March 2013 - San Antonio Breast Cancer Symposium 2012 Highlights

San Antonio Breast Cancer Symposium 2012 Highlights MARCH 2013 VOL 4 NO 3

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM www.ValueBasedCancerCare.com

Gabriel N. Hortobagyi, MD, Delivers the William I. McGuire Memorial Lecture

Photo © SABCS/Todd Buchanan 2012

By Caroline Helwick

T

he honor of delivering the William I. McGuire Memorial Lecture at this year’s meeting went to Gabriel N. Hortobagyi, MD, FACP, Professor of Breast Medical Oncology and Nellie B. Connally Chair in Breast Cancer at the University of Texas M.D. Anderson Cancer Cen­­­ter, Houston. Dr McGuire cofounded the San Antonio Breast Cancer Sym­posium in 1977.

Continued on page 6

Gene-Based Test Identifies Breast Cancer with Low Risk for Late Metastasis

By Charles Bankhead

A

n 8-gene panel has demonstrated potential for identifying patients with estrogen receptor (ER)-positive and HER2negative breast cancer at low risk for late metastasis. Patients classified as low risk by the EndoPredict panel had a significantly lower rate of distant metastasis after 5 and 10 years of follow-up compared with patients who did not meet the test’s criteria for low risk, according to Peter Dubsky, MD, of the Breast Health

©2013 Engage Healthcare Communications, LLC

Center, Associate Professor of Sur­ gery, Medical University of Vienna, Austria.

In a multivariate analysis, only the EndoPredict classification and nodal status emerged as independent predictors of the likelihood of late metastasis. Adding the gene test results to clinical variables (EPclin) significantly improved prognostic performance versus the clinical factors alone, Dr Dubsky said.

Continued on page 14

ATLAS: Ten Years of Tamoxifen Superior to 5 Years

By Audrey Andrews

F

or the treatment of estrogen receptor (ER)-positive early breast cancer, 10 years of treatment with tamoxifen yields better outcomes than 5 years of treatment, according to an analysis from the international ATLAS study that was presented at the 2012 San Antonio Breast Cancer Symposium.

“With these new results, we see statistically fewer recurrences when patients take tamoxifen for 10 years

rather than 5, and it is highly significant for breast cancer mortality and overall mortality,” said Richard Gray, MSc, Professor of Medical Statistics at Oxford University, United Kingdom.

“Looking at the risk ratios, you find about a 30% reduction occurring after 10 years.”

Five years of tamoxifen is the current standard duration of treatment, based on a substantial reduction Continued on page 18

Targetable Pathways Revealed for Triple-Negative Breast Cancer

By Audrey Andrews

T

he molecular make-up of triplenegative breast cancer is becoming better understood, and new evidence suggests that the main biologic pathways can be targeted with drugs, according to Justin Balko, PharmD, PhD, Postdoctoral Research

Fellow and Researcher, VanderbiltIngram Cancer Center, Vanderbilt University Medical Center, Nashville.

In his study on genetic alterations, 90% of the patients had mutations in 5 well-recognized pathways, and drugs Continued on page 20

inside CHEMOTHERAPY . . . . . . . . . . . . .

“Chemo brain” may be present before chemotherapy Leukemia risk after chemotherapy small, but real

4

RADIATION THERAPY . . . . . . . . . . .

Intraoperative radiotherapy fares well against EBRT

8

HER2 BREAST CANCER . . . . . . . . 10 Results of IHC and ISH are reliable indicators of HER2 ADVANCED BREAST CANCER . . . 12 Overall survival trend with eribulin versus capecitabine

SENTINEL NODE MANAGEMENT 16 Black women less likely to receive SLN dissection HORMONE THERAPY . . . . . . . . . . 17 Benefit of higher-dose fulvestrant confirmed Ten years of tamoxifen superior to 5 EMERGING THERAPIES . . . . . . . . 18 Investigational CDK inhibitor extends remission OTHER CLINICAL HIGHLIGHTS . . 21 Venlafaxine lowers endoxifen levels, reduces tamoxifen effectiveness

After 2 prior lines of MBC chemotherapy,

Indication Halaven is indicated for the treatment of patients with metastatic breast cancer (MBC) who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Important Safety Information Neutropenia

• Monitor complete blood counts prior to each dose, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days • Severe neutropenia (ANC <500/mm3) lasting more than 1 week occurred in 12% (62/503) of patients. Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels • Grade 3 and Grade 4 neutropenia occurred in 28% and 29%, respectively, of patients who received Halaven. Febrile neutropenia occurred in 5% of patients and two patients (0.4%) died from complications

Peripheral Neuropathy

• Patients should be monitored closely for signs of peripheral motor and sensory neuropathy

HALAVEN ® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2012 Eisai Inc. All rights reserved. Printed in USA/August 2012 HALA0041 R1

• Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4 in 0.4% of patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less • Neuropathy lasting more than 1 year occurred in 5% of patients.

