premenopausal women
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among postmenopausal women, association of increased dietary intake of soy isoflavone and decreased recurrence risk was limited to subgroups of women with both estrogen receptor-positive and progesterone receptor-positive status women treated with anastrozole Reference - CMAJ 2010 Nov 23;182(17):1857 full-text o limited evidence that increased soy or other phytoestrogen intake may stimulate breast cancer growth in estrogen receptor-positive breast cancer (level 3 [lacking direct] evidence) based on literature review without clinical outcomes soy contains phytoestrogens, mainly isoflavones, especially genistein limited evidence that genistein can stimulate breast cancer growth, genistein may interfere with antitumor activity of tamoxifen in estrogen receptor-positive tumors for women with estrogen receptor-negative tumors, genistein may inhibit breast cancer cell growth, but women with estrogen receptor-negative tumors could develop estrogen receptor-positive tumors Reference - J Womens Health (Larchmt) 2003 Sep;12(7):617 PDF o dietary isoflavone supplements interfered with tamoxifen effect in animal studies (Cancer Res 2002 May 1;62(9):2474 full-text, Ann Pharmacother 2001 Sep;35(9):1118 PDF) o review of soy can be found in Am Fam Physician 2009 Jan 1;79(1):43 full-text green tea consumption > 3 cups/day may be associated with decreased risk of breast cancer recurrence (level 2 [mid-level] evidence) o based on systematic review of observational studies o systematic review of 9 cohort and case-control studies evaluating green tea consumption for breast cancer prevention or recurrence o green tea consumption > 3 cups/day associated with reduced recurrence compared with nondrinkers (relative risk 0.73, 95% CI 0.56-0.96) in analysis of 2 cohort studies o case-control studies (but not cohort studies) suggest green tea consumption may reduce incidence o Reference - Breast Cancer Res Treat 2010 Jan;119(2):477 American Dietetic Association (ADA) oncology evidence-based nutrition practice guideline can be found at National Guideline Clearinghouse 2009 Jan 5:12819
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Activity: •
increased physical activity before or after breast cancer diagnosis associated with reduced all-cause mortality and breast cancer mortality (level 2 [mid-level] evidence) o based on systematic review of observational studies o systematic review of 32 observational studies and 12 randomized trials evaluating the association between physical activity and survival and/or cancer biomarkers in patients with cancer o 17 observational studies evaluated physical activity and survival in 33,718 women with breast cancer
physical activity was assessed before breast cancer diagnosis in 9 studies and after diagnosis in 8 studies o increased physical activity associated with reduced all-cause mortality in 12 of 14 studies, difference statistically significant in 7 studies breast cancer mortality in 13 of 17 studies, difference statistically significant in 6 studies o Reference - J Natl Cancer Inst 2012 Jun 6;104(11):815, editorial can be found in J Natl Cancer Inst 2012 Jun 6;104(11):797 o moderate-intensity physical activity associated with reduced mortality in women with breast cancer (level 2 [mid-level] evidence) based on prospective observational study (included in systematic review above) 933 women with local or regional breast cancer followed for up to 9 years compared to inactive women, women expending at least 9 metabolic equivalent hours per week (about 2-3 hours per week of brisk walking) had reduced mortality if active in year prior to diagnosis (hazard ratio [HR] 0.69, 95% CI 0.45-1.06, p = 0.045) reduced mortality if active 2 years after diagnosis (HR 0.33, 95% CI 0.15-0.73, p = 0.046) women who decreased activity after diagnosis had increased mortality (HR 3.95, 95% CI 1.45-10.5) Reference - J Clin Oncol 2008 Aug 20;26(24):3958 full-text exercise may improve quality of life in breast cancer patients and survivors (level 2 [midlevel] evidence) o based on systematic review of trials with methodologic limitations o systematic review of 14 randomized trials with 717 patients (being treated for breast cancer or with prior history of breast cancer) o only 2 trials met most methodologic quality criteria, but these 2 trials were lacking intention-to-treat analysis o exercise improved quality of life on 2 scales compared to usual care in 3 trials with 194 patients, including 2 high-quality trials o exercise improved cardiorespiratory fitness in 9 trials with 473 patients, significant improvements reported in 5 of 6 outcomes with 1-3 trials reporting each outcome o exercise reduced fatigue in meta-analysis of 6 trials with 319 patients o no significant differences in body weight or lymphedema o Reference - CMAJ 2006 Jul 4;175(1):34 full-text o
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Exercise during treatment: • American Cancer Society guidelines on nutrition and physical activity during and after
cancer treatment include cautions about exercise o if severe anemia, delay exercise until anemia improved o if immunocompromised, avoid exercise in public until white cell count returns to safe levels
if severe fatigue, approach exercise cautiously if undergoing radiation, avoid chlorinated swimming pools if catheter, avoid swimming if peripheral neuropathy or dizziness, consider restricted balance and coordination in planning exercise o Reference - CA Cancer J Clin 2012 Jul;62(4):242 full-text exercise during adjuvant therapy for breast cancer associated with nonsignificant improvement in fatigue and weight gain (level 2 [mid-level] evidence) o based on Cochrane review of mostly moderate-quality trials o systematic review of 9 randomized and nonrandomized trials of exercise in 452 women undergoing adjuvant treatment for breast cancer o exercise significantly improved cardiorespiratory fitness in meta-analysis with 207 patients o exercise associated with nonsignificant improvement in fatigue in meta-analysis with 317 patients o exercise associated with nonsignificant improvement in weight gain in metaanalysis with 147 patients o Reference - Cochrane Database Syst Rev 2006 Oct 18;(4):CD005001 exercise during active treatment may improve quality of life and physical functioning in adults with cancer (level 2 [mid-level] evidence) o based on Cochrane review limited by clinical heterogeneity o systematic review of 56 randomized or quasi-randomized trials evaluating exercise during active treatment phase in 4,826 adults with cancer o analyses were limited by heterogeneity in exercise interventions, control groups, and outcome measure assessment o comparing exercise to control exercise associated with improvement at < 12 weeks in overall quality of life in analysis of 11 trials with 806 adults physical function in analysis of 8 trials with 540 adults social function in analysis of 5 trials with 378 adults role function in analysis of 7 trials with 439 patients fatigue in analysis of 12 trials with 971 adults all results limited by significant heterogeneity o greater improvement with moderate-to-vigorous exercise than mild exercise o Reference - Cochrane Database Syst Rev 2012 Aug 15;(8):CD008465 walking during cancer treatment may improve pain but decrease self-reported physical function (level 2 [mid-level] evidence) o based on randomized trial with limited adherence o 126 patients (mean age 60.2 years) with prostate (55.6%), breast (32.5%), or other cancers were randomized to home-based walking intervention vs. usual care (mean duration 12 weeks) o patients also received usual treatment including external beam radiation therapy (52.3%) and chemotherapy (34.9%) o 32% of exercisers stopped walking, 22% of controls exercised o exercise associated with (at end of cancer treatment) o o o o
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worsening of Medical Outcomes Study physical function role limitations (p = 0.037) decreased Medical Outcomes Study pain at end of cancer treatment (p = 0.046) o younger age was associated with improved Medical Outcomes Study physical function (p = 0.048) o no significant difference in change of pain scores between groups o Reference - Cancer 2009 Oct 15;115(20):4874 full-text walking during adjuvant chemotherapy for breast cancer associated with improved symptoms (level 2 [mid-level] evidence) o based on small randomized trial o 40 women receiving adjuvant chemotherapy for breast cancer were randomized to moderate-intensity home-based walking program vs. control for 12 weeks o walking associated with significantly improved symptom severity scores and mood disturbance o Reference - J Adv Nurs 2011 Jan;67(1):158 supervised group exercise program during treatment for early-stage breast cancer associated with improved breast cancer-specific quality of life (level 2 [mid-level] evidence) o based on randomized trial without attention control o 203 women being treated for early-stage breast cancer were randomized to supervised group exercise program for 12 weeks vs. usual care o 177 women (87%) completed follow-up at 6 months o exercise improved breast cancer specific-quality of life but not general quality of life at 6 months o Reference - BMJ 2007 Mar 10;334(7592):517 full-text, editorial can be found in BMJ 2007 Mar 10;334(7592):484, commentary can be found in Am Fam Physician 2007 Oct 15;76(8):1217
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Exercise for shoulder mobility: • exercise may improve shoulder range of motion but increase wound drainage after breast
cancer treatment (level 2 [mid-level] evidence) o based on Cochrane review with heterogeneity and trials with methodologic limitations o systematic review of 24 randomized trials evaluating exercise interventions for preventing, minimizing, or improving upper limb dysfunction in 2,132 women after breast cancer treatment o only 3 trials had adequate allocation concealment, only 1 trial met all quality criteria evaluated and this trial did not find significant differences o early implementation of exercise (compared with delayed implementation) improved recovery of shoulder flexion range of motion in multiple analyses of 2-3 trials (limited by heterogeneity) slightly increased wound drainage volume in analysis of 3 trials and duration of drainage (by about 1 day) in analysis of 5 trials did not significantly delay wound healing in early postoperative period in analysis of 4 trials
no significant differences between groups in pain in 2 trials no significant differences between groups in lymphedema in 3 trials, while 1 trial favored early exercise at 4-month evaluation o compared to various controls, structured exercise improved shoulder flexion range of motion at 2 weeks postoperatively (analysis of 5 trials), 1 month (analysis of 3 trials, not significant), 3 months (analysis of 4 trials), 6 months (analysis of 3 trials), and 1 year (1 trial) many of these analyses limited by heterogeneity benefit reported in analysis restricted to interventions involving physical therapy reduced shoulder dysfunction score at post intervention and at 6 months in analyses of 2 trials with 87 patients no significant difference between groups in pain in 1 trial no significant difference between groups in risk of lymphedema at any time point in 1 trial o Reference - Cochrane Database Syst Rev 2010 Jun 16;(6):CD005211 exercise may improve shoulder mobility after axillary lymph node dissection for breast cancer (level 2 [mid-level] evidence) o based on systematic review of moderate-quality trials o systematic review of 6 randomized trials evaluating exercise for shoulder mobility and lymphedema after axillary lymph node dissection for breast cancer with 429 patients o no meta-analyses performed o exercise associated with significant improvement in shoulder mobility in all trials o no significant differences in severity of lymphedema o Reference - J Adv Nurs 2010 Sep;66(9):1902 multidimensional physical therapy program associated with improvement in neck and shoulder pain in breast cancer survivors (level 2 [mid-level] evidence) o based on small randomized trial without attention control o 44 breast cancer survivors (stage I to IIIA) who had simple mastectomy or quadrantectomy and reconstruction and with current neck and shoulder pain were randomized to multidimensional physical therapy program for 90 minutes 3 times weekly for 8 weeks vs. usual care o multidimensional program had physical therapist supervision and included individual training (aerobic, mobility, stretching, and strengthening exercises) and physical therapy recovery (stretching, massage) o neck and shoulder pain measured on 0-100 scale o mean neck pain scores comparing multidimensional program vs. usual care 63 vs. 48 before intervention 11 vs. 52 after intervention mean change -52 vs. +4 (p < 0.001) o mean shoulder/axillary pain scores comparing multidimensional program vs. usual care 53 vs. 32 before intervention 5 vs. 40 after intervention
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mean change -48 vs. +8 (p < 0.001) Reference - Clin J Pain 2012 Feb;28(2):113
o Exercise after treatment: • dance/movement therapy associated with decreased fatigue and improved quality of life
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but may not affect body image in patients with breast cancer (level 2 [mid-level] evidence) o based on Cochrane review with limited evidence o systematic review of randomized and quasi-randomized trials evaluating dance/movement therapy in patients with cancer o 2 trials comparing dance/movement therapy vs. wait list in 71 women with breast cancer met inclusion criteria o dance/movement therapy associated with decreased fatigue in 1 trial with 33 women (p < 0.05) improved quality of life in 1 trial with 38 women (p = 0.008) o no significant difference between groups in body image in analysis of 2 trials mental health in 1 trial with 38 women mood and distress in 1 trial with 33 women o Reference - Cochrane Database Syst Rev 2011 Oct 5;(10):CD007103 post-treatment exercise may improve health-related quality of life and reduce fatigue in adult cancer survivors (level 2 [mid-level] evidence) o based on Cochrane review of trials with methodologic limitations o systematic review of 40 randomized or quasi-randomized trials comparing posttreatment exercise to control (usual care or nonexercise intervention) in 3,694 adults with primary or recurrent cancer patients had breast, colorectal, head and neck, lymphoma, or other cancer mode of exercise included strength training, resistance training, walking, cycling, yoga, Qigong, and Tai Chi o all but 2 trials had ≥ 1 limitation including allocation concealment not stated lack of or unclear blinding of outcome assessors high dropout rate and/or lack of intention-to-treat analysis o post-treatment exercise associated with improvements up to 12 weeks in overall health-related quality of life in analysis of 11 trials with 826 adults fatigue in analysis of 10 trials with 745 adults emotional well-being and mental health in analysis of 8 trials with 632 adults overall anxiety in analysis of 4 trials with 455 adults social functioning in analysis of 5 trials with 386 adults o no significant differences at up to 12 weeks in depression in analysis of 4 trials with 455 adults physical functioning in analysis of 5 trials with 386 adults cognitive functioning in analysis of 5 trials with 332 adults o results were not consistent at all time points
Reference - Cochrane Database Syst Rev 2012 Aug 15;(8):CD007566 1-year strength training program associated with increased body image scores and strength in breast cancer survivors with or without lymphedema (level 2 [mid-level] evidence) o based on randomized trial without intention-to-treat analysis o 295 breast cancer survivors with lymphedema or at risk for lymphedema were randomized to weight-lifting program (90-minute session twice weekly) vs. waitlist control for 1 year o 234 (79%) completed follow-up and included in analysis o strength training associated with greater improvement in body image and relationships scale (greatest changes in strength/health and appearance/sexuality scores) o Reference - Breast Cancer Res Treat 2010 Jun;121(2):421 strength and weight training program associated with increased muscle strength and balance in breast cancer survivors with bone loss (level 3 [lacking direct] evidence) o based on randomized trial with low adherence and without clinical outcomes o 249 postmenopausal breast cancer survivors with osteoporosis or osteopenia were randomized to strength and weight training program vs. control for 24 months o adherence 69.4% over 2 years o strength and weight training associated with significant improvements (p ≤ 0.031) in hip flexion and extension knee flexion and extension wrist flexion balance o no difference in number of falls between groups o Reference - J Nurs Scholarsh 2009 Mar;41(1):20 weightlifting may increase risk of self-reported musculoskeletal injury in women with breast cancer-related lymphedema (level 2 [mid-level] evidence) o based on randomized trial without attention control o 195 female breast cancer survivors with or at risk of lymphedema randomized to weightlifting twice weekly vs. usual care for 1 year o weightlifting associated with increased risk of self-reported musculoskeletal injury in patients with lymphedema (odds ratio 19.9, 95% CI 5.1-77.1), but not in patients at risk of lymphedema o Reference - Oncologist 2012;17(8):1120 full-text home-based diet and exercise intervention associated with reduced rate of functional decline and might improve physical function in older, overweight patients with prior cancer (level 2 [mid-level] evidence) o based on randomized trial without attention control and with allocation concealment not stated o 641 overweight (body mass index [BMI] 25-40 kg/m 2) patients aged 65-91 years ≥ 5 years after colorectal, breast, and prostate cancer were randomized to immediate-intervention vs. delayed-intervention (wait list control) for 12 months o
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intervention was home-based tailored program of telephone counseling and mailed materials promoting exercise, improved diet quality, and modest weight loss o 50 patients dropped out of intervention vs. 33 from control (p = 0.04) o all outcomes based on self-report o diet and exercise intervention associated with reduced decline in mean function scores (p = 0.03) small improvement in mean basic lower extremity function score (vs. decreased function with wait list, p = 0.005) improvements in physical activity, dietary behaviors, and overall quality of life (p < 0.05) greater weight loss (2.06 kg [4.5 lbs] vs. 0.92 kg [2 lbs] with wait list, p < 0.001) o Reference - RENEW trial (JAMA 2009 May 13;301(18):1883 full-text), commentary can be found in JAMA 2009 Aug 26;302(8):845 o home-based diet-exercise intervention appears to have sustained physical function and weight loss benefits at 1 year postdiscontinuation based on follow-up study of RENEW trial 558 patients (87.1%) crossed over to other trial arm at 1 year for 1 additional year intervention initiated in 289 patients originally receiving waitlist control intervention discontinued in 269 patients originally receiving intervention in patients discontinuing intervention, diet and exercise intervention associated with improvements from baseline at 2 years in physical activity and BMI (each p = 0.001) diet and exercise intervention in delayed-intervention group associated with similar improvements at 2 years as reported in immediateintervention group at 1 year Reference - J Clin Oncol 2012 Jul 1;30(19):2354, commentary can be found in J Clin Oncol 2012 Jul 1;30(19):2294 review of exercise for breast cancer survivors can be found in Phys Sportsmed 2002 Aug;30(8):33 o
• Yoga: •
yoga may improve short-term health-related quality of life and psychological health in women with breast cancer (level 2 [mid-level] evidence) o based on systematic review limited by methodologic heterogeneity of trials o systematic review of 12 randomized trials evaluating yoga in 742 women with breast cancer trials included patients receiving active therapy (5 trials), patients who had completed therapy (5 trials), or combination (2 trials) comparison groups included no treatment, supportive therapy, or health education o for health-related quality of life, yoga associated with short-term improvement in
global health-related quality of life (p = 0.04) in analysis of 4 trials with 274 patients functional well-being (p = 0.03) in analysis of 4 trials with 226 patients social well-being (p = 0.006) in analysis of 6 trials with 375 patients spiritual well-being (p = 0.01) in analysis of 2 trials with 155 patients o for psychological health, yoga associated with short-term improvement in anxiety (p < 0.01) in analysis of 5 trials with 381 patients depression (p < 0.01) in analysis of 6 trials with 311 patients perceived stress (p = 0.03) in analysis of 3 trials with 164 patients psychological distress (p < 0.01) in analysis of 6 trials with 398 patients o sensitivity analyses reported significant effects only in trials with unclear random sequence generation and/or allocation concealment o no significant differences found in long-term effects o Reference - BMC Cancer 2012 Sep 18;12(1):412 full-text yoga may improve cancer-related fatigue in women treated for breast cancer (level 2 [mid-level] evidence) o based on small randomized trial of 31 women with persistent fatigue 6 months after breast cancer treatment randomized to lyengar yoga vs. health education o yoga associated with reduced fatigue and increased vigor at 3 months (p < 0.05) o Reference - Cancer 2012 Aug 1;118(15):3766 yoga relaxation training may reduce distress in women following breast cancer surgery (level 2 [mid-level] evidence) o based on small randomized trial o 32 women receiving physical therapy for 1 week following surgery for breast cancer randomized to yoga relaxation training sessions (including instructive audio cassette recordings provided upon hospital discharge) for 3 weeks of at-home practice vs. no additional treatment o yoga relaxation training associated with significant reduction in feelings of distress during hospitalization and 4 weeks postoperatively o Reference - Integr Cancer Ther 2011 Mar;10(1):16
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Counseling: Initial diagnosis: • mothers diagnosed with breast cancer would like help regarding whether, what, and how
to tell their children about their illness o based on qualitative interviews with 32 women with breast cancer o Reference - BMJ 2000 Aug 19-26;321(7259):479 full-text, editorial can be found in BMJ 2000 Aug 19-26;321(7259):462
Supportive interventions for nonmetastatic breast cancer: • psychoeducational support may improve quality of life after breast cancer treatment
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(level 2 [mid-level] evidence) o based on small randomized trial of 48 women during first year after breast cancer treatment randomized to psychoeducational support intervention vs. control o Reference - Cancer Nurs 2012 Jan;35(1):E34 cognitive behavioral therapy plus hypnosis may control radiation therapy-related fatigue in women with breast cancer (level 2 [mid-level] evidence)
based on small randomized trial 42 women having breast cancer radiation therapy randomized to cognitive behavioral therapy plus hypnosis vs. no treatment; all received standard medical care o fatigue increased in control group but not in cognitive behavioral therapy patients (p < 0.05) o Reference - Health Psychol 2009 May;28(3):317 addition of cognitive behavioral therapy to physical training may not further improve quality of life for cancer survivors (level 2 [mid-level] evidence) o based on randomized trial without intention-to-treat analysis o 147 cancer survivors (54.7% breast cancer) randomized to cognitive behavioral therapy plus physical training vs. physical training alone and compared to nonintervention cohort of 62 cancer survivors o quality of life significantly improved in both intervention groups compared to nonintervention cohort o no significant difference in quality of life for cognitive behavioral therapy plus physical training vs. physical training alone o Reference - Psychosom Med 2008 May;70(4):422 group interventions o patient education group meetings may improve quality of life in women with nonmetastatic breast cancer (level 2 [mid-level] evidence) based on randomized trial with allocation concealment not stated 312 women with stage I-III breast cancer were randomized to 1 of 4 groups (control, education group, peer discussion group, education-peer discussion combination group) with 10-12 women per group meeting weekly for 8 weeks, assessment at 6 months patients in education groups had significant improvement in quality of life measures including self-esteem, body image, and decrease in intrusive thoughts about illness no significant improvements in peer discussion or control groups trend toward negative outcome in peer discussion group Reference - Arch Gen Psychiatry 1999 Apr;56(4):340 full-text o group teleconferencing may improve feelings of control and social well-being in African American women with breast cancer (level 2 [mid-level] evidence) based on randomized trial without blinding 185 African American women (mean age 56 years) with invasive ductal breast cancer diagnosis and lumpectomy within 6 months were randomized to group therapy via teleconference vs. usual care teleconferencing involved real time interaction for 90 minutes weekly for 8 weeks then booster sessions every other week for 2 sessions; sessions focused on fears, myths, coping, and reconnection to family usual care was any psychosocial support used by patient group teleconferencing associated with significant improvements between groups in social well-being, fear, and fatalism from baseline at 16 weeks in group-by-time analysis, but not for increase in cancer knowledge o o
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Reference - Cancer 2012 Aug 1;118(15):3822 combined psychoeducational and cognitive support group intervention may not improve psychological distress or quality of life in women with primary breast cancer (level 2 [mid-level] evidence) based on randomized trial without intention-to-treat analysis and without attention control 205 women aged 18-70 years with stage I-IIIA primary breast cancer were randomized to combined psychoeducational and cognitive support intervention vs. no treatment group intervention given as two 6-hour psychoeducation sessions and 8 weekly 2-hour group psychotherapy sessions 186 women (90.7%) included in analysis dropout or loss to follow-up in 12.7% for treatment group vs. 5.8% for no treatment group no significant differences in psychological distress, mental adjustment, and quality of life at 6 and 12 months only patients statistically significant improvements (independent of allocation) were those using antidepressive medication Reference - Eur J Cancer 2011 Jun;47(9):1363 group intervention for stress education and physical activity may reduce fatigue and emotional distress in breast cancer survivors (level 2 [mid-level] evidence) based on randomized trial without attention control 87 women who had completed treatment for nonmetastatic breast cancer were randomized to 4-week nurse-led psychoeducational intervention for stress management and physical activity vs. usual care intervention associated with greater improvement in fatigue, energy level, and emotional distress at 3-month follow-up Reference - Cancer Nurs 2008 Mar-Apr;31(2):145
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Supportive interventions for metastatic breast cancer: • limited evidence for short-term benefit of psychological interventions for women with
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metastatic breast cancer o based on Cochrane review o systematic review of 5 randomized trials evaluating psychological interventions in 511 women with metastatic breast cancer o 2 trials evaluated cognitive behavioral therapy, and 3 trials evaluated supportiveexpressive group therapy o benefits limited to some short-term psychological outcomes and not sustained at follow-up o no significant overall effect on survival, but results limited by heterogeneity o Reference - Cochrane Database Syst Rev 2008 Jul 16;(3):CD004253 supportive-expressive group therapy not associated with longer survival in women with metastatic breast cancer (level 2 [mid-level] evidence) o based on 2 randomized trials without attention control
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supportive-expressive group therapy does not prolong survival but may improve mood and pain in women with metastatic breast cancer (level 2 [mid-level] evidence) based on randomized trial without attention control 235 women with metastatic breast cancer and expected survival at least 3 months were randomized to weekly supportive-expressive group therapy vs. control group group therapy associated with greater improvement in psychological symptoms and less pain (p = 0.04), based on significant benefit in women who were more distressed at baseline no significant difference in median survival 17.9 months vs. 17.6 months Reference - N Engl J Med 2001 Dec 13;345(24):1719 full-text, editorial can be found in N Engl J Med 2001 Dec 13;345(24):1767, commentary can be found in N Engl J Med 2002 Apr 18;346(16):1247 supportive-expressive group therapy not associated with longer survival in women with metastatic breast cancer (level 2 [mid-level] evidence) based on randomized trial without attention control 125 women with metastatic or locally recurring breast cancer (122 had metastatic disease) were randomized to weekly 90-minute sessions of supportive-expressive group therapy plus educational materials vs. educational materials only median survival comparing supportive-expressive group therapy vs. control 30.7 months vs. 33.3 months (not significant) 29.3 months vs. 9.3 months in post hoc subgroup analysis of 25 women with estrogen receptor-negative breast cancer (p = 0.002) Reference - Cancer 2007 Sep 1;110(5):1130
Medications: Medications for early and locally advanced breast cancer (Stages I-III): • choice of medications is based on individualized assessment of prognosis, and potential •
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risks and benefits of treatment(2) common medication regimens (in addition to surgery and radiation) include (6) o endocrine therapy - if hormone receptor-positive o trastuzumab - if human epidermal growth factor receptor 2 (HER2, also called HER-2/neu or erbB2) overexpression o chemotherapy used if high risk for recurrence such as hormone receptor-negative, larger tumor, high-grade histology, lymphovascular invasion not used if low risk for recurrence such as hormone receptor-positive, tumor ≤ 1 cm, negative lymph nodes in stage III disease may be considered before surgery (neoadjuvant chemotherapy) if breast conservation is possible instead of mastectomy Adjuvant! Online may help support treatment decision-making by providing patientspecific risks and benefits for adjuvant therapies after surgery
