Breast Cancer Update: a Diagnosis That Extends Beyond the Patient

The authors present a case in which genetic testing for breast cancer may have affected outcomes in a 35-year-old woman.

When is genetic testing for breast cancer warranted?

Awell-appearing 35-year-old woman presents to her primary care provider with a complaint of a mass in her left breast. She has no significant medical history; however, her mother has had recurrent breast cancer. The patient had one pregnancy with an uncomplicated vaginal delivery at age 30. Her daughter was breastfed for 8 months. The patient’s age at menarche was 11 years old.

She has never had a mammogram. However, her chief complaint and family history indicate the need for further workup with clinical breast examination and referral for ultrasonography.

History and Physical Examination

The patient first noticed the mass in the shower 3 months ago. She says the mass has stayed constant in size and is occasionally painful without radiating pain. She denies fatigue, weight loss, fever, night sweats, chest pain, shortness of breath, or changes in bowel movements. She reports no limitation in movement, muscle weakness, dysmenorrhea, or menorrhagia. Her last menses was 5 days ago.

The patient takes drospirenone and ethinyl estradiol 3 mg/0.02 mg tablets once a day for birth control. She also takes over-the-counter biotin 5000 µg once a day. She denies any drug or food allergies.

The patient is a florist and keeps physically active with her job. She also states she likes to run 3 times a week. She eats a healthy diet that includes fish and vegetables. She denies any history

of tobacco use. She reports drinking two 8-ounce glasses of red wine a week.

The patient is married and states she is sexually active only with her husband. She has a healthy 5-year-old daughter. Her mother is healthy but has a history of recurrent breast cancer. Her mother was first diagnosed with breast cancer when she was 40 years old and again at age 50 years. Her mother’s first breast cancer was treated with a double mastectomy with reconstruction and chemotherapy. The second breast cancer was treated successfully with local excision and chemotherapy. Her father has hypertension and arthritis. She has a brother who is healthy. The patient has no other pertinent family history to report.

The patient appears to be in no acute distress and is alert and oriented times 4. She is dressed and groomed appropriately. Her vitals are shown in Table 1.

The patient’s breasts, areolas, and nipples are symmetric and the skin in these areas is light pink without signs of dimpling or discharge. Upon palpation with vertical strip method, a single fixed firm mass in the right upper quadrant of the left breast is found measuring 2 cm from the areola. The mass measures approximately 1.3 cm × 1.6 cm. No enlargement of bilateral axillary or supraclavicular nodes is present.

Diagnostic Studies and Treatment

The ultrasonography report shows a suspicious mass on the left breast in the right upper quadrant (Figure below demonstrates an example of similar findings).1 She is scheduled for same-day bilateral mammography. Her bilateral mammography report confirms a suspicious mass on the left breast in the right upper quadrant indicating a need for core needle biopsy.

Upon follow-up, the pathology report is consistent with luminal A invasive ductal carcinoma. She is referred to a surgical oncologist and treated with neoadjuvant chemotherapy and a double mastectomy with reconstruction.

Genetic Testing

The patient is referred by her primary care physician to a genetic counselor because of the patient’s young age at breast cancer diagnosis and family history. The genetic counselor recommended BRCA testing for all first-degree relatives. The patient, her mother, and her daughter were all found to be BRCA1 positive. Her brother refused testing at this time.

Discussion

Breast cancer is the second most common cancer in women with 1 in every 8 women worldwide being diagnosed.2 Noninvasive neoplasms are confined to the milk ducts and glands, including ductal carcinoma in situ (DCIS) and lobular carcinoma in situ

TABLE 1. Vital Signs

Height, in

Weight. lb

BMI 60

142

22.9

Blood pressure, mm Hg 117/80

Respiratory rate, bpm 16

Temperature, °F 98.2

bpm, breaths per minute

FIGURE. Example of ultrasonography findings in a woman with invasive ductal carcinoma (left, transverse image; right, longitudinal image).1

(LCIS). However, these can both grow into invasive types once they move into the adipose tissue where the nerves, lymph, and vessels are located. These invasive types of breast cancer are infiltrating lobular carcinoma (ILC) and infiltrating ductal carcinoma (IDC). These tumors have a higher risk for metastasis, the most common sites being brain, bone, lungs, and liver.3

Another invasive form of breast cancer is a locally advanced type called inflammatory breast cancer (IBC), which is characterized by rapid onset of erythema and edema. This form is often misdiagnosed as cellulitis or inflamed tissue. Although the incidence of this type of breast cancer is low at 2% to 4%, it is imperative to correctly identify because it accounts for 7% of all breast cancer-related mortality.4

Overall, however, most cases of breast cancer are not high risk, with a survival rate of more than 90%.5 The overall risk is largely determined by tumor staging and grading. Staging is focused on tumor size as well as disease spread to lymph nodes and grading is focused on the histologic characteristics of the tumor.6