Twenty-two percent of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days) • Peripheral neuropathy (5%) was the most common adverse reaction resulting in discontinuation

Pregnancy Category D

• Halaven is expected to cause fetal harm when administered to a pregnant woman and patients should be advised of these risks

QT Prolongation

• In an uncontrolled ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias;

DISCOVER OVERALL SURVIVAL

LISTED AS A PREFERRED SINGLE AGENT IN THE NCCN GUIDELINES®1

HALAVEN: The FIRST and ONLY single-agent therapy proven to significantly extend OVERALL SURVIVAL after 2 prior lines of MBC therapy2-10 UPDATED OVERALL SURVIVAL (OS) ANALYSIS (UNPLANNED): MEDIAN OS, MONTHS (95% CI)2,11,a

P R O P O R T I O N O F PAT I E N T S A L I V E

1.0 0.9 0.8

Halaven

25% (2.6 month)

(n=508)

13.2

0.7

INCREASE

(12.1, 14.4)

0.6

IN MEDIAN OS

Deaths=386

0.5

Treatment of Physician’s Choice

0.4

(n=254)

0.3

10.6

0.2

(9.2, 12.0)

0.1

Deaths=203

0.0 0

6

12

18

24

30

36

54 26

11 5

0 Halaven 0 TPC

TIME (MONTHS) Number of patients at risk

508 254

406 178

274 106

142 61

Results from an updated, unplanned survival analysis of the Phase III, randomized, openlabel, multicenter, multinational EMBRACE* trial of Halaven versus TPC in patients with MBC (N=762), conducted when 77% of events (deaths) had been observed. The primary endpoint was OS. Patients were randomized (2:1) to receive either Halaven 1.4 mg/m2 IV for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization.

At baseline, all patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen. All patients received prior anthracyclineand taxane-based chemotherapy, unless contraindicated. Therapies in the TPC arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxanes [included paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracyclines, 10% other chemotherapy), and 3% hormonal therapy.

CI=confidence interval; Treatment of Physician’s Choice (Control arm)=TPC. a Conducted in the intent-to-treat (ITT) population.

The updated OS analysis was consistent with the primary analysis2 The primary analysis, conducted when ~50% of events (deaths) had been observed, demonstrated a median OS for Halaven vs TPC of 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months (95% CI: 9.3, 12.5), HR†=0.81 (95% CI: 0.66, 0.99) (P=0.041)2,11

QT Prolongation (cont’d)

concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities • Correct hypokalemia or hypomagnesemia prior to initiating Halaven and monitor electrolytes periodically during therapy.

Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment

• For patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic and/or moderate (CrCl 30-50 mL/min) renal impairment, a reduction in starting dose is recommended

Most Common Adverse Reactions

• Most common adverse reactions (≥25%) reported in patients receiving Halaven were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%) • The most common serious adverse reactions reported in patients receiving Halaven were febrile neutropenia (4%) and neutropenia (2%)

References: 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Breast Cancer. Version 1.2012. http:NCCN.org. Published January 20, 2012. Accessed March 5, 2012.‡ 2. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2012. 3. Saad ED et al.

J Clin Oncol. 2010;28(11):1958-1962. 4. Slamon DJ et al. N Engl J Med. 2001;344(11):783-792.

5. Geyer CE et al. N Engl J Med. 2006;355(26):2733-2743. 6. von Minckwitz G et al. J Clin Oncol.

2009;27(12):1999-2006. 7. Miller K et al. N Engl J Med. 2007;357(26):2666-2676. 8. Robert NJ et al.

J Clin Oncol. 2011;29(10):1252-1260. 9. Sparano JA et al. J Clin Oncol. 2010;28(20):3256-3263.

10. Jones SE et al. J Clin Oncol. 2005;23(24):5542-5551. 11. Cortes J et al. Lancet. 2011;377(9769):914-923. *EMBRACE=Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice versus E7389 (Eribulin). †HR=hazard ratio. ‡Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Breast Cancer V.1.2012. © 2012 National Comprehensive Cancer Network, Inc. All rights reserved.