Endocrine therapy for early and locally advanced breast cancer:
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endocrine therapy used for hormone receptor-positive breast cancer, avoid in hormone receptor-negative breast cancer (NZGG Grade A) for early-stage breast cancer o tamoxifen for adjuvant systemic therapy in early-stage breast cancer appears to reduce recurrence risk and all-cause mortality over 15 years (level 2 [mid-level] evidence) optimal duration of tamoxifen therapy appears to be 5 years (level 2 [midlevel] evidence) paroxetine use during tamoxifen treatment may increase risk of breast cancer-related death (level 2 [mid-level] evidence) o in premenopausal women tamoxifen 20 mg/day orally for 5 years is recommended (NZGG Grade A) consider extended therapy with aromatase inhibitor if woman becomes reliably menopausal after completion of 5 years of tamoxifen (NZGG Grade A) addition of luteinizing hormone-releasing hormone (LHRH) agonist consider in women < 40 years old taking tamoxifen who are not postmenopausal after chemotherapy (NZGG Grade B) addition of LHRH agonist (with or without tamoxifen) to chemotherapy may reduce risk for recurrence and death in premenopausal women with estrogen receptor-positive early breast cancer (level 2 [mid-level] evidence) LHRH agonist may reduce recurrence risk in women < 50 years old with early breast cancer not receiving chemotherapy (level 2 [midlevel] evidence) o in postmenopausal women adjuvant endocrine therapy for 5 years recommended in women with hormone receptor-positive breast cancer, using either (NZGG Grade A) aromatase inhibitor monotherapy with anastrozole 1 mg orally once daily or letrozole 2.5 mg orally once daily sequential therapy with 2-3 years of tamoxifen and 2-3 years of aromatase inhibitor for total 5 years tamoxifen for 5 years may be used if aromatase inhibitor contraindicated or not tolerated (NZGG Grade A) aromatase inhibitors may reduce breast cancer recurrence risk compared to tamoxifen in postmenopausal women with estrogen receptor-positive early breast cancer (level 2 [mid-level] evidence) for locally advanced breast cancer in postmenopausal women, endocrine therapy may be used for neoadjuvant (preoperative) therapy to reduce tumor volume before surgery o anastrozole appears at least as effective as tamoxifen for improving operability of large locally advanced hormone receptor-positive breast cancer (level 2 [midlevel] evidence) o letrozole may be more effective than tamoxifen as preoperative therapy to allow breast-conserving surgery (level 2 [mid-level] evidence) adverse effects o tamoxifen has adverse effects including
hot flashes - see Treatment of hot flashes in patients with breast cancer low but increased risk for endometrial cancer, gastrointestinal cancer, stroke, and pulmonary embolism (level 2 [mid-level] evidence) ocular toxicity o adverse effects of aromatase inhibitors - gastrointestinal disturbances, asthenia, headache, hot flashes, and musculoskeletal symptoms are common o adjuvant therapy with aromatase inhibitor (compared to tamoxifen) may increase risk of cardiovascular events and fractures and decrease risk of venous thromboembolism and endometrial carcinoma in postmenopausal women with breast cancer (level 2 [mid-level] evidence) o consider risk for osteoporosis interventions to reduce risk of bone mineral loss include healthy diet, not smoking, maintaining healthy body mass index, regular exercise, calcium, and adequate vitamin D levels (NZGG Grade C) bisphosphonates recommended if osteoporosis (NZGG Grade A), consider if osteopenia (NZGG Grade C) see Endocrine therapy for breast cancer for details
• HER2 inhibitors for early and locally advanced breast cancer: • human epidermal growth factor receptor 2 (HER2) is overexpressed in about 30% of breast •
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cancers and associated with more aggressive disease HER2 inhibitors used in HER2-positive breast cancer and include o trastuzumab (Herceptin) 4 mg/kg IV, then 2 mg/kg IV once weekly for 51 weeks in early breast cancer or until disease progression or intolerable toxicity in metastatic breast cancer monitor cardiac function (including ejection fraction) every 3 months while taking trastuzumab o lapatinib (Tykerb) 1.25 g orally once daily on days 1-21 (plus capecitabine 2 g/m2/day on days 1-14) in 21-day cycles - used for patients with metastatic breast cancer and prior therapy with an anthracycline, a taxane, and trastuzumab o pertuzumab (Perjeta) 840 mg IV over 60 minutes, then 420 mg IV over 30-60 minutes every 3 weeks - used in conjunction with trastuzumab and docetaxel for patients with metastatic breast cancer and no prior anti-HER2 therapy or chemotherapy for metastatic disease for neoadjuvant chemotherapy in human epidermal growth factor receptor 2 (HER2)positive breast cancer o addition of trastuzumab to preoperative regimen appears to increase pathologic complete response and decrease relapse in patients receiving neoadjuvant chemotherapy for HER2-positive breast cancer (level 2 [mid-level] evidence) o addition of lapatinib or pertuzumab to trastuzumab plus neoadjuvant chemotherapy may increase pathological complete response rate (level 3 [lacking direct] evidence) for adjuvant therapy in human epidermal growth factor receptor 2 (HER2)-positive early and locally advanced breast cancer o addition of trastuzumab to adjuvant chemotherapy may increase overall survival and disease-free survival but may increase risk for heart failure (level 2 [mid-level] evidence)
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for progression on trastuzumab o addition of lapatinib to capecitabine may reduce rate of progression in women with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer that progressed on trastuzumab (level 2 [mid-level] evidence) see HER2 inhibitors for breast cancer for details
• Chemotherapy for early and locally advanced breast cancer: • drugs included in common chemotherapy regimens o cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) o anthracyclines (doxorubicin, epirubicin) o taxanes (docetaxel, paclitaxel) o human epidermal growth factor receptor 2 (HER2) inhibitors (trastuzumab) o less frequently used agents include capecitabine, eribulin, ixabepilone, and uracil-
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neoadjuvant (preoperative) chemotherapy o may be used for large tumors to improve resectability before breast-conserving surgery (NZGG Grade A) o recommended for treatment in women with inflammatory or inoperable locally advanced breast cancer without evidence of systemic spread (NZGG Grade A) o Neoadjuvant Therapy Outcomes score predicts 5-year disease-specific survival after neoadjuvant chemotherapy in patients with breast cancer (level 1 [likely reliable] evidence) o preoperative chemotherapy associated with decreased mastectomy rate and adverse effects but may increase risk of locoregional recurrence compared to postoperative chemotherapy in women with early breast cancer (level 2 [midlevel] evidence) o for neoadjuvant chemotherapy in HER2-positive breast cancer addition of trastuzumab to preoperative regimen appears to increase pathologic complete response and decrease relapse in patients receiving neoadjuvant chemotherapy for HER2-positive breast cancer (level 2 [midlevel] evidence) addition of lapatinib or pertuzumab to trastuzumab plus neoadjuvant chemotherapy may increase pathological complete response rate (level 3 [lacking direct] evidence) adjuvant chemotherapy (after surgery) o postoperative chemotherapy not recommended outside of clinical trials in patients who have completed preoperative chemotherapy o decision to use chemotherapy should be individualized, especially if favorable prognosis where absolute benefit is small Adjuvant! Online provides individualized estimates of recurrence and survival with and without adjuvant endocrine and/or chemotherapy in patients with HER2-negative breast cancer treated with surgery and radiation therapy
chemotherapy generally recommended if higher risk for recurrence such as node-positive combinations of tumor > 1 cm, HER2-positive, or hormone receptor-negative other risk factors such as high-grade histology or presence of lymphovascular invasion Oncotype DX may predict whether addition of chemotherapy to tamoxifen will reduce recurrence risk in women with hormone receptor-positive breast cancer who are node-negative (NACB Grade A, Level I/II) or nodepositive (level 2 [mid-level] evidence) urokinase plasminogen activator (uPA) and plasminogen activator inhibitor (PAI)-1 may be used to identify patients with lymph nodenegative disease who do not need or are unlikely to benefit from adjuvant chemotherapy (NACB Grade A, Level I) in women < 55 years old with lymph node-negative breast cancer and Adjuvant!-predicted 10-year breast cancer-specific survival ≥ 95%, mitotic activity index (MAI) may further stratify high-risk and low-risk patients (level 2 [mid-level] evidence) o combination chemotherapy for early breast cancer may reduce 15-year all-cause mortality, breast cancer mortality, and recurrence risk (level 2 [mid-level] evidence); benefits consistent in multiple subgroups regardless of estrogen receptor status and use of tamoxifen (level 2 [mid-level] evidence) anthracycline-based polychemotherapy with high cumulative dose (but not standard dose) may reduce 10-year recurrence rate and mortality compared to CMF for adjuvant therapy (level 2 [mid-level] evidence, NZGG Grade A) taxane-containing regimens (for adjuvant treatment) may improve survival compared to non-taxane-containing regimens (level 2 [mid-level] evidence, NZGG Grade A) dose-dense chemotherapy associated with improved survival and greater toxicity compared with standard chemotherapy in women with nonmetastatic breast cancer, benefit may be limited to hormone receptor-negative patients (level 2 [mid-level] evidence) high-dose chemotherapy plus bone marrow or hematopoietic stem-cell transplantation does not appear to improve overall survival in women with high-risk primary breast cancer (level 2 [mid-level] evidence) o for HER2-positive early and locally advanced breast cancer - addition of trastuzumab to adjuvant chemotherapy may increase overall survival and diseasefree survival but may increase risk for heart failure (level 2 [mid-level] evidence, NZGG Grade A) see Chemotherapy for early and locally advanced breast cancer for details
• Bone-modifying agents in early breast cancer:
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bisphosphonates (as a drug class) may not be associated with reduced rates of recurrence or bone metastases (level 2 [mid-level] evidence); clodronate and zoledronic acid each have mixed results in large randomized trials (level 2 [mid-level] evidence) bisphosphonates may not decrease fracture rate (level 2 [mid-level] evidence) but may decrease bone loss (level 3 [lacking direct] evidence) consider risk for osteoporosis o aromatase inhibitors for breast cancer associated with bone loss and increased fracture risk (level 2 [mid-level] evidence) o interventions to reduce risk of bone mineral loss include healthy diet, not smoking, maintaining healthy body mass index, regular exercise, calcium, and adequate vitamin D levels (NZGG Grade C) o bisphosphonates recommended if osteoporosis (NZGG Grade A), consider if osteopenia (NZGG Grade C) doses for treatment of bone loss associated with adjuvant aromatase inhibitor therapy o denosumab (Prolia) 60 mg subcutaneously once every 6 months o zoledronic acid (Zometa) 4 mg IV every 6 months (not FDA approved for this indication) see Bone-modifying agents in breast cancer for details
• Other medications: • aspirin associated with reduced risk of breast cancer mortality and distant recurrence in
women with early or locally advanced disease (level 2 [mid-level] evidence) o based on cohort study o 4,164 women in Nurses' Health Study diagnosed with breast cancer stage I, II, or III between 1976 and 2002 were followed up to 2006 o breast cancer-related death in 8.2% o decreased risk of breast cancer-related death with aspirin use (p < 0.001 for trend) adjusted relative risk (RR) 1.07 (95% CI 0.7-1.63) for aspirin use 1 day weekly vs. no use adjusted RR 0.29 (95% CI 0.16-0.52) for aspirin use 2-5 days weekly vs. no use adjusted RR 0.36 (95% CI 0.24-0.54) for aspirin use 6-7 days weekly vs. no use o decreased risk of distant recurrence with aspirin use (p = 0.03 for trend) adjusted RR 0.91 (95% CI 0.62-1.33) for aspirin use 1 day weekly vs. no use adjusted RR 0.4 (95% CI 0.24-0.65) for aspirin use 2-5 days weekly vs. no use adjusted RR 0.57 (95% CI 0.39-0.82) for aspirin use 6-7 days weekly vs. no use o decreased risk of all-cause mortality with aspirin use (p = 0.004 for trend) adjusted RR 0.94 (95% CI 0.67-1.32) for aspirin use 1 day weekly vs. no use adjusted RR 0.53 (95% CI 0.37-0.76) for aspirin use 2-5 days weekly vs. no use adjusted RR 0.54 (95% CI 0.41-0.7) for aspirin use 6-7 days weekly vs. no use o Reference - J Clin Oncol 2010 Mar 20;28(9):1467
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glucocorticoids as adjuvant therapy do not appear to improve survival or tumor response in patients with breast cancer (level 2 [mid-level] evidence) o based on systematic review of low-to-moderate quality trials o systematic review of 54 randomized trials, 4 nonrandomized trials, 1 metaanalysis, and 4 case series evaluating glucocorticoids in patients with nonhematologic malignancies o no significant differences in response rates or survival in any randomized trial evaluating glucocorticoids as adjuvant therapy in patients with breast cancer o Reference - BMC Cancer 2008 Mar 28;8:84 full-text prophylactic granulocyte colony-stimulating factor may decrease febrile neutropenia in women with breast cancer receiving chemotherapy (level 2 [mid-level] evidence) o based on Cochrane review of trials with unclear allocation concealment o systematic review of 8 randomized trials comparing colony-stimulating factor (CSF) vs. placebo or no treatment (control) for prevention of chemotherapyinduced febrile neutropenia in 2,156 patients (mostly women) with breast cancer o comparing granulocyte CSF (G-CSF) to control G-CSF associated with decreased febrile neutropenia in analysis of 5 trials with 1,931 women risk ratio (RR) 0.27 (95% CI 0.1-0.75) NNT 7-25 with febrile neutropenia in 16% of control group decreased early mortality in analysis of 6 trials with 1,981 women RR 0.32 (95% CI 0.13-0.77) NNT 61-229 with early mortality in 1.9% of control group trend toward decreased infection (RR 0.86, 95% CI 0.72-1.02) in analysis of 3 trials with 210 women increased bone pain in analysis of 2 trials with 151 women RR 5.88 (95% CI 2.54-13.6) NNH 1-9 with bone pain in 7% of control group no significant difference in infection-related mortality in analysis of 6 trials with 1,981 women, but only 3 infection-related deaths overall (no deaths in G-CSF group vs. 3 deaths in control group) o no significant differences in febrile neutropenia, early mortality, or infection comparing granulocyte macrophage CSF (GM-CSF) vs. placebo but few or no events reported o Reference - Cochrane Database Syst Rev 2012 Oct 17;(10):CD007913 addition of octreotide to tamoxifen may not reduce mortality or recurrence in postmenopausal women following surgical removal of early-stage breast cancer but may increase risk for cholecystectomy (level 2 [mid-level] evidence) o based on randomized trial without blinding o 667 postmenopausal women had surgical removal of early-stage breast cancer and were randomized to octreotide 90 mg intramuscularly monthly vs. no octreotide for 2 years o all women had tamoxifen 20 mg/day orally for 5 years
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comparing octreotide plus tamoxifen vs. tamoxifen alone at median follow-up 7.9 years mortality 20.4% vs. 20.45% (not significant) recurrence in 18.9% vs. 21.6% (not significant) among patients with normal baseline gallbladder imaging, need for cholecystectomy in 23% vs. 1.4% (p < 0.001, NNH 4) Reference - NCIC CTG MA.14 trial (J Clin Oncol 2011 Oct 10;29(29):3869), editorial can be found in J Clin Oncol 2011 Oct 10;29(29):3846, commentary can be found in J Clin Oncol 2012 Apr 20;30(12):1395
Medications for advanced breast cancer (Stage IV): • common medication regimens for Stage IV disease include (6) o hormone receptor-negative - chemotherapy o hormone receptor-positive - endocrine therapy with or without chemotherapy o HER2 overexpression - trastuzumab with or without chemotherapy Chemotherapy for advanced breast cancer: • chemotherapy recommended for women with triple-negative tumors (human epidermal
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growth factor receptor 2 [HER2], estrogen receptor, and progesterone receptor), symptomatic or rapidly progressive organ metastases, or disease refractory to hormone therapy sequential (rather than combined) chemotherapy recommended for most patients who choose to be treated with chemotherapy for disease progression combination chemotherapy associated with increased survival and time to progression compared to single-agent chemotherapy for metastatic breast cancer, but may increase adverse effects (level 2 [mid-level] evidence) additional chemotherapy added to first-line combination regimen may increase tumor response rate but may not affect overall survival in metastatic breast cancer (level 2 [midlevel] evidence) chemotherapy regimens containing anthracycline (doxorubicin or epirubicin) or taxane (paclitaxel or docetaxel) have higher response rates o anthracyclines appear to improve tumor response rates compared with other chemotherapy regimens in women with metastatic breast cancer, but associated with increased toxicity and no differences in overall survival (level 2 [mid-level] evidence) o taxane-containing regimens may improve overall survival, time to progression, and overall response compared to some other chemotherapy regimens in women with metastatic breast cancer (level 2 [mid-level] evidence) for HER2-positive metastatic breast cancer o trastuzumab (Herceptin) may improve survival but associated with increased risk of cardiac dysfunction (level 2 [mid-level] evidence) o addition of lapatinib (Tykerb) to paclitaxel (or to letrozole) may increase progression-free survival (level 2 [mid-level] evidence) o addition of pertuzumab (Perjeta) to trastuzumab plus docetaxel increases progression-free survival (level 1 [likely reliable] evidence) other chemotherapy agents o addition of bevacizumab (Avastin) to taxane-containing chemotherapy prolongs progression-free survival but not overall survival in metastatic breast cancer (level
1 [likely reliable] evidence), increase in progression-free survival may be 1-6 months; bevacizumab (Avastin) no longer labeled for treatment of breast cancer in United States o capecitabine (Xeloda) associated with similar time to disease progression but decreased anemia compared to epirubicin in women receiving docetaxel for advanced breast cancer (level 2 [mid-level] evidence) as monotherapy associated with improved survival and fewer adverse events than classical cyclophosphamide/methotrexate/fluorouracil (CMF) in women with advanced breast cancer not suited for more intense firstline therapy (level 2 [mid-level] evidence) o eribulin (Halaven) may improve survival compared to noneribulin therapy in women who had ≥ 2 prior chemotherapy regimens for locally recurrent or metastatic breast cancer (level 2 [mid-level] evidence) o everolimus (Afinitor) addition of everolimus to exemestane may increase progression-free survival in patients with hormone receptor-positive advanced breast cancer previously treated with nonsteroidal aromatase inhibitors (level 3 [lacking direct] evidence) addition of everolimus to tamoxifen may increase overall survival and time to progression in patients with hormone receptor-positive, HER2-negative metastatic breast cancer resistant to aromatase inhibitors (level 2 [midlevel] evidence) o gemcitabine (Gemzar) appears to have similar efficacy compared to capecitabine in patients with locally advanced or metastatic breast cancer (level 2 [mid-level] evidence) o ixabepilone (Ixempra) plus capecitabine associated with delay in cancer progression or death compared to capecitabine alone in patients with metastatic or locally advanced breast cancer not responding to anthracycline plus taxane (level 2 [mid-level] evidence) o platinum-containing chemotherapy is highly toxic without clear benefit in patients with metastatic breast cancer (level 1 [likely reliable] evidence), but evidence in combination with trastuzumab is limited and inconsistent o high-dose chemotherapy with autograft for metastatic breast cancer associated with increased treatment-related deaths without significant improvement in overall survival (level 2 [mid-level] evidence) see Chemotherapy for metastatic breast cancer for details
• HER2 inhibitors for advanced breast cancer: • human epidermal growth factor receptor 2 (HER2) is overexpressed in about 30% of breast •
cancers and associated with more aggressive disease HER2 inhibitors used in HER2-positive breast cancer and include o trastuzumab (Herceptin) 4 mg/kg IV, then 2 mg/kg IV once weekly for 51 weeks in early breast cancer or until disease progression or intolerable toxicity in metastatic breast cancer monitor cardiac function (including ejection fraction) every 3 months while taking trastuzumab
lapatinib (Tykerb) 1.25 g orally once daily on days 1-21 (plus capecitabine 2 g/m2/day on days 1-14) in 21-day cycles - used for patients with metastatic breast cancer and prior therapy with an anthracycline, a taxane, and trastuzumab o pertuzumab (Perjeta) 840 mg IV over 60 minutes, then 420 mg IV over 30-60 minutes every 3 weeks - used in conjunction with trastuzumab and docetaxel for patients with metastatic breast cancer and no prior anti-HER2 therapy or chemotherapy for metastatic disease for human epidermal growth factor receptor type 2 (HER2)-positive metastatic breast cancer o trastuzumab may improve survival in patients with HER2-overexpressing metastatic cancer but associated with increased risk of cardiac dysfunction (level 2 [mid-level] evidence) o addition of lapatinib to paclitaxel (or to letrozole) may increase progression-free survival in HER2-positive patients with metastatic breast cancer (level 2 [mid-level] evidence) o addition of pertuzumab to trastuzumab plus docetaxel increases progression-free survival in women with HER2-positive metastatic breast cancer (level 1 [likely reliable] evidence) o decline in serum HER2/neu levels 30-120 days after starting trastuzumab associated with increased response rate and longer overall survival in women with metastatic breast cancer (level 2 [mid-level] evidence) for progression on trastuzumab o addition of lapatinib to capecitabine may reduce rate of progression in women with human epidermal growth factor receptor 2 (HER2)-positive locally advanced or metastatic breast cancer that progressed on trastuzumab (level 2 [mid-level] evidence) o combination of trastuzumab plus lapatinib associated with improved progressionfree survival and overall survival compared to lapatinib alone in women with human epidermal growth factor receptor type 2 (HER2)-positive, trastuzumabrefractory metastatic breast cancer (level 2 [mid-level] evidence) o trastuzumab emtansine may increase overall survival compared to lapatinib plus capecitabine in women with HER2-positive locally advanced or metastatic breast cancer progressing after treatment with trastuzumab and a taxane (level 2 [midlevel] evidence) see HER2 inhibitors for breast cancer for details o
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• Endocrine therapy for advanced breast cancer: • endocrine therapy used for hormone receptor-positive breast cancer, avoid in hormone • • •
receptor-negative breast cancer (NZGG Grade A) preferred first-line therapy is a nonsteroidal aromatase inhibitor - anastrozole (Arimidex) 1 mg orally once daily or letrozole (Femara) 2.5 mg orally once daily alternative first-line therapy is tamoxifen (Nolvadex) 20-40 mg/day, an antiestrogen other endocrine therapies (which may be used for disease progression after first-line therapy) include o exemestane (Aromasin) 25 mg orally once daily, a steroidal aromatase inhibitor o fulvestrant (Faslodex) 250 mg intramuscularly once monthly, an antiestrogen
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endocrine therapy associated with similar survival rates compared to chemotherapy for initial treatment of hormone receptor-positive metastatic breast cancer (level 2 [midlevel] evidence); endocrine therapy may be preferred due to better tolerability, except in rapidly progressive disease aromatase inhibitors may have survival benefit over other endocrine therapies in postmenopausal women with advanced breast cancer (level 2 [mid-level] evidence) addition of fulvestrant to anastrozole may increase progression-free survival in women with hormone receptor-positive metastatic breast cancer (level 2 [mid-level] evidence) adverse effects o tamoxifen has adverse effects including hot flashes - see Treatment of hot flashes in patients with breast cancer low but increased risk for endometrial cancer, gastrointestinal cancer, stroke, and pulmonary embolism (level 2 [mid-level] evidence) ocular toxicity o adverse effects of aromatase inhibitors - gastrointestinal disturbances, asthenia, headache, hot flashes, and musculoskeletal symptoms are common see Endocrine therapy for breast cancer for details
• Bone-modifying agents in advanced breast cancer: • bone-modifying agents are recommended for patients with metastatic breast cancer with
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evidence of bone destruction; options include o denosumab (Xgeva) 120 mg subcutaneously every 4 weeks o pamidronate (Aredia) 90 mg IV over ≥ 2 hours every 3-4 weeks o zoledronic acid (Zometa) 4 mg IV over ≥ 15 minutes every 3-4 weeks all patients should have dental examination and needed preventive dentistry prior to using bone-modifying agent, due to risk for osteonecrosis of the jaw bisphosphonates (oral or IV) may reduce risk of skeletal events in women with advanced breast cancer and clinically evident bone metastases (level 2 [mid-level] evidence), but not in women with advanced breast cancer without prior bone metastasis (level 2 [mid-level] evidence) denosumab may reduce risk of skeletal events more than bisphosphonates in women with advanced breast cancer and clinically evident bone metastases (level 2 [mid-level] evidence) bisphosphonates appear effective for painful bone metastases (level 2 [mid-level] evidence) o zoledronic acid, ibandronate, and pamidronate may have similar efficacy for pain relief in patients with painful bony metastases (level 2 [mid-level] evidence) o zoledronic acid may have lower incidence of hypercalcemia (level 3 [lacking direct] evidence) see Bone-modifying agents in breast cancer for details
• Glucocorticoids for advanced breast cancer: • addition of glucocorticoids to therapy for advanced breast cancer may increase response
rate but not survival (level 2 [mid-level] evidence) o based on systematic review of low-to-moderate quality trials
o
o
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systematic review of 54 randomized trials, 4 nonrandomized trials, 1 metaanalysis, and 4 case series evaluating glucocorticoids in patients with nonhematologic malignancies outcomes in meta-analysis of 12 randomized trials of combination therapy with glucocorticoids in women with advanced breast cancer comparing endocrine therapy plus glucocorticoids vs. endocrine therapy alone response rate 44% vs. 32% (p < 0.05, NNT 9) in analysis of 4 trials with 717 women, possibly limited by heterogeneity (p = 0.13) 1-year survival 75% vs. 74% (not significant) in analysis of 4 trials with 797 women, limited by heterogeneity (p = 0.012) comparing chemotherapy plus glucocorticoids vs. chemotherapy alone response rate 57% vs. 46% (p < 0.05, NNT 9) in analysis of 6 trials with 496 women 1-year survival 60% vs. 55% (not significant) in analysis of 4 trials with 509 women glucocorticoids as monotherapy associated with modest activity in postmenopausal women in 10 randomized trials, but these trials tended to be small and have comparator therapies that are no longer used Reference - BMC Cancer 2008 Mar 28;8:84 full-text
o Heparin: • low-molecular-weight heparin reduces symptomatic venous thromboembolism (level 1
[likely reliable] evidence) and possibly 2-year mortality (level 2 [mid-level] evidence) in patients with advanced cancer o based on Cochrane review with heterogeneity o systematic review of 9 randomized trials of parenteral anticoagulation in 2,857 patients with cancer and no clinical evidence of venous thromboembolism (VTE) o 1 trial evaluated unfractionated heparin (UFH), 8 trials evaluated low-molecularweight heparin (LMWH) o most evidence derived from patients with either small cell lung cancer or patients with advanced cancer not amenable to curative treatment o comparing heparin to placebo or no intervention no significant difference in mortality at 12 months (risk ratio [RR] 0.93, 95% CI 0.85-1.02) in overall analysis of 8 trials with 2,530 patients overall analysis limited by heterogeneity significant reduction in mortality in analysis limited to 2 trials of 361 patients with small cell lung cancer heparin associated with reduced mortality at 24 months in analysis of 5 trials with 1,175 patients RR 0.92 (95% CI 0.88-0.97) NNT 10-39 assuming 86% mortality in controls no separate analysis reported for patients with small cell lung cancer less symptomatic VTE in analysis of 7 trials with 2,264 patients
RR 0.55 (95% CI 0.37-0.82) NNT 27-93 assuming 6% symptomatic VTE in controls no significant difference in major bleeding in analysis of 9 trials with 2,844 patients RR 1.3 (95% CI 0.59-2.88) results limited by wide confidence intervals potential explanations for significant difference in mortality at 24 months but not 12 months include different selection of trials used in analyses 1 trial reported subgroup differences with lower mortality in subgroup with life expectancy > 6 months and no significant difference in subgroup with life expectancy < 6 months Reference - Cochrane Database Syst Rev 2011 Apr 13;(4):CD006652
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o Supportive medications: • recommendations for supportive medications from the Central European Cooperative