The development of breast cancer is a multistep process that stems from 2 different theories centered on cellular mutation into tumor cells.2 This process is influenced by genetic and epigenetic factors. The most well-known genetic factors include the antioncogenes breast cancer susceptibility 1 and 2 (BRCA1 and BRCA2) genes.2 The epigenetic factors are divided into modifiable and nonmodifiable risk factors. Modifiable risk factors include premenopausal obesity, use of hormone-replacement therapy, alcohol consumption, smoking, not breastfeeding, and physical inactivity. Nonmodifiable risk factors include age greater than 65, White race, and family history.5 Other risk factors are related to estrogen levels including early menarche, late menopause, nulligravida, advanced maternal age, dense breasts, and higher bone density.2,3

Symptoms

Clinical breast symptoms (eg, mass, pain, nipple discharge) are common in women, with only 3% to 6% resulting from breast cancer.7,8 The majority of these symptoms are caused by benign conditions such as fibroadenoma and fibrocystic breast disease.9 Fibroadenoma is the most common benign lesion of the breast with an incidence of 25%.8 The clinical presentation of breast cancer and fibroadenoma is similar with the most common symptom being a new mass. However, only 8% of patients presenting with a palpable mass will have breast cancer.8

Breast cancer patient presentation can be divided into nonbreast symptoms and breast symptoms, with the latter being more prevalent. The most common breast symptom is a new mass. Other symptoms include nipple abnormalities, breast pain, and breast skin abnormalities.8 Approximately 1 in 6 women with breast cancer presents without a breast mass, and those with nonmass symptoms (eg, nipple abnormalities and breast ulceration, infection, or inflammation) or both a breast mass and non-mass symptoms are more likely to wait 90 days or more to seek care compared with those with a breast mass only.10 Therefore, it is important to educate patients on symptoms of breast cancer to decrease the time it takes patients to present for evaluation.

History and Physical Examination

The primary care provider should obtain an extensive personal and family medical history to identify breast cancer risk factors such as race, heritage, past medical history of cancer, family history of cancer, diet, physical activity, and substance abuse. Additionally, the history should include age at menarche, age at menopause, number of and age at pregnancies, duration of breastfeeding, use of hormone replacement therapy, and bone density.3

Physical examination should be conducted in both seated and supine positions. It should start with the patient seated with hands on hips, inspecting for any nipple discharge, asymmetry, skin retraction, edema, erythema, or hypertrophy. Next, the provider should palpate for any enlarged axillary, supraclavicular, or cervical lymph nodes. Lastly, the provider should palpate the patient’s breasts using the circular or vertical strip method. Masses that are greater than 1 cm, fixed, hard, and heterogenous in texture should raise suspicion for malignancy and require further workup. Additionally, further workup is indicated if an axillary or supraclavicular lymph node is palpated with or without the presence of a mass. The examination documentation should include all the above findings with the circumferential location on the breast and distance from the areola.8

Screening Guidelines

Breast cancer screening guidelines differ based on individual risk level. The most common recommendation for average-risk persons is biennial mammography at 50 to 74 years of age as shown in Table 2. 6,11,12 High-risk individuals are recommended to have an annual breast MRI and mammogram starting at age 30 to 40 years.11,12 High-risk individuals are those with

TABLE 2. Breast Cancer Screening Guidelines6,11,12

USPSTF (2016) ACS (2015) ACOG (2017)

Age 40 to 49 y: Women should make individual decisions and consult with their clinicians Age 50-74 y: Every 2 y Age 40-44 y: Optional Age 45-54 y: Annually Age >55 y: Every 1-2 y Mammogram every 1-2 y starting at age 40-50 y and ending at age 75 y based on shared decisionmaking

ACOG, American College of Obstetricians and Gynecologists; ACS, American Cancer Society; USPSTF, United States Preventative Services Task Force

a lifetime risk of 20% or greater using a risk assessment tool, positive genetic test for a BRCA1 or BRCA2 mutation, firstdegree relative with a BRCA1 or BRCA2 mutation, chest radiation before age 30 years, or Li-Fraumeni syndrome or other high-risk predisposition syndromes.13,14

Diagnostic Studies

Upon suspicious findings on physical examination or mammography, additional imaging modalities should be used to further evaluate the area. Ultrasound is a fast and cost-effective way to differentiate between cystic and solid tumors especially in women with dense breasts. Magnetic resonance imaging is used less commonly because of cost and time but can be useful in higher-risk populations.5

If indicated based on imaging results, further workup is performed by biopsy.3 Tumor type is based on the level of tissue invasion found on biopsy (invasive or noninvasive) and is then categorized into subtypes based on tumor markers, which include estrogen, progesterone, and human epidermal growth factor 2 receptors.15 The staging of the tumor is based on the tumor, node, metastasis (TNM) system, which takes into account tumor type and the subtype, metastasis, and lymph node involvement.3,16 The 2 latter categories are not determined until the time of surgery. However, if a lymph node is suspicious on imaging, a biopsy of the node will be conducted at the same time as the breast biopsy.