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Oncology Group (CECOG) third consensus on medical treatment of metastatic breast cancer o symptomatic anemia use erythropoiesis-stimulating agents (ESAs) ONLY for symptomatic anemia associated with concomitant myelosuppressive chemotherapy due to risk of decreased overall survival, increased tumor progression, or recurrence with some ESAs use lowest ESA dose needed to avoid red blood cell transfusion discontinue treatment when hemoglobin level of 11-12 g/dL achieved transfuse erythrocytes if patient not responsive to ESAs, or for acute symptoms o leukopenia - consider myeloid colony-stimulating factors during chemotherapy for patients with > 20% likelihood of febrile neutropenia history of chemotherapy-associated febrile neutropenia individual risk factors o menopausal symptoms hormone replacement therapy strongly discouraged in all patients with metastatic breast cancer if topical estrogens used to improve quality of life, use preparations with lowest systemic absorption use nonhormonal treatments if possible o Reference - Ann Oncol 2009 Nov;20(11):1771 full-text, commentary can be found in Ann Oncol 2010 Mar;21(3):665 prophylactic granulocyte colony-stimulating factor may decrease febrile neutropenia in women with breast cancer receiving chemotherapy (level 2 [mid-level] evidence) o based on Cochrane review of trials with unclear allocation concealment o systematic review of 8 randomized trials comparing colony-stimulating factor (CSF) vs. placebo or no treatment (control) for prevention of chemotherapyinduced febrile neutropenia in 2,156 patients (mostly women) with breast cancer
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comparing granulocyte CSF (G-CSF) to control G-CSF associated with decreased febrile neutropenia in analysis of 5 trials with 1,931 women risk ratio (RR) 0.27 (95% CI 0.1-0.75) NNT 7-25 with febrile neutropenia in 16% of control group decreased early mortality in analysis of 6 trials with 1,981 women RR 0.32 (95% CI 0.13-0.77) NNT 61-229 with early mortality in 1.9% of control group trend toward decreased infection (RR 0.86, 95% CI 0.72-1.02) in analysis of 3 trials with 210 women increased bone pain in analysis of 2 trials with 151 women RR 5.88 (95% CI 2.54-13.6) NNH 1-9 with bone pain in 7% of control group no significant difference in infection-related mortality in analysis of 6 trials with 1,981 women, but only 3 infection-related deaths overall (no deaths in G-CSF group vs. 3 deaths in control group) no significant differences in febrile neutropenia, early mortality, or infection comparing granulocyte macrophage CSF (GM-CSF) vs. placebo but few or no events reported Reference - Cochrane Database Syst Rev 2012 Oct 17;(10):CD007913
o Medications for recurrent breast cancer: • common medication regimens for local recurrent disease (in addition to surgery if
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operable, in addition to induction chemotherapy if not operable) include (6) o hormone receptor-negative - chemotherapy o hormone receptor-positive - chemotherapy and endocrine therapy o HER2 overexpression - chemotherapy and trastuzumab limited evidence regarding adjuvant systemic therapy for women with isolated locoregional recurrence following primary treatment of operable breast cancer o based on Cochrane review o systematic review of 3 randomized trials evaluating additional systemic therapy in 260 women with potentially curatively resected locoregional recurrence of breast cancer o addition of actinomycin-D improved local control rate but had no apparent effect on overall survival in 1 trial with 32 patients o addition of alfa-interferon to local treatment had no apparent effect on further course of disease in 1 trial with 32 patients o in 1 trial with 178 women, addition of tamoxifen associated with nonsignificant trend toward increased disease-free survival overall (median 6.5 years vs. 2.7 years, p = 0.053) 5-year disease-free survival comparing tamoxifen vs. no tamoxifen 61% vs. 33% (p = 0.006, NNT 4) in postmenopausal women 60% vs. 60% (not significant) in premenopausal women
no significant differences in overall survival (5-year survival with vs. without tamoxifen in 67% vs. 90% [not significant] of premenopausal women, and 75% vs. 75% of postmenopausal women) o Reference - Cochrane Database Syst Rev 2008 Oct 8;(4):CD002195 National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-37 is evaluating adjuvant chemotherapy after complete excision of first locoregional recurrence of breast cancer (Ann Surg Oncol 2008 Nov;15(11):3227 full-text); results not available but trial no longer open for enrollment as of August 14, 2012
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Medications for malignant wounds: • topical miltefosine may slow disease progression in breast cancer patients with superficial
fungating breast lesions (level 2 [mid-level] evidence) o based on Cochrane review with limited evidence o systematic review of randomized or controlled clinical trials evaluating dressings and topical agents in patients with fungating malignant lesions (defined as ulceration and proliferation due to infiltration and erosion of skin by malignant tumor cells) o 2 randomized placebo-controlled trials met inclusion criteria with 63 patients (mostly women with breast cancer) miltefosine 6% solution associated with delayed tumor progression in 1 trial with 52 patients (median days to treatment failure 56 vs. 21, p = 0.007) metronidazole 0.8% gel associated with nonsignificant reduction in malodor in 1 trial with 11 patients o Reference - Cochrane Database Syst Rev 2011 Mar 16;(3):CD003948
Alternative therapies: • systematic reviews do not find definitive evidence of benefit for mistletoe o mistletoe extracts might improve some quality of life measures during
chemotherapy for breast cancer (level 2 [mid-level] evidence) based on Cochrane review of limited evidence systematic review of 21 randomized trials evaluating mistletoe extracts in 3,484 adults with cancer of any type, including at least 8 studies with 996 patients with breast cancer interventions included 5 preparations of mistletoe extracts from 5 manufacturers and 1 preparation not commercially available among 13 trials evaluating survival outcomes 6 trials showed some evidence of benefit, but results limited by poor methodologic quality increased survival (median 4.79 years vs. 2.41 years in controls, p = 0.02) in 1 study with 34 women with stage IIa, IIIA, or IIIB breast cancer mistletoe extracts may not be effective for improving survival in patients with melanoma and head and neck cancer, based on 2 trials among 16 trials evaluating quality of life, psychologic outcomes, or prevalence of chemotherapy-related adverse effects, 14 trials showed
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some evidence of benefit but results limited by poor methodologic quality in 12 trials mistletoe extracts usually well-tolerated and associated with few side effects, based on 12 trials Reference - Cochrane Database Syst Rev 2008 Apr 16;(2):CD003297 o rigorous trials of mistletoe extracts fail to demonstrate efficacy (level 2 [mid-level] evidence) based on systematic review review of 10 randomized trials of mistletoe for cancer, most trials had considerable methodologic weaknesses some weaker trials suggested benefits, especially for quality of life no stronger trials found differences in quality of life, survival, or other outcome measures Reference - Int J Cancer 2003 Nov 1;107(2):262 o another systematic review of 23 studies (16 of which were randomized) found sufficient suggestion of benefit to recommend further research with properly designed trials (Eur J Med Res 2003 Mar 27;8(3):109) o mistletoe not shown to be effective in improving time to tumor progression or overall survival in cancer patients, based on review limited to mistletoe extracts standardized to mistletoe lecithin (Onkologie 2002 Aug;25(4):374) o Reference - Alternative Medicine Alert 2005 May;8(5):55 shark cartilage 1 g/kg/day orally in 3 divided doses reported to be ineffective for delaying disease progression or improving quality of life (level 3 [lacking direct] evidence) in case series of 60 patients with advanced cancer (breast cancer in 16 patients) (J Clin Oncol 1998 Nov;16(11):3649), also published in Alternative Medicine Alert 1999 Feb;2(2):24
Surgery and procedures: Surgery for early and locally advanced breast cancer: • surgery is usually first treatment for early and locally advanced breast cancer o breast-conserving surgery (plus radiation therapy) for early breast cancer appears
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as effective for survival and rate of distant metastases as mastectomy (level 2 [mid-level] evidence), but may be associated with need for re-excision or future mastectomy o mastectomy indicated for patient preference, or if large or multicentric tumor precludes breast conservation therapy o radical mastectomy does not appear to confer survival advantage over total mastectomy over 25 years (level 2 [mid-level] evidence) sentinel lymph node resection o sentinel lymph node (SLN) biopsy is preferred method of axillary lymph node assessment for staging of early breast cancer with no clinical evidence of lymph node involvement o Memorial Sloan-Kettering Cancer Center nomogram can predict likelihood of SLN metastasis and likelihood of additional non-SLN metastasis (level 1 [likely reliable] evidence) o SLN resection alone is as effective as axillary lymph node dissection (ALND) for survival and regional control in women with invasive breast cancer and clinically negative lymph nodes and negative SLN (level 1 [likely reliable] evidence)
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management of positive SLN o ALND has been recommended for patients with positive SLN (micrometastasis or macrometastasis) o ALND no longer routinely required for patients with T1-2 tumors and 1-2 positive SLNs without extracapsular extension who will have adjuvant therapies (radiation therapy plus systemic therapy), based on similar tumor recurrence rates and similar 5-year overall survival comparing SLN dissection alone vs. SLN dissection plus ALND (level 2 [mid-level] evidence) o ALND still indicated if T3 tumor, preoperative palpable lymph nodes, > 2 positive lymph nodes, matted axillary nodes, or having neoadjuvant chemotherapy for Paget's disease of breast, central lumpectomy may result in similar 15-year breast cancer-specific survival as mastectomy (level 2 [mid-level] evidence) breast-conserving surgery for recurrent ipsilateral breast cancer associated with decreased survival compared to mastectomy (level 2 [mid-level] evidence) delaying breast reconstruction until after completion of postmastectomy radiation therapy may reduce complications (level 2 [mid-level] evidence) chronic pain occurs in substantial proportion of women following breast cancer surgery lymphedema may occur in up to 15% of women after surgery for breast cancer (level 2 [mid-level] evidence) see Surgery for early and locally advanced breast cancer for details
• Surgery for advanced breast cancer: • treatment is directed toward palliation and optimizing quality of life (8) • primary tumor resection o primary tumor resection may be considered for symptoms (pain, wound from o
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fungating lesion) survival benefit of primary tumor resection in patients presenting with metastatic breast cancer is not established based on third Central European Cooperative Oncology Group (CECOG) consensus on medical treatment of metastatic breast cancer retrospective studies suggest increased survival with primary tumor resection, but not validated in prospective studies Reference - Ann Oncol 2009 Nov;20(11):1771 full-text, commentary can be found in Ann Oncol 2010 Mar;21(3):665 surgical removal of breast lesion in stage IV breast cancer associated with increased survival (level 2 [mid-level] evidence) based on systematic reviews of observational studies systematic review of 10 retrospective studies comparing surgery vs. no surgery for primary metastatic (stage-IV) breast cancer in 28,739 patients surgical removal of breast cancer lesion in stage-IV cancer associated with increased survival (hazard ratio [HR] 0.65, 95% CI 0.59-0.72), results limited by heterogeneity (p < 0.0001) Reference - Breast Cancer Res Treat 2010 Feb;120(1):9 systematic review and meta-analysis of 15 studies providing survival data of surgery of intact primary tumor in stage IV breast cancer
surgery of primary tumor independently associated with improved survival (HR 0.69, p < 0.0001) according to meta-regression analysis, survival benefit directly proportional to rate of patients exposed to systemic therapies and radiation therapy and inversely correlated with estrogen receptorpositive status of population included Reference - Med Oncol 2012 Dec;29(5):3282 for single or small number of potentially resectable brain metastases in patients with good performance status and no or well-controlled other metastatic disease o National Institute for Health and Clinical Excellence (NICE) recommends offering surgery followed by whole brain radiation therapy (3) o stereotactic radiosurgery (SRS) may provide local tumor control, but does not reduce risk for brain metastases beyond site of SRS (Prog Neurol Surg 2012;25:156) consider prophylactic orthopedic surgery in patients at risk for long bone fractures due to bone metastases(3) local disease with skin ulceration involving chest wall and axilla may be controlled with surgery, systemic treatments, or radiation therapy; uncontrolled local disease should be managed by multidisciplinary team, including supervision by wound care team for fungating tumors(3)
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Focused microwave thermotherapy: • preoperative focused microwave thermotherapy might reduce rate of positive tumor
margins in patients with early-stage invasive breast cancer (level 3 [lacking direct] evidence) o based on randomized trial without statistical significance in interim analysis o 92 patients with primary invasive breast carcinomas having breast conservation therapy were randomized to preoperative focused microwave phased array thermotherapy plus surgery vs. surgery alone o comparing thermotherapy vs. surgery alone in 75 patients included in preplanned interim statistical analysis positive margins in 0% vs. 10% (p = 0.13) second incision in 6% vs. 10% (not significant) o discomfort level during thermotherapy no discomfort in 44% mild in 32% moderate in 9% intolerable in 15% o side effects of thermotherapy from 34 treated patients included skin burn < 3 cm in 9% hematoma or seroma in 18% erythema in 12% edema in 9% nausea in 9% abscess in 3% subcutaneous fibrosis in 3%
nipple retraction in 3% o Reference - Cancer Ther 2008;6(B):395 PDF preoperative focused microwave thermotherapy may reduce tumor volume in large breast carcinomas (level 3 [lacking direct] evidence) o based on randomized trial without clinical outcomes o 34 patients with invasive breast carcinoma who were candidates for mastectomy (but were not candidates for breast conservation therapy) were randomized to anthracycline-based chemotherapy plus focused microwave phased array thermotherapy vs. anthracycline-based chemotherapy alone prior to surgery o comparing chemotherapy plus thermotherapy vs. chemotherapy alone median tumor volume reduction 88.4% vs. 58.8% (p = 0.048) sufficient tumor volume reduction to be eligible for breast conservation therapy in 93.3% vs. 73.3% (no p value reported) o discomfort level during thermotherapy no discomfort in 23% mild in 50% moderate in 23% intolerable in 5% o side effects of thermotherapy included erythema (25% of treatments) skin burn (19% of treatments) o Reference - Cancer Ther 2007;5(B):401 full-text
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Cryotherapy: • 100% survival at 18-months reported in women treated with percutaneous multiprobe
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cryoablation (level 3 [lacking direct] evidence) o based on case series o 11 women with breast cancer (mean age 62.5 years) who refused surgery were treated with percutaneous multiprobe breast cryoablation (either ultrasoundguided or computed tomography- and ultrasound-guided) o negative tumor margins and recurrence-free survival in 100% at 18 months o bruising and breast edema were common but did not require intervention o Reference - J Vasc Interv Radiol 2009 Oct;20(10):1329 percutaneous cryoablation may result in complete tumor ablation prior to surgery for smaller tumors (diameter < 8 mm) with less efficacy for larger diameter tumors (level 3 [lacking direct] evidence) o based on 2 case series 15 women aged 64-82 years with invasive ductal carcinoma (mean tumor diameter 8 mm) were treated with ultrasound-guided cryoablation via 1 cryoprobe before lumpectomy between 30-45 days after ablation complete tumor ablation in 93% Reference - Eur Radiol 2011 Nov;21(11):2344 15 women aged 38-80 years with breast cancer (mean tumor diameter 22 mm) were treated with ultrasound-guided cryoablation via 2 freeze/thaw cycles with 1 cryoprobe before surgery within 5 days
complete tumor ablation in 19% (3 of 5 patients with tumor diameter < 16 mm) no severe adverse effects reported Reference - Eur Radiol 2002 Dec;12(12):3009 DynaMed commentary -- authors note that tumors with diameter ≥ 16 mm may require ≥ 2 cryo probes for complete tumor ablation (only 5 tumors in this study had diameter < 16 mm)
Radiation therapy: •
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postbreast-conserving surgery o whole breast radiation therapy strongly recommended to reduce risk for local recurrence and improve survival (ESMO Level I, Grade A) adjuvant radiation therapy after breast-conserving surgery may reduce 10year recurrence risk and 15-year breast cancer-related mortality (level 2 [mid-level] evidence) standard dose 45-50 Gy in 25-28 fractions of 1.8-2 Gy accelerated fractionation of adjuvant radiation therapy associated with similar recurrence and survival rates as standard radiation therapy regimen but may reduce acute skin toxicity and might increase late skin and subcutaneous toxicity (ESMO Level I, Grade B, level 2 [mid-level] evidence) o additional boost radiation therapy further reduces risk for local recurrence (ESMO Level I, Grade A) 16 Gy of radiation to tumor bed (in 2-Gy fractions) in addition to standard postoperative whole breast radiation therapy reduces local recurrence risk in early breast cancer, especially in younger patients (level 1 [likely reliable] evidence) o alternatives to whole breast radiation therapy accelerated partial breast radiation therapy (APBI) APBI alone considered acceptable as treatment option in patients > 50 years old with tumor size ≤ 3 cm and no histologic findings suggesting lymphovascular invasion (ESMO Level II, Grade B) partial breast radiation therapy may increase risk of local and axillary recurrence compared to whole breast radiation therapy in patients with breast cancer (level 2 [mid-level] evidence) targeted intraoperative radiation therapy appears as effective as adjuvant external beam radiation in decreasing local recurrence in women with early breast cancer (level 2 [mid-level] evidence) brachytherapy not associated with improved survival and may increase risk of complications and mastectomy at 5 years compared to whole breast radiation therapy in women with invasive breast cancer (level 2 [mid-level] evidence) postmastectomy o postmastectomy radiation therapy recommended if ≥ 4 positive axillary nodes (ESMO Level II, Grade B) or stage T3-T4 tumor (ESMO Level III, Grade B), and may be considered for other risk factors such as close margin to pectoralis fascia
adjuvant radiation therapy after mastectomy associated with reduced 5-year local recurrence risk and 15-year mortality (level 2 [mid-level] evidence) o delaying breast reconstruction until after completion of postmastectomy radiation therapy may reduce complications (level 2 [mid-level] evidence) for ductal carcinoma in situ (DCIS) o after breast-conserving surgery for DCIS adjuvant whole breast radiation therapy decreases risk of local recurrence (ESMO Level I, Grade A, level 1 [likely reliable] evidence) consider boost dose to tumor bed for patients at higher risk for local failure (such as young patients) (ESMO Level III, Grade B) o in patients with total mastectomy with clear margins (curative surgery) for DCIS, radiation therapy not recommended (ESMO Level II, Grade B) for locoregional recurrence o if no prior adjuvant radiation therapy, give full-dose radiation therapy to chest wall with or without regional lymph node areas o if prior radiation therapy, value of reradiation not proven for metastatic disease - radiation therapy is part of palliative treatment for o soft tissue masses that are painful or fungating o bone metastases if painful or risk for fracture or neurologic complication o brain metastases adverse effects of radiation therapy may include o cutaneous and cosmetic changes - mometasone furoate 0.1% cream daily until 2 weeks after completion of radiation therapy may reduce symptoms of acute skin toxicity (level 2 [mid-level] evidence) o cardiovascular disease - but risk mainly based on older techniques and appears minimal with current approaches o increased risk for second cancer (myeloid leukemia, lung cancer, esophageal cancer, second breast cancer) see Radiation therapy for breast cancer for details o
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Other management: Patient decision-making: • decision aid may improve knowledge, reduce decisional conflict, and increase satisfaction
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with decision-making about surgical options (level 2 [mid-level] evidence) o based on cluster-randomized trial without attention control o 201 women with newly diagnosed stage I or II breast cancer were treated by surgeons who had been randomized to use vs. nonuse of a decision aid for counseling patients about their surgical options o Reference - JAMA 2004 Jul 28;292(4):435 full-text, editorial can be found in JAMA 2004 Jul 28;292(4):496, commentary can be found in Can J Surg 2006 Dec;49(6):431 nurse case management associated with decrease in mastectomies and increase in breastconserving therapy with adjuvant radiation in women > 65 years old with breast cancer (level 2 [mid-level] evidence) o based on randomized trial without attention control
o o
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335 women > 65 years old with newly diagnosed breast cancer were randomized to nurse case manager vs. usual care alone for 12 months case manager involvement included being present with patient during home visits, inpatient stays, and at physician appointments, and contacting patient by phone, to help ensure that patient was fully informed of her options and treaters were aware of relevant issues intervention associated with increased adjuvant radiation in women who had breast-conserving surgery (78% vs. 45%, p = 0.001, NNT 3) radiation therapy (36% vs. 19%, p = 0.003, NNT 6) breast-conserving surgery (29% vs. 19%, p = 0.031, NNT 10) normal arm function 2 months postoperatively (93% vs. 84%, p = 0.037, NNT 12) proportion of patients who stated they had a real choice in their treatment (82% vs. 70%, p = 0.02, NNT 9) nonsignificant trend toward increased breast reconstruction surgery (9.3% vs. 2.6%, p = 0.054) axillary dissection (71% vs. 45%, p = 0.057) chemotherapy in women with advanced cancer (73% vs. 30%, p = 0.057) decreased modified radical mastectomy (59% vs. 69%, p = 0.043, NNT 10) Reference - J Am Geriatr Soc 2003 Sep;51(9):1252
o Sequencing of treatment for early breast cancer: • variation in sequencing of adjuvant chemotherapy and radiation therapy for early breast
cancer does not appear to affect survival or recurrence but may affect adverse effects (level 2 [mid-level] evidence) o based on Cochrane review of trials with methodologic limitations o systematic review of 3 randomized trials of different sequencing of chemotherapy and radiation therapy in 1,166 women (analyses included 1,097 women) with surgically treated, histologically confirmed early-stage breast cancer (T1-3, N0-1, M0) receiving both adjuvant chemotherapy and radiation therapy o all trials had ≥ 1 methodologic limitation blinding not stated or unclear high loss to follow-up unclear allocation concealment o comparing concurrent treatment to radiation therapy preceding chemotherapy in 2 trials with 853 women no significant differences with different sequencing in overall survival at 5 and 10 year follow-up distant metastases relapse-free survival increased risk of acute anemia in 1 trial of 647 women odds ratio (OR) 1.54 (95% CI 1.1-2.15) NNH 4-45 with 22.6% in sequential group
increased risk of telangiectasia in 1 trial of 647 women OR 3.85 (95% CI 1.37-10.87) NNH 2-59 with 4.7% in sequential group increased risk of pigmentation in 1 trial of 647 women OR 13.55 (95% CI 1.73-106.19) NNH 1-100 with 1% in sequential group o comparing radiation therapy preceding chemotherapy to radiation therapy following chemotherapy in 1 trial with 244 women no significant differences in overall survival or distant metastases local recurrence increased risk of neutropenic sepsis OR 2.96 (95% CI 1.26-6.98) NNH 2-58 with 6.6% in radiation following chemotherapy group o Reference - Cochrane Database Syst Rev 2013 Apr 30;4:CD005212 postsurgical chemotherapy before radiation may reduce distant metastases at 5 years but not overall recurrence or survival compared to radiation before chemotherapy in women with early breast cancer (level 2 [mid-level] evidence) o based on randomized trial with allocation concealment not stated o 244 women with stage I or II breast cancer at risk for distant metastases had breast-conserving surgery and were randomized to chemotherapy for 12 weeks before vs. after radiation therapy o at 5 years chemotherapy before radiation therapy associated with decreased distant metastases (25% vs. 36%, p = 0.05, NNT 9 favoring chemotherapy first) no significant differences between groups in overall survival or recurrence o Reference - N Engl J Med 1996 May 23;334(21):1356 full-text, commentary can be found in N Engl J Med 1996 May 23;334(21):1397, N Engl J Med 1996 Oct 17;335(16):1240 see also Chemotherapy for breast cancer for preoperative (neoadjuvant) vs. postoperative (adjuvant) chemotherapy
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Management of hot flashes: • medications associated with reduced frequency and severity of hot flashes include o antidepressants antidepressants with supporting evidence include venlafaxine (Effexor) 37.5 mg/day, 75 mg/day, or 150 mg/day,
based on multiple trials (level 2 [mid-level] evidence) fluoxetine (Prozac) 20 mg/day, based on 1 trial (level 2 [mid-level] evidence) paroxetine (Paxil) 10 mg/day or 20 mg/day, based on 1 trial (level 2 [mid-level] evidence) some antidepressants may reduce efficacy of tamoxifen paroxetine use during tamoxifen treatment may increase risk of breast cancer-related death (level 2 [mid-level] evidence)
paroxetine, fluoxetine, and bupropion inhibit metabolism of tamoxifen to more active metabolites via cytochrome P450 2D6 (CYP2D6) enzyme, and might decrease the anticancer effect (level 3 [lacking direct] evidence) o clonidine 0.1 mg/day (level 2 [mid-level] evidence) o megestrol acetate 20 mg orally twice daily (level 1 [likely reliable] evidence) o gabapentin (Neurontin) 300 mg 3 times daily (level 2 [mid-level] evidence) psychologic therapies which may reduce hot flash impact on daily life include o cognitive behavioral therapy (level 2 [mid-level] evidence) o hypnosis (level 2 [mid-level] evidence) acupuncture might reduce frequency of hot flashes in women with breast cancer, but evidence inconsistent (level 2 [mid-level] evidence) phytoestrogen/soy supplementation appears ineffective for treatment of hot flashes in women with history of breast cancer (level 2 [mid-level] evidence) see Treatment of hot flashes in patients with breast cancer for details
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• Management of psychosocial distress: Mind-body therapies: • limited evidence of benefit from tai chi on quality of life, psychological, or physical
•
outcomes in patients with breast cancer o based on systematic review o systematic review of 3 randomized trials and 4 nonrandomized clinical trials evaluating effect of tai chi on quality of life, psychological, and physical outcomes in patients with breast cancer o tai chi was compared to walking exercise, psychological support therapy, spiritual growth and/or standard healthcare o no significant difference between tai chi and other therapies in meta-analysis or sensitivity analysis limited to randomized trials o tai chi reported to have favorable effects in 3 nonrandomized trials o Reference - Breast Cancer Res Treat 2010 Apr;120(2):309 mindfulness-based stress reduction may improve mood and quality of life in women with breast cancer (level 2 [mid-level] evidence) o based on 2 randomized trials without attention control o 229 women aged 18-80 years (mean 50 years) with stage 0 to 3 breast cancer randomized to mindfulness-based stress reduction for 8 weeks vs. wait list mindfulness practices included body scan, yoga-based stretches, meditation, group discussions, didactic teaching, and home practice mindfulness-based stress reduction associated with improved mood disturbance (including anxiety, depression, anger, vigor, fatigue, and confusion) (p < 0.001) breast- and endocrine-related quality of life, and general wellbeing (p < 0.05) Reference - J Clin Oncol 2012 Apr 20;30(12):1335 o 68 women (mean age 57 years) with cancer randomized to mindfulness-based stress reduction for 8 weeks vs. wait list
mindfulness-based stress reduction included meditation, yoga, mindful communication skills, and mindful breast self-examination/awareness in group classes as well as daily meditation and yoga at home 70.6% had breast cancer mindfulness-based stress reduction associated with improvements in quality of life and reduced depression, anger, and muscle tension comparing preintervention and postintervention assessments in 48 women (p < 0.05) control group (20 women) reported not to have statistically significant differences in these measures over time statistical comparisons between intervention and control group not reported Reference - Ann Surg Oncol 2012 Feb;19(2):373 qigong might reduce depressive symptoms in women having radiotherapy for breast cancer (level 2 [mid-level] evidence) o based on randomized trial with low adherence o 96 women (mean age 46 years) with breast cancer stage 0-III having radiotherapy randomized to qigong once weekly for 5 weeks vs. waitlist control and followed to 3 months o 54% had mastectomy o 65% with qigong attended ≥ 80% of sessions o qigong associated with nonsignificant reduction in depressive symptoms (p = 0.05) o Reference - Cancer 2013 May 1;119(9):1690
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Touch therapies: • Healing Touch (similar to therapeutic touch) may improve health-related quality of life
(level 2 [mid-level] evidence) o based on randomized trial without intention-to-treat analysis o 78 women ≥ 17 years old receiving radiation therapy for newly diagnosed gynecologic or breast cancer were randomized to Healing Touch treatment vs. mock treatment from lay-persons without training in Healing Touch o 62 women (79%) who completed trial included in analysis o Healing Touch associated with improved pain (p < 0.02) vitality (p < 0.03) physical functioning (p < 0.05) o Reference - Altern Ther Health Med 2004 May-Jun;10(3):34
Breast care nurse interventions: • limited evidence to support interventions by specialist breast care nurses for management
of psychosocial distress in women with breast cancer o based on Cochrane review o systematic review of 5 randomized trials evaluating effects of interventions carried out by specialist breast care nurses in 1,052 women with breast cancer o 3 trials assessed psychosocial nursing interventions around diagnosis and early treatment
breast care nurses could affect some components of quality of life (such as anxiety and early recognition of depressive symptoms) inconclusive results on impact on social and functional aspects of disease supportive breast care nurse interventions during radiation therapy associated with alleviation of perceived distress during radiation therapy treatment, but did not improve coping skills, mood, or overall quality of life in 1 trial nurse-led follow-up interventions not associated with differences in satisfaction with care, access to medical care, or anxiety and depression in 1 trial Reference - Cochrane Database Syst Rev 2008 Jan 23;(1):CD005634
o
o
o Multidimensional rehabilitation: • multidimensional (physical plus psychosocial) rehabilitation programs may improve
physical but not mental health scores in adult cancer survivors (level 2 [mid-level] evidence) o based on Cochrane review of trials with methodologic limitations o systematic review of 12 randomized trials evaluating multidimensional rehabilitation programs in 1,669 adult cancer survivors o multidimensional rehabilitation defined as program including both physical (exercise, dietary recommendations) and psychosocial (counseling, cognitive behavioral therapy, psychoeducational strategies) rehabilitation components o most trials had ≥ 1 limitation including unclear allocation concealment and lack of or unclear blinding o all trials compared multidimensional rehabilitation to control (standard care, less intensive rehabilitation program) o multidimensional rehabilitation associated with increased SF-36 Physical Component score (mean difference 2.22 points, 95% CI 0.12-4.31 points) in analysis of 5 trials o no significant difference in SF-36 Mental Component Summary score in analysis of 3 trials, results limited by significant heterogeneity o Reference - Cochrane Database Syst Rev 2013 Mar 28;(3):CD007730 Management of other common symptoms after breast cancer treatment: • sexual dysfunction o loss of libido(4) may be associated with depression or altered body image due to surgery,
o
irradiation, or systemic therapy treatment may include sexual counseling dyspareunia due to vaginal dryness associated with chemotherapy-induced menopause, or treatment with tamoxifen or aromatase inhibitors (4) treatments may include(4) nonhormonal vaginal moisturizing or lubricating preparations intravaginal estradiol preparations (use with caution due to concern about breast cancer recurrence related to slight increase in systemic estrogen levels which may occur with use, use preparations with lowest estrogen concentrations)
vaginal pH-balanced gel decreases dyspareunia and vaginal dryness (level 1 [likely reliable] evidence) based on randomized trial 98 breast cancer survivors with menopause after chemotherapy or endocrine therapy randomized to vaginal topical pH-balanced gel vs. placebo applied 3 times weekly for 12 weeks pH-balanced gel associated with greater improvement in dyspareunia (p = 0.04) vaginal dryness with pain (p < 0.001) all adverse events considered to be mild and self-limited Reference - Obstet Gynecol 2011 Apr;117(4):922 arthralgia, musculoskeletal symptoms(4) o increased risk with endocrine therapy, more common with aromatase inhibitors than tamoxifen o evaluate for bone metastases, especially if worsening long bone or back pain o treatment may include acetaminophen, nonsteroidal anti-inflammatory drugs, and conservative medical management cognitive dysfunction - if progressive or severe, evaluate for Alzheimer disease or other causes(4) depression - treat with counseling and antidepressants if needed (4) fatigue o increased risk with chemotherapy(4) o evaluate for depression, anemia, hypothyroidism (4) o hands-on touch therapy may reduce fatigue in breast cancer survivors, but biofield healing (touch with therapeutic intention) appears no more effective than mock healing (using same physical touching) (level 2 [mid-level] evidence) based on small randomized trial with baseline differences 76 female breast cancer survivors aged 18-70 years with fatigue were randomized to biofield healing vs. mock healing vs. wait-list control intervention given in two 1-hour sessions per week for 4 weeks biofield healing used hands-on techniques by practitioners of energy chelation with intent to heal practice of energy chelation is 45-60 minutes of practitioner doing hands-on healing with standard hand positions practitioner focuses 5-7 minutes each on specific areas, beginning with feet and ending up on heart mock healing used identical hand placements by skeptical scientists instructed to think about projects unrelated to the patient baseline differences included higher proportion of Caucasian women in both active intervention groups (87%-89%) than wait-list control group (53%)
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shorter time since chemotherapy in both active intervention groups (median 16-25 months) than wait-list control group (median 35 months) compared to wait-list control, fatigue was reduced by biofield healing (p < 0.0005) and by mock healing (p = 0.02); no significant difference between biofield and mock healing about 75% of patients in both active intervention groups believed they had true intervention; belief predicted improvement in quality of life scores more than group assignment Reference - Cancer 2012 Feb 1;118(3):777 o acupuncture might decrease cancer-related fatigue in women with breast cancer (level 2 [mid-level] evidence) based on randomized trial with inadequate attention control 302 women with breast cancer-related fatigue randomized to 1 of 2 groups and followed for 6 weeks acupuncture given in 20-minute sessions once weekly (each needling 3 pairs of acupuncture points) for 6 weeks usual care group received booklet about fatigue and its management 19% did not complete trial but included in primary analysis acupuncture associated with improvement in general fatigue at 6 weeks (p < 0.001) Reference - J Clin Oncol 2012 Dec 20;30(36):4470 weight gain o increased risk with chemotherapy(4) o can be caused by treatment with endocrine therapy, such as tamoxifen (Treat Guidel Med Lett 2005 Jan;3(29):1 TOC) o treat with diet and exercise(4) o diet and exercise program in breast cancer survivors may reduce weight during the program, but some weight regained after program cessation (level 2 [midlevel] evidence) based on small randomized trial without attention control 42 female Hispanic, African American and Afro-Caribbean breast cancer survivors (mean age 51 years) were randomized to immediate weight loss program vs. wait list control for 6 months and followed for 1 year all women had stage 0-IIIa breast cancer, were ≥ 6 months post treatment, sedentary, and had body mass index (BMI) ≥ 25 kg/m 2 (mean BMI 33.2 kg/m2) weight loss program consisted of strength training and low-impact aerobic activity at fitness center for 30 minutes ≤ 5 times/week plus nutritional education plus high-vegetable, low-fat, and calorie-restricted diet (Curves program) at 6 months wait list group started Curves program
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immediate weight loss program group was given advice to lose weight mean weight loss from baseline comparing immediate weight loss program vs. control 3.3% body weight vs. 1.8% body weight at 6 months (p = 0.04) 2% vs. 2.3% at 1 year (following 6-month interventoin in control group) Reference - Obesity (Silver Spring) 2012 Jun 25 early online pentoxifylline plus vitamin E may reduce radiation-induced breast fibrosis in women with breast cancer (level 3 [lacking direct] evidence) o based on nonclinical outcome from small randomized trial o 53 women with localized breast cancer randomized following radiation therapy to pentoxifylline 400 mg 3 times daily orally plus vitamin E 400 units/day orally for 6 months vs. standard follow-up and followed up to 5 years o breast fibrosis was assessed as difference in tissue compliance between treated and untreated breast at 18 months o comparing pentoxifylline plus vitamin E vs. standard follow-up mean difference in tissue compliance 0.88 mm vs. 2.1 mm (p = 0.048) 5-year overall survival 100% vs. 90.6% (not significant) 5-year disease-free survival 96.2% vs. 86.8% (not significant) o Reference - Int J Radiat Oncol Biol Phys 2013 Mar 1;85(3):604
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Follow-up: Recommendations: • 2005 review found 3 guidelines (National Institute for Health and Clinical Excellence
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[NICE], Scottish Intercollegiate Guidelines Network [SIGN], British Association of Surgical Oncology [BASO]) recommended different follow-up protocols after breast cancer and well-designed randomized trials were lacking (World J Surg Oncol 2005 Aug 23;3:54 fulltext) American Society of Clinical Oncology (ASCO) recommendations for follow-up of breast cancer in the adjuvant setting o careful history and physical exam every 3-6 months for first 3 years after primary therapy, then every 6-12 months for next 2 years, then annually continuity of care should be provided by a physician experienced in surveillance of cancer patients and in breast exam, including exam of irradiated breasts follow-up of patients with early breast cancer may be transferred from specialist to primary care physician about 1 year after diagnosis if preferred by patient if being followed primarily by primary care physician, women receiving adjuvant endocrine therapy should be referred for oncology assessment all women should have regular gynecologic follow-up including pelvic exam advise patients treated with tamoxifen to report any vaginal bleeding to physician, due to increased risk of endometrial cancer
longer follow-up intervals may be appropriate after total hysterectomy and oophorectomy o counsel patients about symptoms of recurrence such as new lumps, bone pain, chest pain, dyspnea, abdominal pain, or persistent headaches o refer women with high familial breast cancer risk for genetic counseling, including those with Ashkenazi Jewish heritage history of ovarian cancer at any age in patient or any first- or seconddegree relative any first-degree relative with history of breast cancer diagnosed at < 50 years old ≥ 2 first- or second-degree relatives diagnosed with breast cancer at any age patient or relative with diagnosis of bilateral breast cancer history of breast cancer in a male relative o advise patient to perform monthly self-exams o mammography after breast-conserving therapy perform first posttreatment mammogram 1 year after initial mammogram that led to diagnosis and ≥ 6 months after radiation therapy obtain subsequent studies every 6-12 months for surveillance of abnormalities perform mammography annually if mammogram findings stable after completion of locoregional therapy o testing NOT recommended for routine breast cancer surveillance complete blood count and liver functions tests chest x-ray, bone scan, liver ultrasound, computed tomography scan, fluorodeoxyglucose-positron emission tomography (FDG-PET scan), and breast magnetic resonance imaging (MRI) cancer antigens (CA) 15-3, CA 27.29, and carcinoembryonic antigen tumor markers o Reference - ASCO guideline on breast cancer follow-up and management after primary treatment (J Clin Oncol 2013 Mar 1;31(7):961 full-text) or at National Guideline Clearinghouse 2013 Apr 8:38701 Health Canada's Steering Committee recommendations on follow-up after treatment for breast cancer o all patients should have regular follow-up surveillance responsibility for follow-up should be formally allocated to a single physician adjust visit frequency according to individual patient's needs o all visits should include medical history; ask about vaginal bleeding in women taking tamoxifen symptoms of fatigue fatigue may affect about 25%-33% investigate and rule out physiologic causes of fatigue depression and pain are potentially treatable underlying factors
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sexual functioning o physical exam should include evaluation of breasts, regional lymph nodes, chest wall, lungs, and abdomen assessment of arms for lymphedema o annual visits should include mammographic exam o do not perform routine laboratory (including tumor markers) and radiographic investigations for the purpose of detecting distant metastases o other considerations encourage patients to report new, persistent symptoms promptly, without waiting for next scheduled appointment if a woman wishes to carry out breast self-exam, reasonable to teach her the proper procedure encourage and facilitate psychosocial support discuss weight management with all breast cancer survivors and encourage overweight patients to participate in evidence-based weightmanagement programs chemotherapy may affect cognitive functioning, but subjective complaints of cognitive impairment do not correlate with objective measures osteoporosis perform screening bone mineral density test if patient is postmenopausal premenopausal with risk factors for osteoporosis taking aromatase inhibitors counsel patient on exercise and adequate intake of calcium and vitamin D osteoporosis treatment should include a bisphosphonate o pregnancy inform women considering pregnancy that data on effect of pregnancy on breast cancer recurrence and survival is limited no evidence that subsequent pregnancy adversely affects survival, but most studies have been retrospective case series or small case-control studies o Reference - CMAJ 2005 May 10;172(10):1319 full-text NICE recommendations for follow-up of early breast cancer (2) o follow-up care after completion of adjuvant treatment may be in primary, secondary, or shared-care setting, based on patient preference o provide patient with written, agreed-upon care plan including designated healthcare professionals dates for review of any adjuvant therapy plan for surveillance mammography signs and symptoms to look for and seek advice on contact instructions if immediate referral for specialist care becomes necessary contact details for support services
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o
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mammography offer annual mammography until eligible for National Health Service Breast Screening Programme (NHSBSP)/Breast Test Wales Screening Programme (BTWSP) if already eligible for screening, perform annual mammography for 5 years once eligible for screening, or after 5 years of annual mammography, determine frequency of subsequent studies according to patient-risk category do not perform mammography of ipsilateral soft tissues after mastectomy ultrasound and MRI not recommended for routine posttreatment surveillance, but surveillance ultrasound may detect some recurrences not detectable on mammography, especially in dense breast or when primary tumor was occult on mammography MRI had higher sensitivity but higher false-positive rate, recommended for evaluation of equivocal findings
Surveillance for recurrent disease: Mammography for surveillance: • mammography surveillance might improve overall survival and breast cancer-specific
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survival (level 2 [mid-level] evidence) o based on systematic review of cohort studies with methodologic limitations o systematic review of 8 cohort studies evaluating surveillance regimens that included mammography in 7,337 women previously treated for primary breast cancer without detectable metastatic disease at initial presentation who were followed for at least 5 years o 6 studies did not have a comparison group and 6 studies were retrospective cohorts o increasing number of surveillance mammograms associated with decline in mortality rate in 1 study with 334 women (p = 0.007) o consecutive years of mammographic surveillance associated with decreased risk of all-cause mortality compared to lack of consecutive years of surveillance in 1 study with 303 women (odds ratio [OR] 0.7, 95% CI 0.51-0.86) o 1 or more episodes of surveillance mammography associated with decreased risk of breast cancer-specific death in 1 study with 901 patients (hazard ratio 0.28, 95% CI 0.22-0.37) o Reference - Health Technol Assess 2011 Sep;15(34):v PDF surveillance mammograms appear to reduce breast cancer mortality in women ≥ 65 years old with early breast cancer (level 2 [mid-level] evidence) o based on retrospective cohort study o 1,846 women ≥ 65 years old with stage I and II breast cancer were followed for 5 years o breast cancer mortality was 9.6% o each additional surveillance mammography associated with reduced odds of breast cancer mortality (OR 0.69, 95% CI 0.52-0.92) o Reference - J Clin Oncol 2007 Jul 20;25(21):3001 full-text
Magnetic resonance imaging (MRI) for surveillance:
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breast MRI appears more accurate than clinical exam, mammogram, and ultrasound for detection of breast cancer recurrence (level 2 [mid-level] evidence) o based on systematic review of diagnostic cohort studies where it was unclear if reference standard was interpreted without knowledge of test results o systematic review of 9 studies evaluating diagnostic accuracy of other surveillance tests compared to mammography in 4,002 women previously treated for primary breast cancer without detectable metastatic disease at initial presentation o tests included mammography, ultrasound, MRI, clinical breast exam, or a combination of tests o reference standard was histopathological examination and follow-up of negative tests o prevalence of recurrent disease was not reported o diagnostic performance for breast tumor recurrence during surveillance Test Performance for Detection of Ipsilateral Breast Tumor Recurrence during Routine Surveillance: Mammogram
MRI
Combined Mammogram and Clinical Exam
Clinical Exam
Sensitivity
64%-67%
86%100%
50%-89%
100%
Specificity
85%-97%
93%
76%
67%
Number of studies
2
2
2
1
Abbreviation: MRI, magnetic resonance imaging. Test Performance for Detection of Ipsilateral Breast Tumor Recurrence during Nonroutine Surveillance: Mammogram
Ultrasound
MRI
Clinical Exam
Sensitivity
50%-83%
43%-87%
93%-100% 43%-62%
Specificity
57%-75%
31%-73%
88%-96% 49%-56%
Number of studies
3
2
3
Abbreviation: MRI, magnetic resonance imaging.
2
Test Performance for Detection of Contralateral Breast Tumor Recurrence during Routine Surveillance: Combined Combined Combined Mammogram, Mammogram, Clinical Mammogram Mammogram MRI Ultrasound, Ultrasound, Exam and and Clinical Clinical Exam, Ultrasound Exam and MRI Sensitivity 67%
67%0% 91%
95%
64%
100%
Specificity 50%
50%50% 90%
99%
84%
89%
Number 1 of studies
2
1
1
1
1
Abbreviation: MRI, magnetic resonance imaging. o Reference - Health Technol Assess 2011 Sep;15(34):v PDF Other studies for surveillance: • more intensive approaches to follow-up (addition of chest x-ray and bone scan) may
improve disease-free survival but not overall survival compared with regular physical exams and yearly mammography in women with early breast cancer (level 2 [mid-level] evidence) o based on Cochrane review with inadequate statistical power o systematic review of 4 randomized trials evaluating follow-up strategies for 3,055 women treated for early breast cancer (clinical stage I, II, or III) o 2 trials with 2,563 women compared follow-up based on clinical visits and mammography vs. intensive follow-up including radiologic and laboratory tests o intensive follow-up including radiologic and laboratory tests associated with no significant differences in overall mortality at 5 years (odds ratio [OR] 0.96, 95% CI 0.8-1.15) improved disease-free survival (OR 0.84, 95% CI 0.71-1) no significant differences in subgroup of women ≤ 40 years old (OR 0.94, 95% CI 0.59-1.47) in analysis of 2 trials with 272 women trend toward improved survival in subgroup of women > 40 years old (OR 0.84, 95% CI 0.7-1.01) in analysis of 2 trials with 2,290 women o Reference - Cochrane Database Syst Rev 2005 Jan 25;(1):CD001768, commentary can be found in Am Fam Physician 2005 Jul 1;72(1):77 full-text Tumor markers for detection of recurrence: • low sensitivity limits clinical utility of tumor markers for detecting distant relapse in •
patients with breast cancer (level 2 [mid-level] evidence) serum cancer antigens may be used to monitor advanced breast cancer
primary use is in addition to history, physical exam, and diagnostic imaging in patients with advanced breast cancer and otherwise nonassessable disease (NACB Grade B, Level III) o rising levels may suggest progressive disease, except during first 4-6 weeks of new therapy (NACB Grade B, Level III) o most commonly used cancer antigens are CA 15-3, CA 27.29 and carcinoembryonic antigen (CEA) see Tumor markers in breast cancer for details o
• Coordination of follow-up care: • specialist care and general practitioner care for follow-up after early-stage breast cancer
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my have similar outcomes o no significant differences in health outcomes comparing family physician and cancer center for long-term follow-up after early-stage breast cancer (level 2 [mid-level] evidence) based on randomized trial with allocation concealment not stated 968 patients with early-stage breast cancer who completed adjuvant treatment and were disease-free 9-15 months after diagnosis were randomized to follow-up in cancer center vs. follow-up by their own family physician no significant differences in rates of recurrence (13.2% vs. 11.2%), death (6.2% vs. 6%), or recurrence-related serious clinical events (3.7% vs. 3.5%) no significant differences in any health-related quality of life measures Reference - J Clin Oncol 2006 Feb 20;24(6):848 full-text o no differences in detection of breast cancer recurrence or in quality of life comparing general practitioner and hospital-based specialist for follow-up after primary treatment for breast cancer (level 2 [mid-level] evidence) based on Cochrane review with limited evidence systematic review of 4 randomized trials evaluating follow-up strategies for 3,055 women treated for early breast cancer (clinical stage I, II, or III) 1 trial with 296 women attending outpatient clinic for routine follow-up with no evidence of disease at last visit compared hospital-based specialist vs. general practitioner for follow-up care no significant differences in time to detection of recurrence or quality of life Reference - Cochrane Database Syst Rev 2005 Jan 25;(1):CD001768, commentary can be found in Am Fam Physician 2005 Jul 1;72(1):77 fulltext less frequently scheduled follow-up visits may not be associated with increased visits and telephone calls to general practitioners in women treated for early breast cancer (level 2 [mid-level] evidence) o based on Cochrane review with limited evidence o systematic review of 4 randomized trials evaluating follow-up strategies for 3,055 women treated for early breast cancer (clinical stage I, II, or III) o 1 trial evaluated frequency of follow-up visits o 196 women with history of breast cancer and no disease recurrence were randomized to either
regularly scheduled clinical visits at time of mammography clinical visits every 3 months during first year, every 4 months in second year, every 6 months from years 3 to 5, and then yearly o mammography was done every year for 5 years (or for 2 years if mastectomy) then every 2 years o comparing regularly scheduled follow-up visits vs. less frequent visits, no significant differences in interim use of telephone or frequency of general practice consultations o Reference - Cochrane Database Syst Rev 2005 Jan 25;(1):CD001768, commentary can be found in Am Fam Physician 2005 Jul 1;72(1):77 full-text telephone-based follow-up by specialist nurses increases patient satisfaction and does not affect time to detection of breast cancer recurrence compared to traditional hospital follow-up in women with low-to-moderate risk (level 1 [likely reliable] evidence) o based on randomized trial o 374 women treated for breast cancer with low-to-moderate recurrence risk randomized to telephone-based vs. traditional hospital follow-up telephone follow-up provided by specialist nurses and included consultation with structured intervention and mammography according to hospital policy traditional hospital follow-up included consultation, clinical examination, and mammography as per hospital policy o women followed for mean 24 months o 95% CI for difference in mean anxiety scores adjusted for treatment received was within predefined equivalence range o telephone-based follow-up associated with no significant increase in anxiety regarding not having clinic examinations and face-to-face consultations higher levels of satisfaction (p < 0.001 vs. traditional follow-up) no significant difference in clinical investigations ordered no significant difference in time to recurrence detection (17 recurrences total) o Reference - BMJ 2009 Jan 14;338:a3147 full-text, editorial can be found in BMJ 2009 Jan 14;338:a2753 multidisciplinary rehabilitation may improve shoulder range of motion and quality of life in women with surgically treated breast cancer (level 2 [mid-level] evidence) o based on Cochrane review of trials with inadequate or unclear allocation concealment o systematic review of 2 randomized trials evaluating multidisciplinary rehabilitation in 262 women with surgically treated breast cancer o multidisciplinary rehabilitation improved shoulder range of motion, psychosocial adjustment, and quality of life vs. wait-list in 1 trial with 65 women o multidisciplinary rehabilitation consecutively for 3 weeks plus additional week at 4 and 8 months had no significant effect on physical function but showed trend toward improved quality of life vs. multidisciplinary rehabilitation for 4 consecutive weeks in 1 trial with 197 women
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Reference - Cochrane Database Syst Rev 2012 Dec 12;(12):CD009553 • multidisciplinary care associated with reduced mortality in women with symptomatic invasive breast cancer (level 2 [mid-level] evidence) o based on retrospective cohort study o 13,722 women with symptomatic invasive breast cancer had multidisciplinary care or conventional care between 1995 and 2000 multidisciplinary team lead by specialist breast cancer surgeon and included use of evidence-based guidelines, weekly team meetings to discuss test results and adjuvant treatment, and regular meetings with director of public health conventional care included decisions regarding surgery and adjuvant treatment made solely by surgeons o multidisciplinary care associated with reduced risk of breast cancer-related mortality (hazard ratio [HR] 0.82, 95% CI 0.74-0.91) all-cause mortality (HR 0.89, 95% CI 0.82-0.97) o Reference - BMJ 2012 Apr 26;344:e2718 full-text, editorial can be found in BMJ 2012 Apr 26;344:e2780 Prognosis o
Prediction tools: •
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Adjuvant! clinical prediction tool o requires online registration by medical professional o accurately predicts 10-year overall survival, breast cancer-specific survival, and event-free survival o predicts recurrence rates after (and thus estimated efficacy of) adjuvant chemotherapy, endocrine therapy, or both o validated in study with 4,083 women with stage I and II breast cancer o References J Clin Oncol 2005 Apr 20;23(12):2716 , commentary can be found in Evidence-Based Medicine 2005 Nov-Dec;10(6):186 Lancet Oncol 2009 Nov;10(11):1070 o DynaMed commentary -- Adjuvant! does not provide risk predictions based on human epidermal growth factor receptor type 2 (HER2/neu) status in women < 55 years old with lymph node-negative breast cancer and Adjuvant!-predicted 10-year breast cancer-specific survival ≥ 95%, mitotic activity index may further stratify high-risk and low-risk patients (level 2 [mid-level] evidence) o based on derivation cohort study without validation o 516 women < 55 years old with lymph node-negative breast cancer were assessed using mitotic activity index (MAI) and Adjuvant! prognostic tool o median follow-up 118 months o 122 women had Adjuvant!-predicted 10-year breast cancer-specific survival ≥ 95% observed breast cancer-specific survival 91% breast cancer-specific survival stratified by MAI (p < 0.001) 99% in 74 women with MAI < 3 79% in 48 women with MAI ≥ 3
394 women had Adjuvant!-predicted 10-year breast cancer-specific survival < 95% observed breast cancer-specific survival 74% breast cancer-specific survival stratified by MAI (p < 0.001) 92% in 86 women with MAI < 3 70% in 308 women with MAI ≥ 3 o Reference - J Clin Oncol 2011 Mar 1;29(7):852 Finprog is an online system to enter individual patient data and predict overall survival based on data from 2,032 breast cancer patients in Finland followed for 8 to 11 years (BMJ 2003 Jan 4;326(7379):29 full-text), editorial can be found in BMJ 2003 Jan 4;326(7379):2, commentary can be found in BMJ 2003 Apr 12;326(7393):822 prognostic score predicts 5-year disease-specific survival after surgery as first intervention for stage I-IIIA breast cancer (level 1 [likely reliable] evidence) o based on derivation and validation cohort study o derivation cohort included 3,728 patients with stage I-IIIA breast cancer who had surgery as first intervention and who were followed for mean 6.6 years o validation cohort included 26,711 similar patients who were followed for mean 5.9 years o 5-year disease-specific survival 97.4% for derivation cohort 93.2% for validation cohort o 6 prognostic scores based on 6 risk factors were evaluated in derivation cohort o risk factors associated with 5-year disease-specific survival in derivation cohort and points assigned to derive prognostic score (total score 0-4 points) pathologic stage - 0 points if stage I, 1 point if stage IIA-IIB, 2 points if grade IIIA nuclear grade - 0 points if stage I-II, 1 point if stage III estrogen receptor status - 0 points if positive, 1 point if negative o 5-year disease-specific survival by prognostic score in derivation and validation cohorts Results: o
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•
Score Derivation Cohort Validation Cohort
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0 points 99.5%
98.5%
1 point 98.9%
95.2%
2 points 96.1%
86.3%
3 points 86.2%
72.2%
4 points 65.2%
54.2%
o Reference - J Clin Oncol 2011 Dec 10;29(35):4654 Breast Cancer Severity Scale (BCSS) may predict 5-year survival (level 2 [mid-level] evidence)
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BCSS