The grading of the tumor is based on the Nottingham Grading System (NGS), which determines the degree of differentiation from normal breast epithelial cells. Grade 1 is considered a well-differentiated tumor, grade 2 is considered a moderately differentiated tumor, and grade 3 is considered a poorly differentiated tumor. The grade of the tumor has shown to be equally important in prognostic value compared with tumor staging; therefore, both factors should be taken into account when counseling patients on prognosis and treatment.17

Genetic Screening

Genetic mutations cause 5% to 10% of all breast cancers, with the BRCA1 and BRCA2 mutations accounting for 30% of these cases.18 Additional genes that contribute substantial risk include ATM, CHEK2, and PALB2. 19 These genetic mutations are associated with a higher lifetime risk for breast cancer, younger age at onset, and aggressive disease stage.20 The BRCA1 mutation increases the lifetime risk for breast cancer to 50% to 65% ; the BRCA2 mutation increases the risk to 40% to 55%. The BRCA1 and BRCA2 mutations also increase the lifetime risk for pancreatic, prostate, and ovarian cancer. Notably, ovarian cancer lifetime risk increases with BRCA1 to 40% to 65% and BRCA2 to 15% to 25%.18 The ATM mutation carries a 12.8% to 32.3% lifetime risk for breast cancer in addition to an increased risk for ovarian, pancreatic, and prostate cancer. The CHEK2 mutation carries a 15.2% to 37.3% lifetime risk for breast cancer as well as an increased risk for colorectal cancer. The PALB2 mutation carries a 21.5% to 49.2% lifetime risk for breast cancer as well as an increased risk for pancreatic cancer.19

Genetic testing allows providers to identify at-risk patients and offer individualized education and preventative recommendations such as increased surveillance, use of chemoprevention agents, and prophylactic double mastectomy, with the latter showing the greatest risk reduction.18,21

However, it is important to know when to offer genetic testing because it can also come with disadvantages such as cancerassociated anxiety and depression. Testing may identify other unknown mutations that do not have associated counseling and guidelines available yet. Genetic testing may also be costly. Although the test should be covered as preventative medicine, the cost still varies greatly depending on documented risk, laboratory pricing, and insurance coverage. Furthermore, even though a positive result can result in decreased future costs, the initial cost for preventative measures is still substantial.19

Utilizing genetic testing in patients who qualify offers them the unmatched power of knowing they have the gene and ability to take control of their personal and their family’s future health with increased surveillance or preventative measures. Moreover, taking into account the lifetime risk using a risk calculator may qualify them for insurance coverage for both surveillance and preventative strategies.

The recommendations offered by the American Society of Breast Surgeons, National Comprehensive Cancer Network, and US Preventive Services Task Force help to guide primary care providers in selecting patients who would benefit from genetic testing.11,22,23 Although the guidelines differ between these organizations, they all agree that testing is recommended for women with breast cancer onset before age 50 years, triplenegative breast cancer, or 2 or more primary breast cancers. Testing is also recommended for women without breast cancer who have a first or second-degree relative with early-onset breast cancer, relative with recurrent breast cancer, 2 or more relatives with breast cancer, male relative with breast cancer, or family member with a known mutation

The organizations have differing recommendations regarding genetic screening for patients of Ashkenazi Jewish heritage, personal history of ovarian cancer, and family history of pancreatic or prostate cancer.

Case Resolution

In the case patient, the suspicion for malignancy is initially low given her age, nonsmoking status, and healthy lifestyle; however, a detailed history revealed multiple risk factors for breast cancer.

Her only modifiable risk factor was alcohol consumption, but nonmodifiable risk factors included White race, early menarche, and first-degree relative with early-onset breast cancer. Based on these factors, her lifetime risk is calculated at 21.4% on the National Cancer Institute’s Breast Cancer Risk Assessment Tool.13 Additionally, her history revealed risk factors that met the criteria for genetic testing including a first-degree relative with early-onset breast cancer and a relative with recurrent breast cancer. Her positive BRCA1 mutation testing result increased her lifetime risk even further.

This case highlights the role a primary care provider plays in identifying patient risk and adjusting screening and genetic testing recommendations. If the patient’s primary care provider had calculated her lifetime risk for breast cancer before age 30 based on her history, increased screening with mammography and MRI would have been recommended at an earlier age. Additionally, BRCA1 genetic mutation identification would have increased screening recommendations and referral to an oncologist to discuss preventative measures such as bilateral mastectomy or endocrine therapy. Furthermore, if the patient’s mother had been appropriately referred for genetic counseling and testing because of her early-onset breast cancer, the patient would have been referred for testing at an earlier point.

In conclusion, primary care providers are in a position to identify breast cancer risk factors by taking a thorough patient history. Average-risk patients should be counseled on screening recommendations and lifestyle changes to decrease modifiable risk factors. High-risk patients should be counseled on these measures with the addition of genetic counseling or oncologist referral. These interventions result in earlier breast cancer detection and improved prognosis for not only the patient but also their immediate family members. ■

Shannon Stevenson, PA-C, is a critical care physician assistant at Trident Hospital in Charleston, SC. Kelly S. Reed, PharmD, MPA, PA-C, is an assistant professor in the Physician Assistant Program at Augusta University in Augusta, Georgia.

References

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