1 point if tumor diameter up to 1 cm, 2 points if 1.1-2 cm, 3 points if 2.1-5 cm, 4 points if 5.1 cm or greater 1 point if 1-3 positive lymph nodes, 5 points if 4-9 positive lymph nodes, 10 points if ≥ 10 positive lymph nodes 1 point if either estrogen or progesterone receptors absent, 2 points if both hormone receptors absent o study of 417 patients with breast cancer, median follow-up 20 months, mean age 57 years o overall 5-year survival based on staging 100% in 171 patients who were stage I, mean BCSS 2.4 97% in 190 patients who were stage II, mean BCSS 4.7 68% in 28 patients who were stage III, mean BCSS 7.9 18% in 30 patients who were stage IV, mean BCSS 7 o BCSS 7 or higher predicted poor 5-year survival 92% if BCSS < 7, 44% if higher after excluded stage IV patients, 99% if BCSS < 7, 75% if higher 93% 5-year disease-free survival if BCSS < 7, 60% if higher; discriminatory in patients with stage II and stage III disease o Reference - Am J Surg 2003 Oct;186(4):404 in Am Fam Physician 2004 Apr 15;69(8):2009 prediction model for lymph node metastasis in breast cancer patients ≥ 70 years old o based on prognostic cohort with validation o 700 women ≥ 70 years old with hormone receptor-positive breast cancer divided into derivation (75%) and validation (25%) cohorts o patients had either axillary lymph node dissection, sentinel lymph node biopsy, or both o prediction of lymph node status based on patient age tumor size lymphovascular invasion o patients categorized into risk quartiles by prediction model based on above parameters o in lowest quartile risk group, positive lymph nodes in 5.4% derivation group 0% patients in validation group o Reference - Ann Surg 2009 Mar;249(3):455 nomograms may predict pathologic complete response and metastasis-free survival after preoperative chemotherapy in patients with breast cancer o based on derivation from 496 patients treated with anthracycline and validation in 337 patients who received anthracycline and 237 patients who received paclitaxel plus anthracycline o Reference - J Clin Oncol 2005 Nov 20;23(33):8331 validation of predictive nomogram of ipsilateral breast tumor recurrence after breastconserving therapy can be found in J Clin Oncol 2010 Feb 10;28(5):718 full-text, editorial
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can be found in J Clin Oncol 2010 Feb 10;28(5):709 IBTR! version 2.0 breast cancer nomogram nomogram may predict sentinel lymph node-positive breast cancer involving 4 or more nodes o retrospective analysis of 402 patients with invasive breast cancer and 1-3 involved sentinel lymph nodes who underwent complete axillary dissection o nomogram score based on primary tumor size number of involved sentinel lymph nodes micro or macro size of largest sentinel lymph node metastasis presence of lymphovascular space invasion presence of extranodal extension histology number of negative sentinel lymph nodes o Reference - J Clin Oncol 2008 May 1;26(13):2093 full-text nomogram may predict nonsentinel lymph node involvement in women with breast cancer with a positive sentinel lymph node o based on cohort of 509 women with invasive breast cancer and positive sentinel lymph node who had complete axillary lymph node dissection o risk score based on total sentinel lymph node number positive sentinel lymph node number sentinel lymph node metastasis size extranodal extension tumor size lymphovascular invasion tumor histology o calculator can be found at MD Anderson Cancer Center o Reference - Ann Surg 2012 Jan;255(1):109 prognostic nomogram may not be useful for predicting breast cancer in women with BIRADS 4 lesions (level 2 [mid-level] evidence) o based on retrospective derivation and validation cohort study o 170 women with Breast Imaging Reporting and Data Systems (BI-RADS) 4 lesions at screening mammogram who had diagnostic cytology or biopsy and surgery or follow-up as needed were in derivation cohort and 188 similar patients were in validation cohort o 42.4% in derivation cohort and 30.2% in validation cohort were diagnosed with breast cancer o factors significantly associated with risk of breast cancer in validation cohort increasing age palpable lesion menopausal condition lesion size use of hormone replacement therapy
Gail risk predictive performance of nomogram in validation cohort sensitivity 77.8% specificity 53.1% positive predictive value 77.3% negative predictive value 53.8% Reference - J Surg Oncol 2010 Sep 1;102(3):220
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Tumor markers: •
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tumor tissue tests recommended for every primary invasive breast cancer o estrogen receptors and progesterone receptors (NACB Grade A, Level I) primary role is to identify patients likely to benefit from endocrine therapy; no benefit if estrogen receptor-negative (NACB Grade A, Level I) hormone receptor status is an independent risk factor for survival (level 1 [likely reliable] evidence) o human epidermal growth factor receptor type 2 (HER2) expression (NACB Grade A, Level I) used to predict response to anti-HER2 therapy (trastuzumab) (NACB Grade A, Level I) testing for HER2-positive breast cancer uses immunohistochemistry or fluorescent in situ hybridization (FISH) HER2 amplification associated with decreased overall and relapse-free survival (level 1 [likely reliable] evidence) tumor tissue tests to consider in some patients o Oncotype DX assay (21-gene expression profile) can be used in newly diagnosed node-negative estrogen receptor-positive breast cancer to predict recurrence risk with use of adjuvant tamoxifen therapy (NACB Grade A, Level I/II) low score identifies patients who may be able to avoid chemotherapy (NACB Grade A, Level I/II) high score predicts likelihood of greater benefit with addition of chemotherapy to tamoxifen (NACB Grade B, Level II/III) for women with node-positive, hormone receptor-positive breast cancer limited data found to determine whether Oncotope DX-guided practice improves clinical outcomes Oncotype DX may predict disease-free and overall survival in postmenopausal women treated with tamoxifen, and may predict whether addition of chemotherapy will increase disease-free and overall survival (level 2 [mid-level] evidence) o urokinase plasminogen activator (uPA) and plasminogen activator inhibitor (PAI)-1 may be used to identify patients with lymph node-negative breast cancer unlikely to benefit from adjuvant chemotherapy (NACB Grade A, Level I), but not uniformly recommended across guidelines should be measured with enzyme-linked immunosorbent assay (ELISA) using fresh tumor extracts > 200-300 mg (NACB Grade A, Level I) serum cancer antigens may be used to monitor advanced breast cancer
low sensitivity limits clinical utility of tumor markers for detecting distant relapse in patients with breast cancer (level 2 [mid-level] evidence) o primary use is in addition to history, physical exam, and diagnostic imaging in patients with advanced breast cancer and otherwise nonassessable disease (NACB Grade B, Level III) o rising levels may suggest progressive disease, except during first 4-6 weeks of new therapy (NACB Grade B, Level III) o most commonly used cancer antigens are (CA) 15-3, CA 27.29 and carcinoembryonic antigen (CEA) tumor cell assays under investigation o presence of circulating tumor cells (CTCs) in peripheral blood associated with decreased overall and recurrence-free survival (level 2 [mid-level] evidence) o cytokeratin-positive (CK+) cells in bone marrow (as marker for bone marrow micrometastases) associated with decreased survival in patients with stage I-III breast cancer (level 1 [likely reliable] evidence) tests with limited evidence for clinical use include o serum HER2 extracellular domain levels o gene expression profiles other than Oncotype DX, such as MammaPrint o DNA flow cytometry-based parameters o markers of proliferation o tumor protein 53 (p53) tests o cathepsin D levels o glycoprotein expression see Tumor markers in breast cancer for details o
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Factors which may affect survival: •
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5-year relative survival rates from CONCORD study (1.9 million adults with first primary invasive cancer from 101 cancer registries in 31 countries) can be found in Lancet Oncol 2008 Aug;9(8):730 estimated progression-free survival 7.6 months and overall survival 21.7 months in women starting first-line chemotherapy for metastatic breast cancer o based on systematic review of 36 randomized trials o Reference - J Clin Oncol 2011 Feb 1;29(4):456, editorial can be found in J Clin Oncol 2011 Feb 1;29(4):347 breast cancer diagnosed without screening or during screening interval associated with 80% 10-year survival (level 2 [mid-level] evidence) o based on retrospective cohort study o 7,116 women aged 50-72 years with diagnosis of invasive breast cancer in Norway from 1996 to 2006 were evaluated 26% had diagnosis between 1 of 2 mammography screenings or ≤ 2 years and 2 months after last normal screening (interval group) 74% had diagnosis prior to invitation for mammography screening (nonscreened group) o at baseline, interval group had slightly more lobular cancers, large tumors (diameter > 20 mm), negative axillary lymph nodes, and stage II (vs. stage I) disease (p < 0.001 for each)
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mean follow-up 3.6 years in interval group and 6.3 years in non-screened group 10-year survival rate 79.1% for women with interval cancers vs. 76.8% for women who did not receive screening (hazard ratio 0.98, 95% CI 0.84-1.15, p = 0.53) Reference - BMJ 2012 Nov 16;345:e7536 full-text
o Tumor characteristics and spread: • risk factors for breast cancer mortality include higher histologic grade, larger tumor size,
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ipsilateral breast tumor recurrence, and lymphatic invasion o based on prospective cohort study of 1,540 consecutive women aged 18-75 years with node-negative breast cancer followed for up to 12 years o 98 ipsilateral breast tumor recurrences (6.4%) and 117 deaths (7.4%) occurred o risk factors for ipsilateral breast cancer recurrence included age < 40 years (relative risk [RR] 1.89, 95% CI 1-3.58) presence of intraductal disease (RR 1.81, 95% CI 1.15-2.85) histological grade (G2 or G3 vs. G1) (RR 1.59, 95% CI 0.87-2.94) o risk factors for disease-specific mortality included histologic grade (G2 or G3 vs. G1) (RR 8.59, 95% CI 2.09-35.36) tumor size > 2 cm (vs. < 1 cm) (RR 2.94, 95% CI 1.56-5.56) ipsilateral breast tumor recurrence (RR 2.58, 95% CI 1.05-3.64) progesterone receptor status (negative or equivocal vs. positive or unknown) (RR 2.15, 95% CI 1.36-3.39) lymphatic invasion (RR 1.78, 95% CI 1.17-2.72) o Reference - Breast Cancer Res 2006 Jul 19;8(4):R44 full-text survival varies with histologic type o retrospective cohort study of 164,958 women aged 50-79 years with 1 of 7 histologic types of invasive breast cancer in 9 cancer registries from 1974 to 1998 o 80.2% women had invasive ductal carcinoma, 41.3% overall mortality o 11.8% had invasive lobular carcinoma, 33% mortality o 2.4% had mucinous carcinoma, 34.7% mortality o 1.9% had comedocarcinoma, 29.7% mortality o 1.8% had medullary carcinoma, 44.8% mortality o 1.4% had tubular carcinoma, 18.5% mortality o 0.6% had papillary carcinoma, 37.2% mortality o Reference - Arch Intern Med 2003 Oct 13;163(18):2149 clinical outcome with infiltrating lobular carcinoma similar to infiltrating ductal carcinoma o based on study of 4,140 patients with infiltrating lobular carcinoma compared to 45,169 patients with infiltrating ductal carcinoma o median follow-up 87 months o comparing patients with infiltrating lobular carcinoma vs. patients with infiltrating ductal carcinoma 5-year overall survival 85.6% vs. 84.1% recurrence rate over 5 years 14.3% vs. 16.5% ("disease-free survival" rates did not account for deaths) contralateral breast cancer in 20.9% vs. 11.2% (p < 0.0001) after first recurrence
median survival 22 months vs. 19 months (p = 0.002) 5-year survival 32.8% vs. 26.7% o Reference - Breast Cancer Res 2004 Feb 17;6(3):R149 full-text detection of second tumors prior to onset of symptoms associated with improved survival in breast cancer survivors (level 2 [mid-level] evidence) o based on retrospective cohort study o 1,044 breast cancer survivors who had second invasive tumor ≥ 6 months after initial diagnosis were followed for median 13.7 years after first diagnosis o 67% of women with second cancers were asymptomatic o asymptomatic tumors were (compared to symptomatic) smaller (p < 0.001) more likely to be early-stage tumors (p < 0.0001) less likely to be cancer stage pT2 or larger (p < 0.001) fewer node metastases in contralateral cancer (p = 0.0001) associated with increased disease-specific survival from first cancer diagnosis (p < 0.0001) o despite mammography being more sensitive than clinical examination (86% vs. 57%, p < 0.0001), 13.8% of second cancer cases were only identified clinically o Reference - Ann Oncol 2009 Sep;20(9):1505 full-text in women with metachronous contralateral breast cancer, increased risk of breast cancerrelated death with larger tumor size, positive nodal status, and short time interval to development of contralateral cancer o based on prospective cohort study o from a cohort of 42,670 women with breast cancer in Sweden from 1992 to 2008, 803 women who developed metachronous contralateral breast cancer were assessed for factors associated with breast cancer-related mortality o 13.4% died from breast cancer in median follow-up 9.9 years o in women with metachronous contralateral breast cancer, risk of breast cancerrelated mortality increased with larger tumor size compared to tumors ≤ 2 cm for tumors 2-5 cm, hazard ratio (HR) 2.2 (95% CI 1.3-3.6) for > 5 cm, HR 6.3 (95% CI 3-13) for tumor of any size with extension to chest wall and/or skin, HR 4.1 (95% CI 1.5-12) positive nodal status compared to negative status (HR 2.4, 95% CI 1.5-3.9) contralateral breast cancer ≤ 5 years after primary tumor compared to longer latency (HR 1.7, 95% CI 1.1-2.6) negative estrogen receptor status compared to positive status (HR 2.6, 95% CI 1-4.8) negative progesterone receptor status compared to positive status (HR 2.4, 95% CI 1-5.9) o Reference - J Clin Oncol 2012 Oct 1;30(28):3478 metastases o increasing numbers of bony metastases associated with decreasing survival in women with breast cancer
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based on retrospective cohort of 641 women with stage I-III breast cancer 116 women had bone metastases as sole initial site of metastatic disease median survival in women with bony metastases 53 months with 1 lesion 38 months with 2 lesions 22 months with ≥ 3 lesions Reference - Cancer 2001 Jan 1;91(1):17 occult metastases associated with small reduction in survival in women with nodenegative breast cancer based on cohort analysis of data from NSABP-32 randomized trial 3,887 women with invasive breast cancer and clinically negative nodes were evaluated for macrometastases ≥ 2 mm 15.9% had occult metastases comparing patients with detectable occult metastases vs. no detectable occult metastases at 5 years overall survival 94.6% vs. 95.8% (p = 0.03) cancer-free survival 86.4% vs. 89.2% (p = 0.02) distant cancer-free 89.7% vs. 92.5% (p = 0.04) Reference - N Engl J Med 2011 Feb 3;364(5):412 occult bone marrow metastases not independently associated with reduced survival in women with early-stage invasive breast cancer having chemotherapy based on analysis of data from prospective cohort from American College of Surgeons Oncology Group (ACOSOG) Z0010 trial 5,210 women with early-stage invasive breast cancer had breastconserving surgery and sentinel lymph node (SLN) dissection followed for median 6.3 years bone marrow aspiration at time of operation was initially optional but became mandatory midtrial SLN specimens (hematoxylin-eosin negative) and bone marrow specimens were sent for immunochemical staining 86.2% received systemic chemotherapy 65.5% had bone marrow specimens examined by immunocytochemistry bone marrow positive for tumor in 2% mortality in 8.3% disease progression in 7.2% comparing immunohistochemical evidence of bone marrow metastases vs. no evidence of bone marrow metastases overall survival at 5 years 90.1% vs. 95% (p = 0.01) in univariate analysis no significant difference in overall survival at 5 years in multivariate analysis Reference - JAMA 2011 Jul 27;306(4):385 full-text, editorial can be found in JAMA 2011 Jul 27;306(4):436
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women with metastases in unusual sites and women with metastases in usual sites appear to have similar 5-year survival based on retrospective cohort study 3,783 patients evaluated with median follow-up 5 years 85 (2.2%) had unusual metastases (defined as systemic failures occurring with frequency ≤ 1%) among 764 patients with distant metastases, 5-year cumulative overall survival was 53.5% for women with unusual metastases vs. 53.4% for women without unusual metastases Reference - Cancer 2008 Aug 15;113(4):677 micrometastases o metastases ≤ 2 mm diameter in axillary lymph nodes associated with poorer survival compared with absence of metastases based on systematic review of 58 studies evaluating prognosis of occult lymph node metastases, isolated tumor cells, and micrometastases in 297,533 persons with breast cancer axillary lymph node metastases of ≤ 2 mm diameter associated with poorer overall survival compared with absence of metastases (pooled hazard ratio [HR] 1.44, 95% CI 1.29-1.62) Reference - J Natl Cancer Inst 2010 Mar 17;102(6):410 o isolated tumor cells or micrometastases in regional lymph nodes associated with reduced 5-year disease-free survival in women with early-stage breast cancer not receiving adjuvant therapy based on cohort study in Netherlands all women having sentinel-node biopsy for breast cancer before 2006 for breast cancer with favorable primary-tumor characteristics and isolated tumor cells or micrometastases in regional lymph nodes were compared to women with node-negative disease from 2000 to 2001 856 women with isolated tumor cells or micrometastases did not receive systemic adjuvant therapy 995 women with isolated tumor cells or micrometastases received systemic adjuvant therapy 856 women with node-negative disease did not receive systemic adjuvant therapy women followed for median 5.1 years adjusted hazard ratio (HR) for disease events in women not receiving adjuvant therapy 1.5 (95% CI 1.15-1.94) in women with isolated tumor cells vs. node-negative disease 1.56 (95% CI 1.15-2.13) in women with micrometastases vs. nodenegative disease unadjusted 5-year disease-free survival in women not receiving adjuvant therapy 85.7% with node-negative disease o
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75.9% with micrometastases without adjuvant therapy (p = 0.002 vs. node-negative disease) 77.2% with isolated tumor cells without adjuvant therapy (p < 0.001 vs. node-negative disease, not significant vs. micrometastases) adjusted HR for disease events 0.57 (95% CI 0.45-0.73) in women with isolated tumor cells or micrometastases with adjuvant therapy vs. no adjuvant therapy Reference - N Engl J Med 2009 Aug 13;361(7):653, commentary can be found in N Engl J Med 2009 Nov 12;361(20):1994 o bone marrow micrometastasis at time of breast cancer diagnosis associated with poor prognosis based on meta-analysis of individual patient data from 9 studies with 4,703 patients with stages I-III breast cancer followed for median 5.2 years 1,438 patients (30.6%) had micrometastasis patients with bone marrow micrometastasis had larger tumors tumors with a higher histologic grade more frequent lymph node metastasis more hormone receptor-negative tumors micrometastasis associated with reduced overall survival, breast cancerspecific survival, disease-free survival, and distant disease-free survival Reference - N Engl J Med 2005 Aug 25;353(8):793 full-text, commentary can be found in N Engl J Med 2005 Nov 17;353(20):2191 circulating tumor cells (CTCs) o increased numbers of CTCs may be associated with worse overall survival based on retrospective cohort study 185 patients (median age 49 years) with metastatic or recurrent breast cancer evaluated median survival 15 months for patients with ≥ 5 CTCs per 750 mL of whole blood vs. 28.3 months for patients with < 5 CTCs per 750 mL of whole blood (p < 0.001) Reference - Cancer 2008 Nov 1;113(9):2422 full-text o number of CTCs before treatment and at first follow-up significantly predicted disease progression and overall survival in prospective study of 177 patients with measurable metastatic breast cancer (N Engl J Med 2004 Aug 19;351(8):781), editorial can be found in N Engl J Med 2004 Aug 19;351(8):824, commentary can be found in N Engl J Med 2004 Dec 2;351(23):2452 residual breast cancer following neoadjuvant chemotherapy associated with reduced distant relapse-free survival o based on retrospective analysis of 382 patients treated with fluorouracil, doxorubicin, and cyclophosphamide (preceded by paclitaxel in 241 patients) o residual breast cancer determined by pathologic measurement of primary tumor and nodal metastases
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Reference - J Clin Oncol 2007 Oct 1;25(28):4414 full-text, commentary can be found in J Clin Oncol 2008 Jun 20;26(18):3094 in mammographic lesions < 14 mm, casting-type calcifications associated with lower longterm survival in prospective study of 343 mammograms of invasive breast cancers of size 1-14 mm (Lancet 2000 Feb 5;355(9202):429), correction can be found in Lancet 2000 Apr 15;355(9212):1372, commentary can be found in Lancet 2000 Apr 29;355(9214):1551, Am Fam Physician 2000 Jun 15;61(12):3713 20-year cause-specific survival with inflammatory breast cancer increased from 9% of 134 patients 1975 to 1977 to 20% of 416 patients 1993 to 1995 (BMC Cancer 2005 Oct 22;5:137 full-text) o
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young age o young age at presentation (< 35 years old) associated with higher incidence of metastatic disease and higher mortality based on retrospective cohort of 1,320 consecutive patients with breast cancer Reference - BMC Cancer 2006 Jul 20;6:194 full-text o increased mortality in women < 40 years old compared to women aged 45-49 years at diagnosis of breast cancer among women not receiving adjuvant cytotoxic chemotherapy based on retrospective analysis of 10,356 women with primary breast cancer who were < 50 years old at diagnosis association of younger age and mortality not found for women who received adjuvant cytotoxic chemotherapy Reference - BMJ 2000 Feb 19;320(7233):474 full-text, editorial can be found in BMJ 2000 Feb 19;320(7233):457 (correction can be found in BMJ 2000 Apr 29;320(7243):1173), commentary can be found in BMJ 2000 Jul 1;321(7252):53 o higher risk of relapse and death in younger premenopausal women than older premenopausal women, especially if estrogen receptor-positive tumors based on pooled results of 4 randomized trials of adjuvant chemotherapy with 3,700 women, including 314 patients < 35 years old Reference - Lancet 2000 May 27;355(9218):1869, editorial can be found in Lancet 2000 May 27;355(9218):1839, commentary can be found in Lancet 2000 Sep 9;356(9233):944, Lancet 2000 Sep 23;356(9235):1113 o women < 40 years old have higher mortality than women aged 40-49 years among women with breast cancer cohort study of 1,701 women in India with nonmetastatic, noninflammatory breast carcinoma, median follow-up 66 months 62% overall survival, estimated 10-year overall survival was 52.6% estimated 10-year overall survival among 437 women aged < 40 years old 46.5% 62.3% if T1, 58.3% if T2, 36.6% if T3, 10.4% if T4 76.8% if node-negative, 24.2% if node-positive estimated 10-year overall survival among 557 women aged 40-49 years 59.8%
73.2% if T1, 66.3% if T2, 41.9% if T3, 33.5% if T4 73.9% if node-negative, 43.6% if node-positive estimated 10-year overall survival among 433 women aged 50-59 years 58.9% 55.9% if T1, 57.1% if T2, 46.4% if T3, 46.7% if T4 68.8% if node-negative, 41.6% if node-positive estimated 10-year overall survival among 274 women > 60 years old 48% 70% if T1, 55.5% if T2, 47.9% if T3, 18.1% if T4 64.4% if node-negative, 34.5% if node-positive Reference - World J Surg Oncol 2004 Jan 22;2:2 full-text o women < 40 years old at diagnosis appear to have higher mortality in early-stage disease compared to women ≥ 40 years old based on retrospective cohort of 243,012 women with breast cancer stratified by age (6.4% < 40 years old vs. 93.6% ≥ 40 years old) compared with older women, women < 40 years old at breast cancer diagnosis had (all p values < 0.05) higher breast cancer mortality (adjusted hazard ratio [HR] 1.39) higher breast cancer mortality with stage I diagnosis (adjusted HR 1.44) higher breast cancer mortality with stage II diagnosis (adjusted HR 1.09) lower mortality with stage IV diagnosis (adjusted HR 0.85) Reference - J Am Coll Surg 2009 Mar;208(3):341 older age o age ≥ 65 years at diagnosis associated with increased breast cancer mortality in women with hormone receptor-positive early breast cancer based on post hoc analysis of TEAM trial 9,766 postmenopausal women with hormone receptor-positive early breast cancer were stratified by age at diagnosis 10.7% mortality during median 5.1-year follow-up disease-specific mortality defined as time from randomization to breast cancer-related mortality after multivariate analysis age at diagnosis associated with increased risk of (vs. women < 65 years old) breast cancer mortality hazard ratio (HR) 1.25 (95% CI 1.01-1.54) in women aged 65-74 years HR 1.63 (95% CI 1.23-2.16) in women ≥ 75 years old other mortality HR 2.66 (95% CI 1.96-3.63) in women aged 65-74 years HR 7.3 (95% CI 5.29-10.07) in women ≥ 75 years old Reference - JAMA 2012 Feb 8;307(6):590 full-text o in women > 70 years old with early breast cancer treated with conservative surgery plus adjuvant tamoxifen, mortality from breast cancer reported in 17%
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based on cohort study 354 women ≥ 70 years old with primary, operable breast cancer and no palpable axillary lymph nodes were treated with conservative surgery and adjuvant tamoxifen conservative surgery consisted of breast-conserving surgery (quandrantectomy) without axillary dissection or postoperative radiation therapy median follow-up 15 years breast cancer mortality 17% crude cumulative incidence axillary disease in 4.2% ipsilateral breast tumor recurrence in 8.3% Reference - Cancer 2008 Feb 1;112(3):481 full-text
Race and ethnicity: • breast cancer mortality higher among black women than white women < 65 years old in
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United States o based on retrospective cohort study o 20,424 black women and 204,506 white women diagnosed with first primary breast cancer from 1988 to 2003 were analyzed o hazard ratios comparing black women vs. white women for breast cancer mortality 1.9 (95% CI 1.83-1.96) all-cause mortality 1.52 (95% CI 1.48-1.55) o black women had increased risk of breast cancer mortality for each stage 0-IV and unstaged cancer and for each age group < 40 years old, 40-49 years, 50-64 years o increased risk not found for black women ≥ 65 years old o Reference - J Surg Res 2009 May 1;153(1):105 British women of black race may have more aggressive tumors than British women of white race o based on retrospective cohort study o 445 women with invasive breast cancer presenting to 1 clinic in London 1994 to 2005 o comparing black women vs. white women presentation at younger age (median 46 years vs. 67 years) higher frequency of grade 3 tumors lymph node-positive disease negative estrogen receptor and progesterone receptor status basal-like (triple-negative status) tumors poorer survival with tumors ≤ 2 cm (hazard ratio [HR] 2.9, 95% CI 0.98-8.6, p = 0.05) o Reference - Br J Cancer 2008 Jan 29;98(2):277
Weight and body mass: • obesity associated with poorer survival in women with breast cancer o based on systematic review of observational studies
systematic review of 45 cohort studies evaluating survival in obese and nonobese women with breast cancer o sample size ranged from 100 to 424,168 (median 1,192) o obese women had poorer survival in analysis of 43 studies poorer overall survival hazard ratio (HR) 1.33 (95% CI 1.21-1.47) poorer breast cancer-specific survival HR 1.33 (95% CI 1.19-1.5) o no significant difference in risk between obese premenopausal and postmenopausal women o Reference - Breast Cancer Res Treat 2010 Oct;123(3):627, editorial can be found in Breast Cancer Res Treat 2010 Oct;123(3):637 body mass index (BMI) ≥ 30 kg/m 2 associated with increased all-cause mortality in study of 1,254 women aged 20-54 years with invasive breast cancer followed 8-10 years (Cancer Epidemiol Biomarkers Prev 2006 Oct;15(10):1871) elevated waist-to-hip ratio, based on 603 patients with breast cancer followed 4-10 years (Am J Epidemiol 2003 Nov 15;153(10):963) increased body weight and negative estrogen receptor each were associated with 2-fold higher risk of death from breast cancer in women with early-stage breast cancer, based on cohort of 1,376 women followed for median 6.8 years after diagnosis (Arch Surg 2004 Sep;139(9):954) obesity associated with reduced survival in women with hormone receptor-positive breast cancer treated with chemotherapy (level 2 [mid-level] evidence) o based on cohort analysis of data from 3 randomized trials o 4,770 women with hormone receptor-positive operable breast cancer from 1 randomized trial evaluating chemotherapy regimens were assessed 31% were normal or underweight (BMI < 25 kg/m 2) 32% were overweight (BMI 25-29.9 kg/m 2) 37% were obese (BMI ≥ 30 kg/m2) o compared to lower BMI categories, obesity associated with reduced survival in analysis of women with hormone receptor-positive disease (hazard ratio for death 1.37, 95% CI 1.13-1.67) o no significant association between obesity and survival in women with other disease subtypes o similar association between obesity and mortality found in 2 additional trials o Reference - Cancer 2012 Dec 1;118(23):5937 full-text overweight associated with increased risk of mortality and disease recurrence in premenopausal women having adjuvant anastrozole for hormone receptor-positive breast cancer o based on analysis of data from randomized trial o 1,803 premenopausal women with stage IB, IC, or II hormone receptor-positive breast cancer who were randomized to goserelin plus tamoxifen vs. goserelin plus anastrozole were stratified by BMI and followed for mean 5 years o comparing overweight vs. normal weight in women taking anastrozole, overweight associated with increased risk of mortality (hazard ratio [HR] 2.14, 95% CI 1.17-3.92) disease recurrence (HR 1.6, 95% CI 1.06-2.41) o
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anastrozole associated with increased mortality compared to tamoxifen (p = 0.004) in subgroup of overweight women o no significant differences in recurrence or mortality comparing overweight vs. normal weight in women taking tamoxifen o Reference - J Clin Oncol 2011 Jul 1;29(19):2653 obesity and overweight not associated with increased mortality risk in postmenopausal women with breast cancer who received adjuvant therapy with letrozole or tamoxifen o based on cohort analysis of data from BIG 1-98 randomized trial o 4,760 postmenopausal women with nonmetastatic hormone receptor-positive invasive breast cancer who received monotherapy with letrozole or tamoxifen for 5 years were followed for median 8.7 years o baseline BMI was ≥ 30 kg/m 2 in 23%, and 25-29 kg/m 2 in 36% o mortality rate 17% o mortality risk compared to BMI < 25 kg/m 2 (normal weight) nonsignificant increase associated with BMI ≥ 30 kg/m 2 (obesity) (hazard ratio 1.19, 95% CI 0.99-1.44) no significant difference compared to BMI 25 to < 30 kg/m 2 (overweight) o no significant difference in disease-free survival, breast cancer-free survival, or distant recurrence-free survival comparing obesity or overweight status to normal weight o Reference - J Clin Oncol 2012 Nov 10;30(32):3967 o
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Psychosocial factors: • conflicting data regarding association of psychosocial factors and survival in patients with
breast cancer o based on systematic review o systematic review of 37 studies of psychosocial factors and breast cancer in 61,611 female patients with breast cancer o 31 studies were descriptive studies and 6 studies evaluated psychologic intervention o factors with inconsistent findings across studies fighting spirit stressful events anxiety hopelessness/helplessness joy depression/negative mood perceived social support repressive defensiveness/emotional constraints adjustment fatalism/stoic appearance denial/avoidance anger/hostility expressive activities group participation in religious/nonreligious activities
somatization, obsessive-compulsive symptoms, paranoia, psychotic behavior, interpersonal sensitivity marriage o factors with no impact on survival or recurrence risk (and no evidence suggesting impact) coping in 4 studies beliefs about cancer incurability in 1 study locus of control in 5 studies vigor/activity in 2 studies fatigue/inertia in 1 study confusion/bewilderment in 1 study self-esteem in 2 studies o factors with positive impact on survival or recurrence risk (and no conflicting evidence) cognitive/role functioning in 1 study minimizing in 2 studies guilt in 1 study extroversion in 1 study hobbies in 1 study female child in 1 study o only factor with negative impact (and no conflicting evidence) was positive constructing daydreaming in 1 study o Reference - Breast Cancer Res 2007;9(4):R44 full-text psychosocial factors may not be associated with recurrence or survival in women with nonmetastatic breast cancer o based on population-based prospective cohort study o 708 women ≤ 60 years old with nonmetastatic breast cancer had depression, anxiety, coping style, and social support assessed at median 11 months after diagnosis and were followed for median 8.2 years o mortality was 24% and distant recurrence occurred in 33% during follow-up o no significant associations between any measured psychosocial factor and distant disease-free survival or overall survival o Reference - J Clin Oncol 2008 Oct 1;26(28):4666 low socioeconomic status o women living in communities with lowest socioeconomic status had increased mortality (level 2 [mid-level] evidence) based on retrospective cohort study 35,029 women ≥ 65 years old with stage I-IIIA breast cancer and up to 11 years of follow-up were analyzed increased risk for death associated with living in lowest socioeconomic communities (hazard ratio [HR] 1.1, 95% CI 1.04-1.16) compared to living in highest socioeconomic communities Reference - Am J Clin Oncol 2008 Apr;31(2):125 o low socioeconomic status associated with late-stage breast cancer at diagnosis, type of treatment received, and death
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based on study of 5,719 women with breast cancer race was not significantly associated with outcomes after adjustment for socioeconomic status Reference - J Natl Cancer Inst 2002 Apr 3;94(7):490
Comorbidities: • preexisting dementia associated with increased mortality in breast cancer o based on retrospective cohort of 31,935 women ≥ 65 years old with breast cancer o 7.4% had preexisting dementia diagnosis o comparing patients with vs. without dementia 1-year cancer-specific mortality 7.6% vs. 3.8% (p < 0.05) 1-year noncancer mortality 9% vs. 3% (p < 0.05) 5-year cancer-specific mortality 17.9% vs. 13.1% (p < 0.05) 5-year noncancer mortality 31.8% vs. 16.2% (p < 0.05) o Reference - Arch Intern Med 2008 Oct 13;168(18):2033, commentary can be found
in Arch Intern Med 2009 Mar 23;169(6):633 Delay in diagnosis: • delay in diagnosis associated with decreased survival but not after controlling for stage o systematic review of 87 observational studies of duration of symptoms and
survival in 101,954 patients delay in diagnosis of 3-6 months associated with decreased survival longer delay was not associated with shorter survival when effect of stage on survival was taken into account o Reference - Lancet 1999 Apr 3;353(9159):1119 delays by providers in diagnosis of ≥ 3 months do not appear to decrease survival o based on retrospective analysis of 36,222 patients with breast cancer o Reference - Lancet 1999 Apr 3;353(9159):1132, commentary can be found in Lancet 1999 Apr 3;353(9159):1112, Lancet 1999 Jun 19;353(9170):2154, Lancet 1999 Oct 23;354(9188):1478 length of delay not associated with prognostic factors or survival rates o based on 40 patients with delay in breast cancer diagnosis of 3-36 months o Reference - Am J Surg 2006 Oct;192(4):506, summary can be found in Am Fam Physician 2007 Jan 15;75(2):250 o o
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Smoking: • smoking associated with increased mortality in women with breast cancer o based on systematic review and cohort study o systematic review of 7 cohort studies examined association between smoking and
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breast cancer mortality in women with breast cancer compared to never smoking, smoking significantly associated with significant increased breast cancer mortality in 4 studies 2,265 women diagnosed with breast cancer were followed for median 12 years compared with never smoking, current smoking associated with increased risk of breast cancer mortality (hazard ratio 2.01, 95% CI 1.27-3.18) non-breast cancer mortality (hazard ratio 3.84, 95% CI 2.5-5.89)
no significant association between former smoking and breast cancer mortality Reference - Breast Cancer Res Treat 2012 Nov;136(2):521
o Additional factors affecting survival: • cosmetic breast augmentation prior to cancer detection associated with increased risk of
breast cancer-specific mortality (level 2 [mid-level] evidence) o based on systematic review of observational studies o systematic review of 29 observational studies with data to assess effects of cosmetic breast augmentation prior to cancer detection in women with breast cancer o comparing women with implants who had breast cancer to women without implants who had breast cancer, cosmetic breast implants associated with increased risk of breast cancer-specific mortality (hazard ratio 1.38, 95% CI 1.08-1.75) in analysis of 5 studies with > 18,000 women nonsignificant increase in risk of nonlocalized stage of breast cancer at diagnosis (p = 0.058) in analysis of 12 studies o Reference - BMJ 2013 Apr 29;346:f2399 full-text
Recurrence risk: Tumor size and lymph node status: • tumor size is strongest predictor of distant metastases and relapse rate in node-negative
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breast cancer o based on cohort of 826 women with node-negative breast cancer followed for mean 13.5 years o Reference - J Clin Oncol 1995 May;13(5):1144 larger tumor size correlated with lower breast cancer-specific survival, except in women with basal-like breast cancer (BLBC) o based on cohort study o 1,520 breast cancers (196 of which were BLBC) were evaluated o increasing tumor size associated with worsening breast cancer-specific survival in non-BLBC cases (p < 0.001) but not in BLBC cases (not significant) o Reference - Breast Cancer Res Treat 2009 Sep;117(1):199 number of positive lymph nodes and size of primary tumor were independent determinants of disease-free survival o study of 501 women with node-positive breast cancer treated by mastectomy alone, mean follow-up 10 years o in patients with < 4 positive nodes, tumor size was an indicator of prognosis o in breast cancer patients with T1 lesions and < 4 positive lymph nodes, long-term disease-free survival comparable to patients with node-negative breast cancer of same size o 15 patients with single positive lymph node and primary tumor size of < 11 mm had 100% long-term disease-free survival o Reference - J Clin Oncol 1996 Dec;14(12):3105 in QuickScan Reviews in Fam Pract 1997 Jul;22(4):17 metastatic lymph node ratio (MLNR) associated with breast cancer recurrence o based on retrospective cohort study
441 female patients (median age 59 years) with T1-2 N1-3 breast cancer included in Castellon (Spain) Cancer Registry o recurrence occurred in 26% o MLNR (number of metastatic lymph nodes over total number of resected lymph nodes) independently predicted risk of recurrence o Reference - World J Surg 2009 Aug;33(8):1659 primary breast cancer with ≥ 10 involved lymph nodes associated with increased risk of metachronous contralateral breast cancer o based on prospective cohort study o from a cohort of 42,670 women with breast cancer in Sweden from 1992 to 2008, 35,897 women with data available for initial tumor size and nodal status were assessed for risk factors for metachronous contralateral breast cancer o 2.5% developed metachronous contralateral breast cancer in median follow-up 9.9 years o increased risk of contralateral breast cancer associated with primary breast cancer with ≥ 10 involved lymph nodes compared to nodenegative breast cancer (adjusted hazard ratio 1.8, 95% CI 1.2-2.7) tumor of any size with extension to chest wall and/or skin compared to tumor < 2 cm (adjusted hazard ratio 2.2, 95% CI 1.3-3.6) o Reference - J Clin Oncol 2012 Oct 1;30(28):3478 o
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Risk for axillary recurrence: • 5-year incidence of isolated axillary recurrence 1% o based on 19,789 women with stage 0 to III breast cancer 1989 to 2003 o 220 had isolated axillary recurrence, with median survival 4.9 years after
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recurrence (range 2 months to 15 years) o Reference - Arch Surg 2006 Sep;141(9):867 isolated axillary node recurrence after negative sentinel lymph node biopsy (SLNB) is rare (< 1%) o based on systematic review of cohort studies o systematic review of 45 cohort studies evaluating reporting isolated axillary recurrence after negative SLNB in 23,357 patients with breast cancer followed for median 39 months o 127 (0.5%) patients had isolated axillary recurrence o Reference - Br J Surg 2011 Mar;98(3):326
Risk for late recurrence: • risk for late recurrence (after being disease-free for ≥ 5 years) is 7%-13% o based on retrospective cohort study o 2,838 patients with stage I-III breast cancer who were disease-free for ≥ 5 years o
after adjuvant or neoadjuvant systemic therapy were evaluated among 216 patients (8%) with late recurrence, 5-year residual risk for recurrence was 7% for stage I (95% CI 3%-15%) 11% for stage II (95% CI 9%-13%) 13% for stage III (95% CI 10%-17%)
o
late recurrence was associated with stage, grade, hormone receptor status, and endocrine therapy Reference - J Natl Cancer Inst 2008 Aug 20;100(16):1179
o Other risk factors for recurrence: • women < 35 years old with operable breast cancer have higher recurrence rate than older
women
based on retrospective study of 2,040 women who had surgery for primary invasive breast cancer o 256 (12.5%) were < 35 years old o age < 35 years predicted recurrence overall and in women with positive lymph nodes o Reference - BMC Cancer 2004 Nov 17;4:82 full-text women < 35 years old may have increased risk for occurrence of metachronous contralateral breast cancer o 45,229 women with operable stage I-IIIA breast cancer evaluated o median follow-up 5.8 years o 1,477 developed new cancer in contralateral breast (metachronous contralateral breast cancer) o standardized incidence ratios for metachronous contralateral breast cancers 11.4 for women < 35 years old (95% CI 8.6-14.8) 4.9 for women aged 35-39 years (95% CI 3.9-6.1) 2.4 for women aged 40-49 years (95% CI 2.1-2.7) 1.8 for women aged 50-59 years (95% CI 1.5-2) 1.5 for women aged 60-69 years (95% CI 1.3-1.8) 1.7 for women aged 70-79 years (95% CI 1.5-2) 1.2 for women ≥ 80 years old (95% CI 0.9-1.6) o Reference - Breast Cancer Res Treat 2008 Jul;110(1):189 anemia developing during chemotherapy may be associated with risk for local recurrence in premenopausal women with primary breast cancer (level 2 [mid-level] evidence) o based on retrospective cohort study o 424 premenopausal women with early-stage primary breast cancer and hormone receptor-expressing tumors had adjuvant cyclophosphamide/methotrexate/5fluorouracil (CMF) and were followed for median 5 years o patients with < 3 cycles of CMF or without serum hemoglobin levels at between cycles 3 and 6 of CMF were excluded o 18.2% developed anemia (hemoglobin < 12 g/dL) while on CMF therapy o local relapse occurred in 19.6% anemic vs. 8.9% nonanemic patients (p = 0.0006) o Reference - Clin Cancer Res 2008 Apr 1;14(7):2082 full-text o DynaMed commentary -- whether patients with and without anemia had similar chemotherapy durations was not reported; anemia as prognostic factor could be confounded by interruption or earlier termination of chemotherapy higher serum estrogen levels may be associated with increased risk for recurrence or new primary breast cancer o based on nested case-control study o
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Women's Healthy Eating and Living Study (WHEL) was randomized diet trial with breast cancer patients followed for mean 7.3 years o 153 peri- or postmenopausal women with recurrent or new primary early-stage breast cancer were matched to 153 recurrence-free controls from WHEL o risk of recurrence or new cancer increased with increasing baseline concentrations of total estradiol, bioavailable estradiol, and free estradiol o Reference - Cancer Epidemiol Biomarkers Prev 2008 Mar;17(3):614 PDF stressful life experiences do not increase recurrence risk o based on 5-year prospective study of 170 women < 60 years old newly diagnosed with operable breast cancer o Reference - BMJ 2002 Jun 15;324(7351):1420 full-text, commentary can be found in BMJ 2002 Sep 7;325(7363):548 o
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BRCA mutations: •
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BRCA1 and BRCA2 (breast cancer susceptibility genes) mutation carriers have similar prognosis (survival and distant recurrences) as patients with sporadic breast cancer o based on 2 cohort studies o prospective cohort study of 3,220 women (mean age 45.3 years) with incident breast cancer in Canada, United States, and Australia 1995 to 2000 mean follow-up 7.9 years 93 women had BRCA1 mutations, 71 had BRCA2 mutations, 1 had both mutations 1,550 had sporadic breast cancer 1,505 had familial breast cancer (without known BRCA1 or BRCA2 mutations) no significant differences in mortality or distant recurrence in multivariate analyses comparing carriers of BRCA1 or BRCA2 mutations and patients with sporadic breast cancer BRCA2 carriers had higher mortality and risk for distant recurrence in univariate analysis but no significant difference after adjusting for age, tumor stage and grade, nodal status, hormonal receptors, and year of diagnosis Reference - J Clin Oncol 2012 Jan 1;30(1):19, editorial can be found in J Clin Oncol 2012 Jan 1;30(1):2 o breast cancer-specific mortality not significantly different in carriers of BRCA1 and BRCA2 mutations in medical record review of 1,545 women with breast cancer (N Engl J Med 2007 Jul 12;357(2):115 full-text), editorial can be found in N Engl J Med 2007 Jul 12;357(2):175, commentary can be found in N Engl J Med 2007 Oct 11;357(15):1555 BRCA mutation carriers have similar rates of recurrence after breast-conserving surgery and radiation therapy compared to nonmutation carriers o based on retrospective cohort study o 131 patients (median age 43 years) with family history of breast and/or ovarian cancer treated with breast-conserving surgery and radiation therapy screened for BRCA1 and BRCA2 gene mutations and 261 women with breast cancer and without family history of breast cancer were evaluated
o o o o
median follow-up 8.75 years BRCA1/2 mutations found in 20.6% with family history decreasing age associated with breast cancer recurrence (p < 0.05) no significant differences in breast cancer recurrence as first event Comparing Recurrence by Tumor Type: Women with BRCA Mutations
Women with Family History but No Mutations
Women without Family History
Median time to breast 80 months cancer recurrence
39 months
46 months
Breast cancer recurrence
24%
22%
19%
Contralateral breast cancer
37%
18.3%*
7.3%*
Abbreviation: BRCA, breast cancer susceptibility gene. * p < 0.001 vs. BRCA mutations. o
Reference - Eur J Cancer 2005 Oct;41(15):2304
Pregnancy-associated breast cancer: •
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recent pregnancy (within 2 years of diagnosis) may be a negative prognostic factor o based on 2 cohort studies o cohort study of women in Nova Scotia giving birth 1980 to 2001 among 123,323 women giving birth, 716 were diagnosed with invasive breast cancer women with < 2 years between childbirth and diagnosis of breast cancer had significantly increased risk for having later-stage disease and poorer survival than women with interval ≥ 5 years Reference - Obstet Gynecol 2008 May;111(5):1167 o retrospective study of 5,652 women < 46 years old at time of diagnosis of primary breast cancer women diagnosed within 2 years after last childbirth had 58.7% 5-year survival and 46.1% 10-year survival women whose last childbirth was > 2 years before diagnosis had 78.4% 5year survival and 66% 10-year survival Reference - BMJ 1997 Oct 4;315(7112):851 full-text pregnancy-associated breast cancer (PABC) may be associated with poorer prognosis o based on case-control study o 797 women with PABC compared to 4,177 age-matched controls with breast cancer
PABC defined as occurring within 9 months before to 1 year after delivery comparing PABC cases vs. controls mortality 39.2% vs. 33.4% (p = 0.002) pregnancy-associated cases presented with more advanced disease, larger tumors and increased percentage of hormone receptor-negative tumors o other associations with increased mortality advanced stage race (African American patients > non-Hispanic white patients) hormone receptor-negative tumors pregnancy o Reference - Obstet Gynecol 2008 Jul;112(1):71 women < 35 years old with PABC may have prognosis similar to other young women with breast cancer o based on retrospective cohort study o 652 women ≤ 35 years old with breast cancer evaluated (104 breast cancers were pregnancy-associated) o median follow-up for living patients 114 months o comparing patients with PABC vs. non-PABC overall survival 64.6% vs. 64.8% (not significant) 10-year locoregional recurrence rate 23.4% vs. 19.2% (not significant) distant metastases in 45.1% vs. 38.9% (not significant) o PABC had significantly more advanced T classification, N classification, and stage group (p < 0.04) o Reference - Cancer 2009 Mar 15;115(6):1174 full-text diagnosis during lactation associated with increased risk of cause-specific death o based on cohort of 42,511 women aged 16-49 years, diagnosed with cancer from 1967 to 2002 o cohort classified as not pregnant, pregnant, or lactating at time of cancer diagnosis o increased risk of cause-specific death if lactating at time of diagnosis of ovarian cancer (hazard ratio [HR] 1.95, p < 0.05) o Reference - J Clin Oncol 2009 Jan 1;27(1):45 o o
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Pregnancy after breast cancer: pregnancy after breast cancer does not appear to increase risk for mortality o based on systematic review o systematic review of 7 case-control studies and 7 cohort studies evaluating effect of pregnancy on overall survival of women with history of breast cancer o meta-analysis included 1,244 women who got pregnant and 18,145 women with no pregnancy after history of breast cancer o pregnancy following breast cancer diagnosis associated with reduced risk of death (relative risk [RR] 0.59, 90% CI 0.5-0.7) o no significant association in subgroup analysis in women known to be free of relapse (RR 0.85, 95% CI 0.53-1.35) o Reference - Eur J Cancer 2011 Jan;47(1):74 Prevention and Screening •
Prevention: Lifestyle changes: Recommendations: • American Cancer Society (ACS) recommendations for lifestyle factors which may reduce
risk for breast cancer o engage in regular physical activity o minimize weight gain through caloric restriction (including diet rich in vegetables and fruit) o avoid or limit alcohol use o Reference - ACS 2012 guideline on nutrition and physical activity for cancer prevention (CA Cancer J Clin 2012 Jan-Feb;62(1):30 full-text)
Physical activity: • physical activity may reduce risk of breast cancer in postmenopausal women (level 2 [mid-
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level] evidence) o based on multiple cohort studies o moderate physical activity associated with reduced risk of breast cancer in postmenopausal women (level 2 [mid-level] evidence) based on cohort of 95,396 postmenopausal women from Nurses' Health Study 4,728 incident cases of invasive breast cancer in 20 years follow-up physical activity equivalent to brisk walking 1 hour/day associated with reduced risk of breast cancer compared to physical activity < 1 hour/week (hazard ratio [HR] 0.85, 95% CI 0.78-0.93) among women with exercise equivalent to average-pace walking for 30 minutes/day at time of menopause, women who increase physical activity had reduced breast cancer risk compared to women who did not increase activity (HR 0.9, 95% CI 0.82-0.91) Reference - Arch Intern Med 2010 Oct 25;170(19):1758 full-text, commentary can be found in Arch Intern Med 2010 Nov 8;170(20):1792 o other cohort studies finding association of physical activity and reduced risk for breast cancer 74,171 women aged 50-79 years followed mean 4.7 years, of whom 1,780 developed breast cancer (JAMA 2003 Sep 10;290(10):1331 full-text), editorial can be found in JAMA 2003 Sep 10;290(10):1377, commentary can be found in JAMA 2003 Dec 24;290(24):3193, CMAJ 2004 Mar 2;170(5):787, Clin J Sport Med 2005 Mar;15(2):115 41,836 postmenopausal women followed for up to 18 years (mean 13.3 years), of whom 2,548 developed breast cancer (Arch Intern Med 2006 Dec 11;166(22):2478 full-text), commentary can be found in Arch Intern Med 2007 Aug 13-27;167(15):1690 strenuous long-term exercise associated with reduced risk for breast cancer (level 2 [midlevel] evidence) o based on prospective cohort study of 110,599 women aged 20-79 years followed for 7 years o 2,649 developed invasive breast cancer and 593 developed in situ breast cancer o Reference - Arch Intern Med 2007 Feb 26;167(4):408 full-text
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total leisure-time physical activity associated with reduced risk for premenopausal breast cancer (level 2 [mid-level] evidence) o based on prospective cohort study o 64,777 premenopausal women in Nurses' Health Study II reported leisure-time physical activity from age 12 years to time of questionnaire and were followed for 6 years o 550 women developed premenopausal breast cancer o women with mean total activity ≥ 39 metabolic equivalent hours per week (equivalent to 3.25 hours per week of running or 13 hours per week of walking) during lifetime had reduced risk of premenopausal breast cancer (relative risk [RR] 0.77, 95% CI 0.64-0.93) compared to women reporting less activity o age-adjusted incidence rate of breast cancer per 100,000 person-years 136 for mean ≥ 54 metabolic equivalent per hours per week over lifetime 194 for mean < 21 metabolic equivalent per hours per week over lifetime o Reference - J Natl Cancer Inst 2008 May 21;100(10):728 full-text
Diet: Low-fat diet: • reduction of dietary fat intake to < 20% of calories may be associated with slight reduction
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in incidence of breast cancer in postmenopausal women (level 2 [mid-level] evidence), but dietary targets not achieved by most women o based on randomized trial with inadequate statistical power o 48,835 postmenopausal women aged 50-79 years without prior breast cancer were randomized to dietary modification vs. control o dietary intervention designed with goals of reducing intake of total fat to 20% of calories and increasing consumption of fruits and vegetables to at least 5 servings daily and grains to at least 6 servings daily o mean follow-up 8.1 years o comparing dietary modification vs. control mean estimated total fat consumption as percentage of calories was 24.3% vs. 35.1% at year 1 mean estimated total fat consumption as percentage of calories was 28.8% vs. 37% at year 6 nonsignificant reduction in annualized incidence of invasive breast cancer (0.42% vs. 0.45%, p = 0.07) cumulative incidence 3.35% vs. 3.66% (NNT 323, 95% CI no difference to NNT 155) o subgroup analyses found significant risk reduction with intervention for adherent women and for women with high-fat diet (> 36.8%) at baseline o Reference - JAMA 2006 Feb 8;295(6):629 full-text, editorial can be found in JAMA 2006 Feb 8;295(6):691, commentary can be found in JAMA 2006 Jul 19;296(3):278, ACP J Club 2006 Jul-Aug;145(1):6, Evid Based Nurs 2006 Oct;9(4):112 lower fat intake may not be associated with decreased risk of cancer in women with higher risk for breast cancer (level 2 [mid-level] evidence) o based on randomized trial with low adherence rate
4,690 women with extensive mammographic density randomized to intensive dietary counseling (goal fat 15% of calories, carbohydrates 65% of calories) vs. control for mean 10 years o 32% with intervention had fat intake > 25% of calories at 8-10 years o no significant difference in invasive breast cancer or total breast cancer incidence o Reference - Cancer Res 2011 Jan 1;71(1):123 full-text low-fat diet does not appear to reduce risk for breast cancer (level 2 [mid-level] evidence) o based on observational studies o Reference - J Fam Pract 2007 Jul;56(7):583 o
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Phytoestrogens: • meta-analysis concluded that soy intake may be associated with small reduction in breast
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cancer risk (level 2 [mid-level] evidence) o meta-analysis combined 12 case-control studies, 2 nested case-control studies, and 4 cohort studies o only 1 of 4 cohort studies (studies with lesser likelihood of bias) and neither of 2 nested case-control studies suggested inverse association between soy intake and breast cancer risk o Reference - J Natl Cancer Inst 2006 Apr 5;98(7):459 full-text, editorial can be found in J Natl Cancer Inst 2006 Apr 5;98(7):430 higher soy intake may be associated with reduced risk for breast cancer in postmenopausal women (level 2 [mid-level] evidence) o based on prospective cohort study of 35,303 Chinese women in Singapore followed for ≥ 7 years o 629 women developed breast cancer o risk for breast cancer was reduced for women with soy intake > 10.6 mg isoflavone per 1,000 kcal compared to women with intake < 10.6 mg (relative risk [RR] 0.82, 95% CI 0.7-0.97) o postmenopausal women had highest risk reduction (RR 0.74, 95% CI 0.61-0.9), reduction not observed for premenopausal women o Reference - Br J Cancer 2008 Jul 8;99(1):196 full-text reduced risk associated with soy intake may differ by receptor status (level 2 [mid-level] evidence) o based on case-control study o 678 women with breast cancer matched to 3,390 controls without breast cancer o reduced risk for breast cancer was associated with soy intake in top tertile for estrogen receptor-positive cancers (odds ratio [OR] 0.74, 95% CI 0.580.94) human epidermal growth factor receptor 2 (HER2)-negative cancers (OR 0.78, 95% CI 0.61-0.99) estrogen receptor-positive/progesterone receptor-positive/HER2 cancers (OR 0.73, 95% CI 0.54-0.97) when all receptors jointly examined o Reference - Int J Cancer 2008 Oct 1;123(7):1674 high dietary intake of isoflavones and mammalian lignans NOT associated with breast cancer risk in Dutch cohort of 15,555 women aged 49-70 years (Am J Clin Nutr 2004
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Feb;79(2):282 full-text), editorial can be found in Am J Clin Nutr 2004 Feb;79(2):183, commentary can be found in Am J Clin Nutr 2004 Aug;80(2):528 tofu or isoflavone intake associated with lower risk of breast cancer in premenopausal but not postmenopausal Japanese women in case-control study with 167 cases and 854 controls (Br J Cancer 2005 Jul 11;93(1):15 full-text) high dietary intake of phytoestrogens associated with reduced risk of breast cancer in case-control study with 144 pairs (Lancet 1997 Oct 4;350(9083):990 in Altern Ther Health Med 1998 Jan;4(1):97), editorial can be found in Lancet 1997 Oct 4;350(9083):971, commentary can be found in Lancet 1998 Jan 10;351(9096):137; phytoestrogens found mainly in soy products and other legumes (Nutr Cancer 1996;26(2):123)
Vitamins and minerals: • calcium and vitamin D intake have inconsistent evidence for effect on breast cancer risk
(level 2 [mid-level] evidence) o based on systematic review and randomized trial o higher calcium and vitamin D intake associated with lower risk of breast cancer (level 2 [mid-level] evidence) based on systematic review of observational studies systematic review of observational studies evaluating vitamin D intake, calcium intake, circulating 25(OH)D levels and/or 1-alpha,25(OH) 2D levels factors associated with reduced risk of breast cancer highest vitamin D intake (compared to lowest intake) (relative risk [RR] 0.91, 95% CI 0.85-1) using random-effects model (results significant using fixed-effects model) in analysis of 11 studies highest calcium intake (compared with lowest intake) (RR 0.81, 95% CI 0.72-0.9) in analysis of 15 studies; association became borderline significant after adjusting for publication bias highest levels of circulating 25(OD)D (compared with lowest levels) (odds ratio [OR] 0.55, 95% CI 0.38-0.8) in analysis of 7 studies no significant relationship between circulating 1-alpha,23(OH) 2D and risk of breast cancer in analysis of 4 studies Reference - Breast Cancer Res Treat 2010 Jun;121(2):469 o calcium plus vitamin D does not appear to prevent breast cancer (level 2 [midlevel] evidence) based on randomized trial with multiple limitations 36,282 postmenopausal women randomized to calcium carbonate (elemental calcium 500 mg) plus vitamin D3 200 units vs. placebo orally twice daily for mean 7 years no significant difference in incidence of invasive breast cancer (3.1% vs. 3.2%, hazard ratio [HR] 0.96, 95% CI 0.85-1.09) Reference - J Natl Cancer Inst 2008 Nov 19;100(22):1581 full-text, editorial can be found in J Natl Cancer Inst 2008 Nov 19;100(22):1562, commentary can be found in J Natl Cancer Inst 2009 May 6;101(9):690 DynaMed commentary -- multiple factors limit ability of this study to find significant differences, potentially invalidating finding of no effect
baseline calcium intakes close to 1,200 mg/day are higher than most population studies only 59% intervention group were taking intended doses of supplements at end of study personal use of any calcium supplementation reported by 54% participants at study baseline and 69% participants at 9 years with mean dose 325-425 mg/day (N Engl J Med 2006 Feb 16;354(7):684 full-text), editorial can be found in N Engl J Med 2006 Feb 16;354(7):752 (correction can be found in N Engl J Med 2006 Mar 9;354(10):1102), commentary can be found in N Engl J Med 2006 May 25;354(21):2287, ACP J Club 2006 JulAug;145(1):4, Evid Based Nurs 2006 Oct;9(4):114 combined folic acid, vitamin B6, and vitamin B12 not associated with risk of total invasive cancer, breast cancer, or cancer mortality in women at high risk for cardiovascular disease (level 2 [mid-level] evidence) o based on randomized trial with allocation concealment not stated o 5,442 female health professionals ≥ 42 years old with ≥ 3 coronary risk factors were randomized to combination folic acid 2.5 mg, vitamin B6 50 mg, and vitamin B12 one mg vs. placebo daily for 7.3 years o no significant differences in rates of total invasive cancer, breast cancer, or death from cancer o Reference - Women's Antioxidant and Folic Acid Cardiovascular Study (JAMA 2008 Nov 5;300(17):2012 full-text), commentary can be found in Ann Intern Med 2009 Mar 17;150(6):JC3 high folate and vitamin B6 intake associated with lower risk of breast cancer in nested case-control study (712 pairs) from Nurses' Health Study (J Natl Cancer Inst 2003 Mar 5;95(5):373 full-text in Prescriber's Letter 2003 May;10(5):28), commentary can be found in J Natl Cancer Inst 2003 Jul 16;95(14):1091 vitamin A has inconsistent evidence o vitamin A intake or supplementation associated with reduced risk of breast cancer in prospective cohort study (N Engl J Med 1993 Jul 22;329(4):234 full-text), commentary can be found in N Engl J Med 1993 Nov 18;329(21):1579 o fenretinide (a form of vitamin A) did not prevent recurrent breast cancer in 5-year trial although possible benefit reported in premenopausal subgroup (J Natl Cancer Inst 1999 Nov 3;91(21):1847 full-text) (JAMA 2005 Jul 13;294(2):218 full-text), commentary can be found in JAMA 2005 Dec 7;294(21):2695
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Green tea: • FDA concludes that it is highly unlikely that green tea reduces risk of breast cancer; 2
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studies did not show risk reduction, while 1 weaker and more limited study suggested green tea may reduce breast cancer risk (FDA Press Release 2005 Jun 30) higher green tea consumption, but not black tea consumption, associated with lower risk of breast cancer in case-control study with 501 cases and 594 controls (Int J Cancer 2003 Sep 10;106(4):574) review of chemoprevention benefits of green tea can be found in Prev Med 2009 Aug;49(2-3):83
Other dietary considerations:
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omega-3 fatty acid intake not clearly associated with cancer incidence (level 2 [mid-level] evidence) o systematic review of 38 articles describing 20 prospective cohorts for 11 different types of cancer 65 estimates of association between omega-3 fatty acid consumption and cancer were reported, data not pooled due to heterogeneity for breast cancer, 1 estimate was for increased risk, 3 estimates were for decreased risk, and 7 estimates did not find significant association Reference - JAMA 2006 Jan 25;295(4):403 full-text, correction can be found in JAMA 2006 Apr 26;295(16):1900, commentary can be found in JAMA 2006 Jul 19;296(3):282 o high levels of dietary n-3 fatty acids from fish or shellfish associated with reduced risk of breast cancer in cohort study of 35,298 Singapore Chinese women aged 4574 years followed 2-7 years (Br J Cancer 2003 Nov 3;89(9):1686 full-text) high fiber and low-fat diet associated with reduced risk of breast cancer (level 2 [midlevel] evidence) o based on cohort of 11,726 postmenopausal women o Reference - Br J Cancer 2004 Jan 26;90(1):122 full-text increased consumption of onions and garlic may be associated with reduced incidence of numerous types of cancer (level 2 [mid-level] evidence) o based on integrated network of Italian and Swiss case-control studies o Reference - Am J Clin Nutr 2006 Nov;84(5):1027 full-text neither tomato nor lycopene intake found to reduce risk of breast cancer o based on FDA review for premarket approval of qualified health claim o Reference - J Natl Cancer Inst 2007 Jul 18;99(14):1074 full-text, editorial can be found in J Natl Cancer Inst 2007 Jul 18;99(14):1060
Limiting alcohol intake: • increased alcohol intake may be risk factor for breast cancer (level 2 [mid-level] evidence) o based on meta-analysis of > 50 epidemiological studies o 25% increased risk of breast cancer with 2 drinks/day and dose-response
relationship Reference - Cancer 1994 Aug 1;74(3 Suppl):1101 moderate alcohol consumption (≥ 30 g/day) associated with increased risk for breast cancer (level 2 [mid-level] evidence) o based on 38,454 women in Women's Health Study followed for mean 10 years o Reference - Am J Epidemiol 2007 Mar 15;165(6):667 full-text o
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Chemoprevention: • United States Preventive Services Task Force (USPSTF) recommendations on
chemoprevention of breast cancer o tamoxifen or raloxifene NOT recommended for women at LOW or AVERAGE risk of breast cancer (USPSTF Grade D) o discussion of benefits and risks recommended for women at HIGH risk of breast cancer and at low risk for adverse effects of chemoprevention (USPSTF Grade B) o Breast Cancer Risk Assessment Tool can be used to determine breast cancer risk
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tamoxifen and raloxifene each reduce risk of invasive breast cancer but increase risk of venous thromboembolism (level 1 [likely reliable] evidence) o tamoxifen 20 mg once daily for 5 years in high-risk women reduces risk of invasive breast cancer (NNT 77) but increases risks for endometrial cancer (NNH 322), pulmonary embolism (NNH 500), bothersome hot flashes (NNH 6), bothersome vaginal discharge (NNH 11), cataracts (NNH 77), and possibly stroke o raloxifene 60 mg once daily for 3-4 years reduces risk of breast cancer (NNT 126) but increases risks for venous thromboembolic disease (NNH 143), hot flashes (NNH 25), and leg cramps (NNH 33) o tamoxifen and raloxifene have similar efficacy for reducing risk for invasive breast cancer (level 1 [likely reliable] evidence) exemestane 25 mg once daily may reduce risk of invasive breast cancer in postmenopausal women at risk for breast cancer (level 2 [mid-level] evidence) see Chemoprevention of breast cancer for details review of tamoxifen, raloxifene, and surgery as methods to reduce risk of breast cancer can be found in N Engl J Med 2000 Jul 20;343(3):191
Nonsteroidal anti-inflammatory drugs (NSAIDs) including aspirin: • NSAID use may be associated with reduced risk for breast cancer (level 2 [mid-level]
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evidence) o based on systematic review and meta-analysis of 38 studies (18 cohort, 19 casecontrol, 1 clinical trial) evaluating NSAID use and breast cancer risk in 2,788,715 participants o NSAID use associated with reduced risk for breast cancer overall (relative risk [RR] 0.88, 95% CI 0.84-0.93) o aspirin use associated with reduced risk for breast cancer (RR 0.87, 95% CI 0.820.92) o ibuprofen use associated with reduced risk (RR 0.79, 95% CI 0.64-0.97) o Reference - J Natl Cancer Inst 2008 Oct 15;100(20):1439 full-text, editorial can be found in J Natl Cancer Inst 2008 Oct 15;100(20):1420 not all studies consistently find reduced risk with NSAID use o neither NSAID nor acetaminophen use associated with reduced risk of breast cancer in premenopausal women (level 2 [mid-level] evidence) based on prospective cohort study 112,292 premenopausal women in Nurses' Health Study II aged 25-42 years at baseline were followed for 14 years 1,345 incident cases of premenopausal breast cancer no significant associations between breast cancer risk and aspirin use nonaspirin NSAID use acetaminophen use associations did not vary with duration or frequency of use or dosage Reference - Arch Intern Med 2009 Jan 26;169(2):115 full-text, editorial can be found in Arch Intern Med 2009 Jan 26;169(2):121 PDF
NSAID use not associated with risk for breast cancer, except daily aspirin use may be associated with reduced risk for estrogen receptor-positive breast cancer (level 2 [mid-level] evidence) based on cohort of 127,383 women aged 51-72 years followed for up to 7 years Reference - Breast Cancer Res 2008 Apr 30;10(2):R38 full-text frequent use of aspirin > 100 mg/day, nonselective NSAIDs, or cyclooxygenase (COX)-2 inhibitors associated with reduced risk of breast cancer in case-control study with 1,090 cases and 44,990 controls (BMC Cancer 2005 Dec 12;5:159 full-text) aspirin 100 mg every other day in women does not prevent cancer (level 1 [likely reliable] evidence) o based on randomized trial o 39,876 healthy women > 45 years old who completed 3-month placebo run-in period were randomized to aspirin 100 mg vs. placebo orally every other day (and also randomized to vitamin E 600 units vs. placebo orally every other day) for mean 10 years (range 8 to 11 years) o no significant differences in incidence of any cancer excluding nonmelanoma skin cancer (7.2% vs. 7.2%), any cancer death (1.4% vs. 1.5%), breast cancer (3.05% vs. 3.12%), colon cancer (0.52% vs. 0.56%), rectal cancer (0.15% vs. 0.13%), lung cancer (0.45% vs. 0.58%, p = 0.08), or leukemia (0.19% vs. 0.12%, p = 0.1) o Reference - JAMA 2005 Jul 6;294(1):47 full-text, editorial can be found in JAMA 2005 Jul 6;294(1):105, commentary can be found in Am Fam Physician 2005 Nov 15;72(10):2087, JAMA 2005 Nov 16;294(19):2432, Evid Based Med 2006 Feb;11(1):10, ACP J Club 2006 Jan-Feb;144(1):8 o vitamin E 600 units every other day did not prevent cancer either (JAMA 2005 Jul 6;294(1):56 full-text), editorial can be found in JAMA 2005 Jul 6;294(1):105, commentary can be found in J Fam Pract 2005 Oct;54(10):838, JAMA 2005 Nov 16;294(19):2432, ACP J Club 2006 Jan-Feb;144(1):8, Evid Based Med 2006 Feb;11(1):11 o
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Prophylactic mastectomy: • bilateral prophylactic mastectomy may reduce breast cancer incidence and breast cancer
mortality in women at risk for breast cancer (level 2 [mid-level] evidence) o based on Cochrane review of observational studies o systematic review of 39 cohort studies, convenience samples, or case series evaluating prophylactic mastectomy in 7,384 women at risk of breast cancer in at least 1 breast o 20 studies included only women choosing bilateral prophylactic mastectomy o bilateral mastectomy associated with reduced incidence of breast cancer in individual trials, particularly in women with breast cancer susceptibility gene 1/2 (BRCA) mutations breast cancer mortality in individual trials level of emotional concern about developing breast cancer in 1 trial o inconsistent evidence for effect of contralateral prophylactic mastectomy on breast cancer mortality, but limited evidence suggests it may reduce breast cancer incidence o Reference - Cochrane Database Syst Rev 2010 Nov 10;(11):CD002748
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contralateral prophylactic mastectomy associated with reduced breast cancer mortality in women < 50 years old with early-stage estrogen receptor-negative breast cancer (level 2 [mid-level] evidence) o based on observational study o analysis of Surveillance, Epidemiology, and End Results (SEER) database including 107,106 women with breast cancer who had mastectomy, including 8,902 who had contralateral prophylactic mastectomy o 5-year adjusted breast cancer survival was higher with vs. without contralateral prophylactic mastectomy (88.5% vs. 83.7%) o significant reduction in breast cancer-specific mortality occurred in women aged 18-49 years with stages II-III estrogen receptor-negative breast cancer o Reference - J Natl Cancer Inst 2010 Mar 17;102(6):401 full-text case report of primary invasive breast cancer after prophylactic bilateral subcutaneous mastectomy can be found in World J Surg Oncol 2005 Aug 4;3:52 full-text
Other prevention strategies: • bisphosphonates may reduce risk of breast cancer in women (level 2 [mid-level] evidence) o based on systematic review limited by clinical heterogeneity o systematic review of 4 observational studies (2 cohort and 2 case-control studies)
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comparing users of bisphosphonates to non-users for prevention of breast cancer in 507,369 women breast cancer in 15,363 women bisphosphonate use in 84,931 women o analyses limited by variation in type of bisphosphonates used and unclear dosing and frequency of use o use of bisphosphonates associated with reduced risk of breast cancer overall (risk ratio 0.85, 95% CI 0.74-0.98) in analysis of 4 studies, results limited by significant heterogeneity in subgroup analysis of women with invasive breast cancer (risk ratio 0.68, 95% CI 0.59-0.8) o longer duration of bisphosphonate use associated with greater reduction in breast cancer risk o Reference - Clin Breast Cancer 2012 Aug;12(4):276 longer duration of breastfeeding associated with reduced risk for breast cancer (level 2 [mid-level] evidence) o based on meta-analysis of 47 studies comparing 50,302 women with breast cancer and 96,973 controls o Reference - Lancet 2002 Jul 20;360(9328):187, commentary can be found in Lancet 2003 Jan 11;361(9352):176, Evidence-Based Medicine 2003 MarApr;8(2):63 see also BRCA mutation testing and management
Screening: •
mammography for breast cancer screening o effect of mammography screening on mortality may reduce breast cancer mortality in women aged 39-69 years (level 2 [mid-level] evidence)
not associated with decreased overall mortality (level 2 [mid-level] evidence) o for women aged 40-49 years, conflicting recommendations regarding mammography screening United States Preventive Services Task Force (USPSTF) recommends against routine screening for breast cancer for women aged 40-49 years but instead suggests individualized decision-making (USPSTF Grade C) annual mammography starting at age 40 years recommended by American Cancer Society (ACS), American College of Obstetricians and Gynecologists (ACOG), and American College of Radiology/Society of Breast Imaging (ACR/SBI) Canadian Task Force on Preventive Health Care (CTFPHC) recommends against routine screening for breast cancer in women aged 40-49 years o for women aged 50-74 years screening mammography recommended every 2 years by USPSTF (USPSTF Grade B) screening recommended annually by ACS, ACOG, and ACR/SBI screening mammography recommended every 2-3 years by CTFPHC o for women ≥ 75 years old USPSTF, ACR/SBI, and CTFPHC make no recommendation (USPSTF Grade I) while ACS and ACOG continue to recommend screening mammography annually regular mammography screening among women ≥ 80 years old associated with earlier disease stage at diagnosis and lower breast cancer mortality (level 2 [mid-level] evidence) o breast cancer may be overdiagnosed (breast cancer that will not cause death or symptoms in patient's lifetime) with mammography screening, but rate of overdiagnosis unclear o screening by mammography associated with high rate of false positives o screening mammography less sensitive if hormonal replacement therapy (HRT) or history of breast surgery o screening mammography less specific (higher false-positive rate) if HRT or high body mass index clinical breast exam reported to be effective (level 3 [lacking direct] evidence) based on extrapolation from indirect evidence o ACS and ACOG recommend clinical breast exam every 1-3 years for women aged 20-39 years and annually beginning at age 40 years, but USPSTF makes no recommendation (USPSTF Grade I) o screening by clinical breast exam or mammography associated with high rate of false positives; unclear if false-positive mammograms have long-term effects breast self-exam screening has no clear benefit and possible harm (level 2 [mid-level] evidence) o USPSTF recommends against teaching breast self-examination (USPSTF Grade D) o breast self-exam considered an option by ACS and (for high-risk women) by ACOG additional imaging studies for breast cancer screening
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annual magnetic resonance imaging (MRI) screening recommended by ACS and ACR/SBI as adjunct to mammography if BRCA (breast cancer susceptibility gene) mutation or lifetime risk ≥ 20% MRI more sensitive than either mammography, ultrasound, or clinical breast exam for breast cancer screening (level 3 [lacking direct] evidence) but also increases false positives (level 2 [mid-level] evidence) o addition of ultrasound to mammography in high-risk women with dense breasts increases sensitivity of breast cancer screening (level 3 [lacking direct] evidence) but also increases false positives (level 1 [likely reliable] evidence) • genetic counseling and evaluation for breast cancer susceptibility gene (BRCA) testing recommended if family history associated with increased risk for BRCA1 or BRCA2 mutations (USPSTF Grade B) • most active recruitment approaches increase use of breast cancer screening o tailored interventions may modestly increase mammography rates (level 2 [midlevel] evidence) o individualized risk communication associated with increased uptake of screening mammography (level 2 [mid-level] evidence) • see Breast cancer screening for details Quality Improvement o
Physician Quality Reporting System Quality Measures: •
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71. Breast Cancer: Hormonal Therapy for Stage IC-IIIC, Estrogen Receptor/Progesterone Receptor (ER/PR) Positive Breast Cancer o Percentage of female breast cancer patients ≥ 18 years old with stage IC-IIIC, ER or PR positive breast cancer who were prescribed tamoxifen or aromatase inhibitor (AI) during the 12-month reporting period 99. Breast Cancer Resection Pathology Reporting: pT Category (Primary Tumor) and pN Category (Regional Lymph Nodes) with Histologic Grade o Percentage of breast cancer resection pathology reports that include the pT category (primary tumor), the pN category (regional lymph nodes), and the histologic grade 194. Oncology: Cancer Stage Documented o Percentage of patients, regardless of age, with a diagnosis of cancer who are seen in the ambulatory setting who have a baseline American Joint Committee on Cancer (AJCC) cancer stage or documentation that the cancer is metastatic in the medical record at least once within 12 months 251. Immunohistochemical (IHC) Evaluation of Human Epidermal Growth Factor Receptor 2 Testing (HER2) for Breast Cancer Patients o measure based on whether quantitative evaluation of Human Epidermal Growth Factor Receptor 2 (HER2) by Immunohistochemistry (IHC) uses the system recommended in the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines for HER2 testing in breast cancer 262. Image Confirmation of Successful Excision of Image–Localized Breast Lesion o Image confirmation of lesion(s) targeted for image-guided excisional biopsy or image-guided partial mastectomy in patients with nonpalpable, image-detected breast lesion(s)
lesions may include: microcalcifications mammographic or sonographic mass or architectural distortion focal suspicious abnormalities on magnetic resonance imaging (MRI) or other breast imaging amenable to localization such as positron emission tomography (PET) mammography a biopsy marker demarcating site of confirmed pathology as established by previous core biopsy 263. Preoperative Diagnosis of Breast Cancer o Percent of patients undergoing breast cancer operations who obtained the diagnosis of breast cancer preoperatively by a minimally invasive biopsy method 264. Sentinel Lymph Node Biopsy for Invasive Breast Cancer o Percentage of clinically node negative (clinical stage T1N0M0 or T2N0M0) breast cancer patients who undergo a sentinel lymph node (SLN) procedure see Physician Quality Reporting System Quality Measures for additional information
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Quality Indicators: 23 quality indicators for care of breast cancer in vulnerable elders can be found in J Am Geriatr Soc 2007 Oct;55 Suppl 2:S258 • European Society of Breast Cancer Specialists (EUSOMA) consensus on quality indicators in breast cancer care can be found in Eur J Cancer 2010 Sep;46(13):2344 Guidelines and Resources •
Guidelines: Guideline comparison: • comparison of 4 guidelines (American College of Obstetricians and Gynecologists [ACOG]
2011, American College of Physicians [ACP] 2007, Kaiser Permanente Care Management Institute [KPCMI] 2010, United States Preventive Services Task Force [USPSTF] 2009) on screening for breast cancer in women at average risk can be found at National Guideline Clearinghouse 2012 Apr 16:35284 International guidelines: • Breast Health Global Initiative (BHGI) guidelines on breast cancer in limited-resource
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countries o early detection and access to care can be found in Breast J 2006 Jan-Feb;12 Suppl 1:S16 o diagnosis and pathology can be found in Breast J 2006 Jan-Feb;12 Suppl 1:S27 o treatment and allocation of resources can be found in Breast J 2006 Jan-Feb;12 Suppl 1:S38 o radiotherapy can be found in Breast J 2006 Jan-Feb;12 Suppl 1:S96 BHGI guideline implementation on breast healthcare in limited-resource countries o breast healthcare in low-income and middle-income countries can be found in Cancer 2008 Oct 15;113(8 Suppl):2221 full-text or at National Guideline Clearinghouse 2009 Nov 16:13344 o early detection resource allocation can be found in Cancer 2008 Oct 15;113(8 Suppl):2244 full-text or at National Guideline Clearinghouse 2010 Nov 1:15171 o diagnosis resource allocation can be found in Cancer 2008 Oct 15;113(8 Suppl):2257 full-text or at National Guideline Clearinghouse 2010 Nov 1:15172
treatment resource allocation can be found in Cancer 2008 Oct 15;113(8 Suppl):2269 full-text or at National Guideline Clearinghouse 2010 Nov 1:15173 o breast healthcare program resource allocation can be found in Cancer 2008 Oct 15;113(8 Suppl):2282 full-text or at National Guideline Clearinghouse 2010 Nov 1:15174 o full supplement (with multiple guidelines for international breast health and cancer control implementation) can be found in Cancer 2008 Oct 15;113(8 Suppl):2215 BHGI consensus statements o breast cancer management in low-resource countries (LRCs) can be found in Breast 2011 Apr;20 Suppl 2:S3 o breast cancer management in middle-resource countries (MRCs) can be found in Breast 2011 Apr;20 Suppl 2:S12 o problem solving for breast healthcare delivery in low- and middle-resource countries (LMCs) can be found in Breast 2011 Apr;20 Suppl 2:S20 Central European Cooperative Oncology Group (CECOG) third consensus on medical treatment of metastatic breast cancer can be found in Ann Oncol 2009 Nov;20(11):1771 full-text, commentary can be found in Ann Oncol 2010 Mar;21(3):665 Society of Nuclear Medicine (SNM) practice guideline on breast scintigraphy with breastspecific gamma-cameras 1.0 can be found in J Nucl Med Technol 2010 Dec;38(4):219 fulltext SNM practice guideline on somatostatin receptor scintigraphy 2.0 can be found in J Nucl Med Technol 2011 Dec;39(4):317 international expert panel consensus statement on inflammatory breast cancer: standardized diagnosis and treatment can be found in Ann Oncol 2011 Mar;22(3):515 fulltext First International Consensus Conference guidelines on advanced breast cancer (ABC 1) can be found in Breast 2012 Jun;21(3):242 international consensus conference recommendations on current status and future of neoadjuvant systemic therapy in primary breast cancer can be found in Ann Surg Oncol 2012 May;19(5):1508 full-text consensus statement on locoregional treatment of primary breast cancer can be found in Cancer 2010 Mar 1;116(5):1184 International Society for Fertility Preservation (ISFP) guideline on fertility preservation in young women with breast cancer can be found in J Assist Reprod Genet 2012 Jun;29(6):469 international consensus recommendation on breast cancer in pregnancy can be found in Eur J Cancer 2010 Dec;46(18):3158 o
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United States guidelines: • National Comprehensive Cancer Network (NCCN) guidelines can be found at NCCN
website (free registration required), guidelines include o breast cancer o breast cancer risk reduction o breast cancer screening and diagnosis o genetic/familial high-risk assessment of breast and ovarian cancer o invasive breast cancer
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National Comprehensive Cancer Network (NCCN) guideline on caring for breast cancer survivors can be found at NCCN website (free registration required) Institute for Clinical Systems Improvement (ICSI) guideline on diagnosis of breast disease can be found at ICSI 2012 Jan PDF or at National Guideline Clearinghouse 2012 Jul 30:36057 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) o ACSO/CAP recommendation on immunohistochemical testing of estrogen and progesterone receptors in breast cancer can be found in J Clin Oncol 2010 Jun 1;28(16):2784 or at National Guideline Clearinghouse 2010 Dec 6:16041 o ASCO/CAP recommendation on human epidermal growth factor receptor 2 testing in breast cancer can be found in J Clin Oncol 2007 Jan 1;25(1):118, 2009 update can be found in Arch Pathol Lab Med 2009 Apr;133(4):611 full-text American Society of Clinical Oncology (ASCO) o ASCO recommendations on role of bone-modifying agents in breast cancer metastatic to bone can be found in J Oncol Pract 2011 Mar;7(2):117 full-text or at National Guideline Clearinghouse 2011 Jul 11:32598, executive summary can be found in J Clin Oncol 2011 Mar 20;29(9):1221 o ASCO recommendation on use of tumor markers in breast cancer can be found in J Clin Oncol 2007 Nov 20;25(33):5287 full-text or at National Guideline Clearinghouse 2007 Oct:11741, commentary can be found in J Clin Oncol 2008 Apr 20;26(12):2057 o ASCO recommendation on sentinel lymph node biopsy in early-stage breast can cancer can be found in J Clin Oncol 2005 Oct 20;23(30):7703 full-text, commentary can be found in J Clin Oncol 2006 Jan 1;24(1):210 o ASCO clinical practice guideline on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer can be found in J Clin Oncol 2010 Aug 10;28(23):3784 or at National Guideline Clearinghouse 2010 Oct 25:23925 o ASCO guideline on breast cancer follow-up and management after primary treatment can be found in J Clin Oncol 2013 Mar 1;31(7):961 full-text or at National Guideline Clearinghouse 2013 Apr 8:38701 o ASCO 2009 guideline update on use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer reduction can be found in Gynecol Oncol 2009 Oct;115(1):132 full-text, correction can be found in Gynecol Oncol 2010 Mar;116(3):592 o ASCO guideline on postmastectomy radiotherapy can be found in J Clin Oncol 2001 Mar 1;19(5):1539 American College of Radiology (ACR) Appropriateness Criteria for o stage I breast carcinoma can be found at ACR 2011 PDF or at National Guideline Clearinghouse 2012 Mar 12:35133, or in J Am Coll Radiol 2012 Jul;9(7):463 o metastatic bone disease can be found at ACR 2012 PDF or at National Guideline Clearinghouse 2012 Nov 12:37930 o palpable breast masses can be found at ACR 2012 PDF or at National Guideline Clearinghouse 2013 Jul 1:43866 ACR Appropriateness Criteria for interventional procedures o locally advanced breast cancer can be found at ACR 2011 PDF or at National Guideline Clearinghouse 2011 Sep 19:32632
conservative surgery and radiation for stage I and II breast carcinoma can be found in Breast J 2011 Sep-Oct;17(5):448 or at ACR 2011 PDF or at National Guideline Clearinghouse 2011 Sep 19:32631 o postmastectomy radiotherapy can be found at ACR 2012 PDF or at National Guideline Clearinghouse 2012 Dec 10:37924, previous version can be found in Int J Radiat Oncol Biol Phys 2009 Mar 15;73(4):997 o local regional recurrence and salvage surgery can be found at ACR 2010 PDF or at National Guideline Clearinghouse 2011 Aug 1:32603 o American College of Radiology (ACR) Appropriateness Criteria for nonspine bone metastases can be found at ACR 2011 PDF or at National Guideline Clearinghouse 2012 Apr 23:35159 American College of Radiology (ACR) practice guideline on performance of magnetic resonance imaging-guided breast interventional procedures can be found at ACR 2011 PDF American College of Radiology/American College of Surgeons/College of American Pathology/Society of Surgical Oncology (ACR/ACS/CAP/SSO) guideline on standard for breast conservation therapy in management of invasive breast carcinoma can be found in CA Cancer J Clin 2002 Sep-Oct;52(5):277 American Cancer Society (ACS) guideline on nutrition and physical activity for cancer prevention can be found in CA Cancer J Clin 2012 Jan-Feb;62(1):30 full-text American Cancer Society (ACS) guideline on nutrition and physical activity for cancer survivors can be found in CA Cancer J Clin 2012 Jul;62(4):242 full-text or at National Guideline Clearinghouse 2012 Oct 8:37279 American College of Obstetricians and Gynecologists (ACOG) o committee opinion 412 on aromatase inhibitors in gynecologic practice can be found in Obstet Gynecol 2008 Aug;112(2 Pt 1):405 PDF, reaffirmed 2013 Jan o practice bulletin 126 on management of gynecologic issues in women with breast cancer can be found in Obstet Gynecol 2012 Mar;119(3):666 or at National Guideline Clearinghouse 2012 Apr 23:36055, commentary can be found in ACOG News Release 2012 Feb 21 American Society for Radiation Oncology (ASTRO) o ASTRO evidence-based guideline on use of fractionation for whole breast irradiation can be found in Int J Radiat Oncol Biol Phys 2011 Sep 1;81(1):59 fulltext or at National Guideline Clearinghouse 2012 Sep 24:36830 o ASTRO consensus statement on use of accelerated partial-breast irradiation and whole-breast irradiation in early breast cancer can be found in Int J Radiat Oncol Biol Phys 2009 Jul 15;74(4):987 full-text or at National Guideline Clearinghouse 2012 Sep 24:36839 American College of Radiology/American Society for Radiation Oncology (ACR/ASTRO) guideline on intensity modulated radiation therapy can be found in Am J Clin Oncol 2012 Dec;35(6):612 or at ACR 2011 PDF National Academy of Clinical Biochemistry (NACB) guidelines on use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers can be found in Clin Chem 2008 Dec;54(12):e11 full-text or at National Guideline Clearinghouse 2010 Sep 17:15553 University of Michigan Health System (UMHS) guideline on common breast problems can be found at UMHS 2007 Oct PDF (reviewed 2010 Sep) o
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expert consensus guideline on adjuvant therapy in stage I carcinoma of breast: influence of multigene analyses and molecular phenotyping can be found in Breast J 2012 JulAug;18(4):303 Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group recommendation on tumor gene expression profiling in patients with breast cancer can be found in Genet Med 2009 Jan;11(1):66 PDF or at National Guideline Clearinghouse 2009 Aug 24:13604 expert consensus recommendation on managing late periprosthetic fluid collections (seroma) in patients with breast implants can be found in Plast Reconstr Surg 2011 Jul;128(1):1, editorial can be found in Plast Reconstr Surg 2011 Jul;128(1):13 Commonwealth of Massachusetts Board of Registration in Medicine Expert Panel recommendation on immediate implant-based breast reconstruction following mastectomy for cancer can be found in J Am Coll Surg 2011 Dec;213(6):800
United Kingdom guidelines: • National Institute for Health and Clinical Excellence (NICE) guidelines on o familial breast cancer can be found at NICE 2013 Jun:CG164 PDF, summary can be
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found in BMJ 2013 Jun 25;346:f3829 o diagnosis and treatment of advanced breast cancer can be found at NICE 2009 Feb:CG81 PDF or at National Guideline Clearinghouse 2009 Sep 21:14311, summary can be found in BMJ 2009 Feb 25;338:b509 o diagnosis and treatment of early and locally advanced breast cancer can be found at NICE 2009 Feb:CG80 PDF or at National Guideline Clearinghouse 2009 Sep 21:14312, summary can be found in BMJ 2009 Feb 25;338:b438 o classification and care of women at risk of familial breast cancer in primary, secondary, and tertiary care can be found at NICE 2006 Oct:CG41 o eribulin for treatment of locally advanced or metastatic breast cancer can be found at NICE 2012 Apr:TA250 PDF or at National Guideline Clearinghouse 2012 Sep 10:36884 National Institute for Health and Clinical Excellence (NICE) guideline on denosumab for prevention of skeletal-related events in adults with bone metastases from solid tumors can be found at NICE 2012 Oct:TA265 PDF or at National Guideline Clearinghouse 2013 Jan 7:38576 United Kingdom expert guidance document on treatment of metastatic breast cancer can be found in Clin Oncol (R Coll Radiol) 2012 Apr;24(3):169 Scottish Intercollegiate Guidelines Network (SIGN) national clinical guideline on management of breast cancer in women can be found at SIGN 2005 Dec PDF British Association of Surgical Oncology (BASO) Association of Breast Surgery guideline on surgical management of breast cancer can be found in Eur J Surg Oncol 2009;35 Suppl 1:1 Royal College of Obstetricians and Gynaecologists (RCOG) guideline on pregnancy and breast cancer can be found at RGOC 2011 Mar PDF or at National Guideline Clearinghouse 2012 May 14:34962
Canadian guidelines: • Cancer Care Ontario (CCO) Program in Evidence-based Care practice guidelines on o role of IMRT in breast cancer can be found at CCO 2010 Oct 27 PDF or at National
Guideline Clearinghouse 2012 Nov 26:35096
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baseline staging tests in primary breast cancer can be found at CCO 2011 Nov 1 PDF management of ductal carcinoma in situ of breast can be found at CCO 2006 Sep 19 PDF nonmetastatic breast cancer locoregional therapy surgical management of early-stage invasive breast cancer can be found at CCO 2011 Sep 15 PDF breast irradiation in women with early-stage invasive breast cancer following breast-conserving surgery can be found at CCO 2011 Sep 15 PDF systemic therapy role of taxanes in neoadjuvant chemotherapy for women with nonmetastatic breast cancer can be found at CCO 2011 Oct 5 PDF role of trastuzumab in adjuvant and neoadjuvant therapy in women with HER2/neu-overexpressing breast cancer can be found at CCO 2011 Sep 15 PDF adjuvant taxane therapy for women with early-stage invasive breast cancer can be found at CCO 2011 Sep 30 PDF adjuvant ovarian ablation in treatment of premenopausal women with early stage invasive breast cancer can be found at CCO 2010 Jul 6 PDF or at National Guideline Clearinghouse 2012 Sep 17:37867 prophylactic use of filgrastim in patients with breast cancer can be found at CCO 2009 Oct 1 PDF or at National Guideline Clearinghouse 2011 Feb 7:16385 zoledronic acid as adjuvant therapy in combination with adjuvant endocrine therapy for premenopausal women with early-stage hormone receptor-positive breast cancer can be found at CCO 2010 Jan 25 PDF or at National Guideline Clearinghouse 2011 Feb 7:16389 metastatic breast cancer role of trastuzumab (herceptin) in treatment of women with HER2/neuoverexpressing metastatic breast cancer can be found at CCO 2011 Sep 15 PDF role of gemcitabine in management of metastatic breast cancer can be found at CCO 2011 Sep 15 PDF vinorelbine in stage IV breast cancer can be found at CCO 2003 Nov PDF role of aromatase inhibitors in treatment of postmenopausal women with metastatic breast cancer can be found at CCO 2003 Oct PDF continued use of trastuzumab beyond disease progression in patients with metastatic breast cancer can be found at CCO 2009 Aug 17 PDF or at National Guideline Clearinghouse 2010 Dec 27:15655 fulvestrant for systemic therapy of locally advanced or metastatic breast cancer in postmenopausal women can be found at CCO 2008 Sep 25 PDF
use of bisphosphonates in women with breast cancer (both metastatic and nonmetastatic) can be found at CCO 2012 May 15 PDF Alberta Health Services (AHS) clinical practice guidelines on o adjuvant radiation therapy for invasive breast cancer can be found at AHS 2012 Apr PDF o magnetic resonance imaging for breast cancer screening, preoperative assessment, and follow-up can be found at AHS 2012 Jan PDF or at National Guideline Clearinghouse 2012 May 7:34595 o aromatase inhibitors as adjuvant therapy in postmenopausal women with earlystage hormone receptor positive breast cancer can be found at AHS 2011 Jun PDF or at National Guideline Clearinghouse 2013 Mar 18:38597 o breast radiation after breast-conserving surgery can be found at AHS 2010 May PDF o optimal use of taxanes in metastatic breast cancer can be found at AHS 2009 Dec PDF o sentinel lymph node biopsy and axillary node dissection in early-stage breast cancer can be found at AHS 2011 Dec PDF o staging investigations for asymptomatic and newly diagnosed breast cancer can be found at AHS 2012 Jul PDF or at National Guideline Clearinghouse 2013 Feb 18:38579 o risk reduction and surveillance strategies for individuals at high genetic risk for breast and ovarian cancer can be found at AHS 2011 Apr PDF or at National Guideline Clearinghouse 2013 Mar 18:38601 Canadian evidence-based consensus guidelines on (published as CMAJ special supplement) o chemoprevention of breast cancer can be found in CMAJ 2001 Jun 12;164(12):1681 full-text, commentary can be found in CMAJ 2001 Nov 27;165(11):1468 o diagnosis of breast cancer lesions detected by mammography can be found at 1998 Feb 10 PDF palpable breast lump can be found at 1998 Feb 10 PDF o nonmetastatic breast cancer locoregional therapy management of ductal carcinoma in situ can be found in CMAJ 2001 Oct 2;165(7):912 full-text mastectomy vs. lumpectomy can be found in CMAJ 2002 Jul 23;167(2):154 full-text, commentary can be found in CMAJ 2002 Nov 12;167(10):1099 sentinel lymph node biopsy can be found in CMAJ 2001 Jul 24;165(2):166 full-text, commentary can be found in CMAJ 2002 May 14;166(10):1254 axillary dissection can be found at 1998 Feb 10 PDF breast radiotherapy after breast-conserving surgery can be found in CMAJ 2003 Feb 18;168(4):437 full-text o
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locoregional postmastectomy radiotherapy can be found in CMAJ 2004 Apr 13;170(8):1263 full-text, commentary can be found in CMAJ 2005 Jan 4;172(1):18 systemic therapy adjuvant systemic therapy for women with node-negative breast cancer can be found in CMAJ 2001 Jan 23;164(2):213 full-text, correction can be found in CMAJ 2001 Feb 20;164(4):465 adjuvant systemic therapy for women with node-positive breast cancer can be found in CMAJ 2001 Mar 6;164(5):644 full-text, commentary can be found in CMAJ 2001 Sep 4;165(5):525, 527 treatment for women with stage III or locally advanced breast cancer can be found in CMAJ 2004 Mar 16;170(6):983 full-text, commentary can be found in CMAJ 2004 Aug 3;171(3):220 management of complications management of chronic pain in patients with breast cancer can be found in CMAJ 2001 Oct 30;165(9):1218 full-text, commentary can be found in CMAJ 2002 Jul 9;167(1):14 role of hormone replacement therapy in women with history of breast cancer can be found in CMAJ 2002 Apr 16;166(8):1017 full-text lymphedema can be found in CMAJ 2001 Jan 23;164(2):191 full-text follow-up after treatment for breast cancer can be found in CMAJ 2005 May 10;172(10):1319 full-text
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recurrent or metastatic breast cancer: diagnosis, treatment, and follow-up can be found in Ann Oncol 2012 Oct;23 Suppl 7:vii11 full-text European Society of Medical Oncology (ESMO) clinical practice guidelines on o primary breast cancer (diagnosis, treatment, and follow-up) can be found in Ann Oncol 2011 Sep;22 Suppl 6:vi12 full-text o locally recurrent or metastatic breast cancer (diagnosis, treatment, and follow-up) can be found in Ann Oncol 2011 Sep;22 Suppl 6:vi25 full-text o BRCA in breast cancer can be found in Ann Oncol 2011 Sep;22 Suppl 6:vi31 fulltext Spanish Society for Medical Oncology (SEOM) o clinical guideline on treatment of early breast cancer can be found in Clin Transl Oncol 2010 Nov;12(11):711 o clinical guideline on treatment of metastatic breast cancer can be found in Clin Transl Oncol 2010 Nov;12(11):719 o Spanish Society of Medical Oncology (SEOM) clinical guideline on using molecular markers in clinical practice can be found in Clin Transl Oncol 2011 Aug;13(8):587 o Spanish Society for Medical Oncology (SEOM) guideline on hereditary cancer can be found in Clin Transl Oncol 2011 Aug;13(8):580 European Society of Breast Cancer Specialists (EUSOMA) recommendations on management of young women with breast cancer can be found in Eur J Cancer 2012 Dec;48(18):3355 full-text
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Croatian Senology Society HLZ clinical guidelines on diagnosis, treatment and monitoring of patients with non-invasive breast cancer can be found in Lijec Vjesn 2012 SepOct;134(9-10):259 [Croatian] German Society of Radiation Oncology (Deutsche Gesellschaft für Radioonkologie [DEGRO]) practice guidelines on o radiotherapy of breast cancer I: breast-conserving therapy can be found in Strahlenther Onkol 2007 Dec;183(12):661 o radiotherapy of breast cancer II: postmastectomy radiotherapy, irradiation of regional lymphatics, and treatment of locally advanced disease can be found in Strahlenther Onkol 2008 Jul;184(7):347 o palliative radiotherapy of brain metastases and leptomeningeal carcinomatosis can be found in Strahlenther Onkol 2010 Feb;186(2):63 o palliative radiotherapy of bone metastases and metastatic spinal cord compression can be found in Strahlenther Onkol 2009 Jul;185(7):417 review of clinical recommendations of DEGRO and Gynecological Oncology Working Group (AGO) on preferred standard palliative radiotherapy of bone and cerebral metastases, metastatic spinal cord compression, and leptomeningeal carcinomatosis in breast cancer can be found in Breast Care (Basel) 2010;5(6):401 full-text German National 2008 guideline update on early detection of breast cancer can be found in J Cancer Res Clin Oncol 2009 Mar;135(3):339 French Expert Review Board of Nice/Saint-Paul de Vence guideline on radiotherapy for invasive breast cancer can be found in Crit Rev Oncol Hematol 2011 Aug;79(2):91 Haute Autorité de Santé (HAS) conseils sur cancer du sein se trouvent sur le site Haute Autorité de Santé 2010 Jan [French] Groupe Européen de Curiethérapie-European Society for Therapeutic Radiology and Oncology (GEC-ESTRO) recommendation on patient selection for accelerated partialbreast irradiation after breast-conserving surgery can be found in Radiother Oncol 2010 Mar;94(3):264 Hungarian Breast Cancer Consensus Conference recommendations on o imaging methods in current diagnosis of and screening for breast cancer can be found in Magy Onkol 2010 Sep;54(3):211 [Hungarian] o pathologic diagnosis and histopathology record of breast cancer can be found in Magy Onkol 2010 Sep;54(3):217 [Hungarian] o current surgical therapy in breast cancer can be found in Magy Onkol 2010 Sep;54(3):227 [Hungarian] o pharmaceutical therapy of breast cancer can be found in Magy Onkol 2010 Sep;54(3):237 [Hungarian] o principles of radiotherapy (in breast cancer) can be found in Magy Onkol 2010 Sep;54(3):257 [Hungarian] o pregnancy and breast cancer can be found in Magy Onkol 2010 Sep;54(3):267 [Hungarian] Institut Curie guideline on simplified rules for everyday delineation of lymph node areas for breast cancer radiotherapy can be found in Br J Radiol 2010 Aug;83(992):683 expert clinical recommendations on diagnosis, treatment and monitoring of patients with invasive breast cancer can be found in Lijec Vjesn 2012 Jan-Feb;134(1-2):1 [Croatian]
Asian guidelines:
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First Okinawa Breast Oncology Meeting consensus statement on challenge to reduce breast cancer mortality in Okinawa can be found in Jpn J Clin Oncol 2013 Feb;43(2):208 Asian Oncology Summit (AOS) 2009 consensus statement on management of HER2positive breast cancer in Asia can be found in Lancet Oncol 2009 Nov;10(11):1077 expert guideline on HER2 detection in breast cancer can be found in Zhonghua Bing Li Xue Za Zhi 2009 Dec;38(12):836 [Chinese] Chinese Anti-Cancer Association consensus statement on diagnosis and treatment of HER2-positive breast cancer can be found in Zhonghua Zhong Liu Za Zhi 2010 Feb;32(2):158 [Chinese] expert consensus on diagnosis and treatment of bone metastasis and skeletal related events in breast cancer patients can be found in Zhonghua Zhong Liu Za Zhi 2009 Feb;31(2):156 [Chinese]
Mexican guidelines: • Grupos de Desarrollo de las Instituciones Públicas del Sistema Nacional de Salud de
•
México (Secretaría de Salud, IMSS, ISSSTE, SEDENA, SEMAR, DIF, PEMEX) guías de práctica clínica en prevención, tamizaje y referencia oportuna de casos de cáncer de mama en el primer nivel de atención se pueden encontrar en Secretaría de Salud-México 2011 PDF [Spanish] third revision of national consensus on diagnosis and treatment of breast cancer can be found in Ginecol Obstet Mex 2010 Jan;78(1):72 [Spanish], Ginecol Obstet Mex 2010 Feb;78(2):138 [Spanish], Ginecol Obstet Mex 2010 Mar;78(3):199 [Spanish]
Central and South American guidelines: • Seguro Social Costa Rica (CCSS) guideline on treatment of breast cancer (Guía de Práctica
Clínica para el Tratamiento del Cáncer de Mama) can be found at CCSS 2012 PDF ZIP [Spanish], patient version can be found at CCSS 2012 PDF ZIP [Spanish]
Australian and New Zealand guidelines: • New Zealand Guidelines Group (NZGG) guideline on management of early breast cancer
can be found at NZGG 2009 Aug PDF or at National Guideline Clearinghouse 2009 Aug:15462
Middle Eastern guidelines: • National Comprehensive Cancer Network (NCCN) guideline on breast cancer modified for
Middle East and North Africa region can be found in J Natl Compr Canc Netw 2010 Jul;8 Suppl 3:S8
Review articles: • • • • • •
review can be found in Mayo Clin Proc 2007 Sep;82(9):1131 review can be found in Mayo Clin Proc 2004 Jun;79(6):810 review can be found in Lancet 2005 May 14;365(9472):1727, commentary can be found in Lancet 2005 Nov 5;366(9497):1605 review can be found in Adv Stud Med 2005 Jun;5(6):294 PDF, editorial can be found in Adv Stud Med 2005 Jun;5(6):316 PDF review of common breast problems can be found in Am Fam Physician 2012 Aug 15;86(4):343 review of triple-negative breast cancer can be found in N Engl J Med 2010 Nov 11;363(20):1938
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review of medications for triple-negative (estrogen receptor, progesterone receptor, and HER2-negative) advanced breast cancer can be found in Ann Oncol 2010 Oct;21 Suppl 7:vii30 full-text review of breast cancer risk, soy isoflavones, and estrogen therapy can be found in Nutr J 2008 Jun 3;7:17 full-text review of hybrid SPECT/CT imaging as additional lymphatic mapping tool in patients with breast cancer can be found in World J Surg 2008 Sep;32(9):1930 full-text review of minimally invasive ablative therapies for invasive breast carcinomas can be found in World J Surg 2007 Dec;31(12):2284 review of advances in local-regional treatment for early breast cancer can be found in Clin Breast Cancer 2010 Jun;10(3):180 review of breast cancer staging and surgical treatment options can be found in Cleve Clin J Med 2008 Mar;75 Suppl 1:S10 review of breast cancer screening can be found in Am Fam Physician 2007 Jun 1;75(11):1660 full-text, editorial can be found in Am Fam Physician 2007 Jun 1;75(11):1623 full-text review of investigation of suspected breast cancer can be found in BMJ 2007 Aug 18;335(7615):347 review of image-guided breast biopsy can be found in Clin Radiol 2010 Apr;65(4):259 review of early breast cancer can be found in Lancet 2009 Apr 25;373(9673):1463 review of management of breast cancer can be found in BMJ 2008 Jul 4;337:a421 and BMJ 2008 Jul 11;337:a540 review of enhancing postoperative recovery after breast surgery can be found in Br J Surg 2011 Feb;98(2):181 review of follow-up after breast cancer can be found in Aust Fam Physician 2006 Apr;35(4):219 review of care of cancer survivors can be found in Am Fam Physician 2005 Feb 15;71(4):699 review of evaluation of palpable breast masses can be found in Am Fam Physician 2005 May 1;71(9):1731, correction can be found in Am Fam Physician 2005 Sep 1;72(5):761 reviews of magnetic resonance imaging (MRI) in breast cancer can be found in o Lancet 2011 Nov 19;378(9805):1804, commentary can be found in Lancet 2011 Nov 19;378(9805):1758 o J Am Board Fam Pract 2005 Nov-Dec;18(6):478 full-text review of radiation therapy for early-stage breast cancer after breast-conserving surgery can be found in N Engl J Med 2009 Jan 1;360(1):53, commentary can be found in N Engl J Med 2009 Apr 16;360(16):1676 review of radiation therapy planning can be found in Radiat Oncol 2006 Jul 20;1:22 fulltext systematic review of intensity-modulated radiotherapy can be found in Lancet Oncol 2008 Apr;9(4):367, correction can be found in Lancet Oncol 2008 Jun;9(6):513 systematic review of risk factors and strategies for prevention of persistent pain after breast cancer treatment can be found in J Pain 2011 Jul;12(7):725 review of quality indicators for sentinel lymph node biopsy in breast cancer can be found in Ann Surg Oncol 2010 Feb;17(2):579
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review of alternative therapies for breast cancer can be found in Altern Ther Health Med 2001 May-Jun;7(3):36, commentary can be found in Altern Ther Health Med 2001 JulAug;7(4):20 and in Altern Ther Health Med 2001 Sep-Oct;7(5):20 review of women at high risk for breast cancer can be found in J Am Board Fam Med 2009 Jan-Feb;22(1):43 full-text review of assessing breast cancer risk in women can be found in Am Fam Physician 2008 Dec 15;78(12):1361 review of breast cancer in pregnancy can be found in Lancet 2012 Feb 11;379(9815):570 review of early breast cancer therapy and cardiovascular injury can be found in J Am Coll Cardiol 2007 Oct 9;50(15):1435 review of prevention and diagnosis of breast cancer can be found in Mayo Clin Proc 2007 Aug;82(8):999 review of managing bone health with zoledronic acid can be found in Climacteric 2011 Jun;14(3):321 review of approach to inflammatory breast cancer can be found in Can Fam Physician 2009 Jan;55(1):25 full-text literature review of locoregional treatment in metastatic breast cancer can be found in Breast Cancer Res Treat 2010 Feb;119(3):537 review of weight, physical activity, diet, and prognosis in breast and gynecologic cancers can be found in J Clin Oncol 2010 Sep 10;28(26):4074 case presentations in special situations o case presentation and review of invasive micropapillary carcinoma after augmentation mammoplasty can be found in World J Surg Oncol 2008 Mar 14;6:33 full-text o case report and review of breast cancer during pregnancy can be found in BMJ 2005 Jun 11;330(7504):1375
MEDLINE search: to search MEDLINE for (Breast cancer in women) with targeted search (Clinical Queries), click therapy, diagnosis, or prognosis Patient Information •
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47-page guide for questions and answers on breast cancer from Canadian Breast Cancer Initiative 2001 PDF information on breast cancer from MacMillan Cancer Support information on secondary breast cancer from MacMillan Cancer Support comprehensive booklet from AHRQ covers Surgery Choices for Women with Early-Stage Breast Cancer or in Spanish handouts from American Academy of Family Physicians o breast cancer screening or in Spanish o genetic testing for breast cancer risk or in Spanish o breast cyst aspiration or in Spanish handout from EBSCO Health Library PDF or in Spanish PDF handout on mammography from EBSCO Health Library PDF or in Spanish PDF handout on food choices for lowering cancer risk can be found in Am Fam Physician 2000 Oct 1;62(7):1697
handout on healthcare after cancer treatment can be found in Am Fam Physician 2005 Feb 15;71(4):713 ICD-9/ICD-10 Codes •
ICD-9 codes: • • • • • • • • • • •
174.0 malignant neoplasm of nipple and areola of female breast 174.1 malignant neoplasm of central portion of female breast 174.2 malignant neoplasm of upper-inner quadrant of female breast 174.3 malignant neoplasm of lower-inner quadrant of female breast 174.4 malignant neoplasm of upper-outer quadrant of female breast 174.5 malignant neoplasm of lower-outer quadrant of female breast 174.6 malignant neoplasm of axillary tail of female breast 174.8 malignant neoplasm of other specified sites of female breast 174.9 malignant neoplasm of breast (female), unspecified site 233.0 carcinoma in situ of breast 793.8 nonspecific (abnormal) findings on radiological and other examination of breast o 793.80 unspecified abnormal mammogram o 793.81 mammographic microcalcification o 793.82 inconclusive mammogram o 793.89 other (abnormal) findings on radiological examination of breast
ICD-10 codes: •
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C50 malignant neoplasm of breast o C50.0 nipple and areola o C50.1 central portion of breast o C50.2 upper-inner quadrant of breast o C50.3 lower-inner quadrant of breast o C50.4 upper-outer quadrant of breast o C50.5 lower-outer quadrant of breast o C50.6 axillary tail of breast o C50.8 overlapping lesion of breast o C50.9 breast, unspecified ICD-10-CA modification in Canada: code range C50.0-C50.9 subdivided and fourth digit added to identify 0 right 1 left 9 unspecified side D05 carcinoma in situ of breast o D05.0 lobular carcinoma in situ o D05.1 intraductal carcinoma in situ o D05.7 other carcinoma in situ of breast o D05.9 carcinoma in situ of breast, unspecified R92 abnormal findings on diagnostic imaging of breast Z80.3 family history of malignant neoplasm of breast Z85.3 personal history of malignant neoplasm of breast
References
General references used: •
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1. Institute for Clinical Systems Improvement (ICSI). Diagnosis of breast disease. Bloomington (MN). ICSI 2012 Jan PDF or at National Guideline Clearinghouse 2012 May 25:36057 2. National Institute for Health and Clinical Excellence (NICE). Breast cancer (early and locally advanced): diagnosis and treatment. NICE 2009 Feb:CG80 PDF or at National Guideline Clearinghouse 2009 Sep 21:14312, summary can be found in BMJ 2009 Feb 25;338:b438 3. National Institute for Health and Clinical Excellence (NICE). Advanced breast cancer: diagnosis and treatment. NICE 2009 Feb:CG81 PDF or at National Guideline Clearinghouse 2009 Sep 21:14311, summary can be found in BMJ 2009 Feb 25;338:b509 4. Hayes DF. Clinical practice. Follow-up of patients with early breast cancer. N Engl J Med. 2007 Jun 14;356(24):2505-13, commentary can be found in N Engl J Med 2007 Sep 6;357(10):1052, Am Fam Physician 2007 Dec 15;76(12):1864 5. Benson JR, Jatoi I, Keisch M, Esteva FJ, Makris A, Jordan VC. Early breast cancer. Lancet. 2009 Apr 25;373(9673):1463-79 6. Maughan KL, Lutterbie MA, Ham PS. Treatment of breast cancer. Am Fam Physician. 2010 Jun 1;81(11):1339-46 full-text, editorial can be found in Am Fam Physician 2010 Jun 1;81(11):1330 7. Edge BS, Byrd RD, Compton CC, Fritz GA, Greene LF, Trotti A III; American Joint Committee on Cancer (AJCC) Cancer Stating Manual. 7th ed. American Joint Committee on Cancer; 2010:347-376 o information, including clinical staging form and information on pathologic classification, can be found at AJCC PDF o Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Manual, Seventh Edition (2010) published by Springer SBM, LLC. 8. Association of Breast Surgery at Baso 2009. Surgical guidelines for the management of breast cancer. Eur J Surg Oncol. 2009;35 Suppl 1:1-22
Recommendation grading systems used: •
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New Zealand Guidelines Group (NZGG) grades of recommendation o Grade A - supported by good evidence (based on a number of studies that are valid, consistent, applicable, and clinically relevant) o Grade B - supported by fair evidence (based on studies that are valid, but there are some concerns about the volume, consistency, applicability, and clinical relevance of the evidence that may cause some uncertainty but are not likely to be overturned by other evidence) o Grade C - supported by international expert opinion o Grade I - evidence is insufficient, lacking, of poor quality, or opinions conflict; balance of benefits and harms cannot be determined o Good Practice Point - opinion of guideline development team, or feedback from consultation within New Zealand where no evidence available o Reference - NZGG guideline on management of early breast cancer (NZGG 2009 Aug PDF or at National Guideline Clearinghouse 2009 Aug:15463) European Society for Medical Oncology (ESMO) grades of recommendation
grades of recommendation Grade A - evidence of level I or consistent findings from multiple studies of types II, III, or IV Grade B - evidence of level II, III, or IV and findings are generally consistent Grade C - evidence of level II, III, or IV but findings are inconsistent Grade D - little or no systematic empirical evidence o levels of evidence Level I - evidence obtained from meta-analysis of multiple, well-designed, controlled studies; randomized trials with low false-positive and low falsenegative errors (high power) Level II - evidence obtained from at least 1 well-designed experimental study; randomized trials with high false-positive and/or negative errors (low power) Level III - evidence obtained from well-designed, quasi-experimental studies such as nonrandomized, controlled single-group, pre-post, cohort, and time or matched case-control series Level IV - evidence from well-designed, nonexperimental studies such as comparative and correlational descriptive and case studies Level V - evidence from case reports o References ESMO clinical practice guideline on diagnosis, treatment, and follow-up of primary breast cancer (Ann Oncol 2011 Sep;22 Suppl 6:vi12 full-text) ESMO clinical practice guideline on diagnosis, treatment, and follow-up of locally recurrent or metastatic breast cancer (Ann Oncol 2011 Sep;22 Suppl 6:vi25 full-text) National Academy of Clinical Biochemistry (NACB) grading system o strength of recommendations Grade A - high - further research very unlikely to change Panel’s confidence in estimate of effect Grade B - moderate - further research likely to have important impact on Panel's confidence in estimate of effect and likely to change estimate Grade C - low - further research very likely to have important effect on Panel's confidence in estimate of effect and likely to change estimate Grade D - very low - any estimate of effect very uncertain o levels of evidence Level I - evidence from single, high-powered, prospective, controlled study specifically designed to test marker, or evidence from meta-analysis, pooled analysis, or overview of level II or III studies Level II - evidence from study in which marker data are determined in relationship to prospective therapeutic trial performed to test therapeutic hypothesis but not specifically designed to test marker utility Level III - evidence from large prospective studies Level IV - evidence from small retrospective studies Level V - evidence from small pilot studies Expert opinion o
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Reference - NACB guideline on use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers (Clin Chem 2008 Dec;54(12):e11 full-text or at National Guideline Clearinghouse 2010 Sep 17:15553) United States Preventive Services Task Force (USPSTF) grades of recommendation (June 2007-June 2012) o Grade A - USPSTF recommends the service with high certainty of substantial net benefit o Grade B - USPSTF recommends the service with high certainty of moderate net benefit or moderate certainty of moderate-to-substantial net benefit o Grade C - clinicians may provide the service to select patients depending on individual circumstances, however, only small benefit is likely for most individuals without signs or symptoms o Grade D - USPSTF recommends against providing the service with moderate-tohigh certainty of no net benefit or harms outweighing benefits o Grade I - insufficient evidence to assess balance of benefits and harms o Reference - USPSTF Grade Definitions United States Preventive Services Task Force (USPSTF) grades of recommendation (prior to May 2007) o Grade A - USPSTF strongly recommends that clinicians provide the service to eligible patients, based on good evidence that the service improves important health outcomes and that benefits substantially outweigh harms o Grade B - USPSTF recommends that clinicians provide the service to eligible patients, based on at least fair evidence that the service improves important health outcomes and that benefits outweigh harms o Grade C - USPSTF makes no recommendation for or against routinely providing the service, based on at least fair evidence that the service can improve health outcomes but the balance of benefits and harms is too close to justify a general recommendation o Grade D - USPSTF recommends against routinely providing the service to asymptomatic patients, based on at least fair evidence that the service is ineffective or that harms outweigh benefits o Grade I - USPSTF concludes that the evidence is insufficient to recommend for or against routinely providing the service o Reference - USPSTF Grade Definitions o
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Special acknowledgements: •
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Ranjna Sharma, MD (Instructor in Surgery, Harvard Medical School; Beth Israel Deaconess Medical Center – Breast Cancer Center; Massachusetts, United States) provides peer review. Robert Cassady, MD (former Chairman of Radiation Oncology and Physician, Lahey Clinic; Massachusetts, United States) provides peer review.
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