Accessed March 5, 2012. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

Visit www.halaven.com

Please see accompanying brief summary of Halaven full Prescribing Information.

Chemotherapy

“Chemo Brain” May Be Present Before Chemotherapy

By Caroline Helwick

C

hemotherapy may not necessarily be the reason that patients with breast cancer often complain of “fuzzy thinking” and difficulty solving problems, according to

research showing that cognitive changes are present in some patients at baseline, and may be related to fatigue and anxiety.

Bernadine Cimprich, PhD, RN, Pro­

HALAVEN® (eribulin mesylate) Injection BRIEF SUMMARY – See package insert for full prescribing information.

2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.

Recommended dose delays • Do not administer HALAVEN on Day 1 or Day 8 for any of the following: – ANC <1,000/mm3 – Platelets <75,000/mm 3 – Grade 3 or 4 non-hematological toxicities.

• The Day 8 dose may be delayed for a maximum of 1 week.

– If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose.

– If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate the next cycle no sooner than 2 weeks later.

Recommended dose reductions • If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a reduced dose as set out in Table 1.

• Do not re-escalate HALAVEN dose after it has been reduced.

Table 1 Recommended Dose Reductions Recommended Event Description HALAVEN Dose 2 Permanently reduce the 1.4 mg/m HALAVEN dose for any of the following: ANC <500/mm3 for >7 days ANC <1,000 /mm3 with fever or infection Platelets <25,000/mm3 1.1 mg/m2 Platelets <50,000/mm3 requiring transfusion Non-hematologic Grade 3 or 4 toxicities Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicity Occurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2 0.7 mg/m2 Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 Discontinue HALAVEN ANC = absolute neutrophil count.

Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

5 WARNINGS AND PRECAUTIONS 5.1 Neutropenia Severe neutropenia (ANC <500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with alanine aminotransferase or aspartate aminotransferase >3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin >1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.

Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3.

5.2 Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1. Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.

5.3 Embryo-Fetal Toxicity There are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.

5.4 QT Prolongation In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome.

6 ADVERSE REACTIONS The following adverse reactions are discussed in detail in other sections of the labeling: • Neutropenia • Peripheral neuropathy • QT interval prolongation The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%).

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).

The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.

Table 2 Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1 MedDRA ver 10.0 HALAVEN (n=503) Control Group (n=247) All Grades ≥ Grade 3 All Grades ≥ Grade 3 Blood and Lymphatic System Disordersa Neutropenia 82% 57% 53% 23% Anemia 58% 2% 55% 4% Nervous system disorders b 35% 8% 16% 2% Peripheral neuropathy Headache 19% <1% 12% <1% General disorders and administrative site conditions Asthenia/Fatigue 54% 10% 40% 11% Mucosal inflammation 9% 1% 10% 2% Pyrexia 21% <1% 13% <1% Gastrointestinal disorders Constipation 25% 1% 21% 1% Diarrhea 18% 0 18% 0 Nausea 35% 1% 28% 3% Vomiting 18% 1% 18% 1% Musculoskeletal and connective tissue disorders Arthralgia/Myalgia 22% <1% 12% 1% Back pain 16% 1% 7% 2% Bone pain 12% 2% 9% 2% Pain in extremity 11% 1% 10% 1% Investigations Weight decreased 21% 1% 14% <1% Metabolism and nutrition disorders Anorexia 20% 1% 13% 1% Respiratory, thoracic, and mediastinal disorders Cough 14% 0 9% 0 Dyspnea 16% 4% 13% 4% Skin and subcutaneous tissue disorders 10% NAc Alopecia 45% NAc

Table 2 (cont'd) MedDRA ver 10.0

fessor Emeritus at the University of Michigan School of Nursing in Ann Arbor, said that altered neural activation before treatment, along with fatigue, contributed to cognitive probHALAVEN (n=503) All Grades ≥ Grade 3

Control Group (n=247) All Grades ≥ Grade 3

Infections and Infestations Urinary Tract Infection 10% 1% 5% 0 Based upon laboratory data. b Includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. c Not applicable; (grading system does not specify > Grade 2 for alopecia).

Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of patients who received HALAVEN. Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.

Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN. Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the HALAVENtreated group: • Eye Disorders: increased lacrimation • Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth • General Disorders and Administration Site Conditions: peripheral edema • Infections and Infestations: upper respiratory tract infection • Metabolism and Nutrition Disorders: hypokalemia • Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness • Nervous System Disorders: dysgeusia, dizziness • Psychiatric Disorders: insomnia, depression • Skin and Subcutaneous Tissue Disorders: rash 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category D There are no adequate and well-controlled studies with HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen.

Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose.

Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption.

8.3 Nursing Mothers It is not known whether HALAVEN is excreted into human milk. No studies in humans or animals were conducted to determine if HALAVEN is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from HALAVEN, a decision should be made whether to discontinue nursing or to discontinue HALAVEN taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have not been established.

8.6 Hepatic Impairment Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C).

8.7 Renal Impairment For patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of HALAVEN was not studied in patients with severe renal impairment (CrCl <30 mL/min).

10 OVERDOSAGE Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day.

There is no known antidote for HALAVEN overdose.

12 CLINICAL PHARMACOLOGY 12.3 Pharmacokinetics Specific Populations Hepatic Impairment A study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=5) hepatic impairment.

Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function.

Renal Impairment No formal PK trials were conducted with HALAVEN in patients with renal impairment. Available data suggests that geometric mean dose-normalized systemic exposure is similar for patients with mild renal impairment (CrCl 50-80 mL/min) relative to patients with normal renal function. However, for patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dosenormalized systemic exposure increased 2-fold compared to patients with normal renal function.

12.6 Cardiac Electrophysiology The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies have not been conducted with eribulin mesylate.

Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay.

The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling • Advise patients to contact their health care provider for a fever of 100.5°F or greater or other signs or symptoms of infection such as chills, cough, or burning or pain on urination.

• Advise women of childbearing potential to avoid pregnancy and to use effective contraception during treatment with HALAVEN. –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– a

HALAVEN® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2012 Eisai Inc. All rights reserved. Printed in USA / March 2012 ERI 346

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Value-Based Cancer Care

ERIBPUS-4306_M04_A_SIZE_Brief_Summary.indd 1

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March 2013

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lems in women who were diagnosed with breast cancer before they received chemotherapy, based on a study that included 65 women with stage 0 through stage IIa breast cancer.

Of these women, 28 were slated for adjuvant chemotherapy and 37 for radiation alone. These patients were age-matched to 32 healthy controls.

The investigators used functional magnetic resonance imaging (fMRI) to assess changes in the left inferior frontal gyrus of the brain during tasks associated with working memory. The women had undergone fMRI scans before adjuvant therapy

Worry and stress associated with a breast cancer diagnosis, along with anticipatory anxiety before chemotherapy, can affect cognitive function.

“Cognitive effects can worsen over time.”

—C. Kent Osborne, MD

and 1 month after therapy. Healthy controls had fMRI scans performed after a negative mammogram and again 5 months later.

Patients who received chemotherapy reported significantly greater fatigue than those undergoing radiation or healthy controls. They also performed more poorly on the verbal memory tasks before treatment, which corresponded to reduced brain activity on fMRI. Healthy controls had more activation in the left inferior frontal gyrus, and the radiotherapy group fell in between these 2 groups on fMRI. The level of fatigue was correlated with performance on the memory task.

C. Kent Osborne, MD, Director, Breast Cancer Center, and Professor of Medicine and Cellular and Structural Biology, Baylor College of Medicine, Houston, TX, who moderated the press conference where these findings were presented, said that these findings make sense.

Worry and stress associated with a breast cancer diagnosis, along with anticipatory anxiety before chemotherapy, can affect cognitive function, Dr Osborne agreed, calling for more attention to this problem. “Cognitive effects can worsen over time,” Dr Osborne added. n

3/28/12 3:08 PM

Vol. 4

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No. 3

In This Issue San Antonio Breast Cancer Symposium 2012 Highlights

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM

Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889

CHEMOTHERAPY

SENTINEL NODE MANAGEMENT

“Chemo brain” may be present before chemotherapy Dose-dense chemotherapy in breast cancer More….

SLN surgery correctly stages lymph nodes after neoadjuvant chemotherapy More….

RADIATION THERAPY

ATLAS: 10 years of tamoxifen superior to 5 years Benefit of higher doses of fulvestrant confirmed More….

Intraoperative radiotherapy fares well against EBRT Hypofractionation validated for breast radiotherapy: less potential for toxicity

Associate Editor Lara J. Lorton lara@engagehc.com 732-992-1882 Publisher Cristopher Pires cris@engagehc.com 732-992-1896

Editorial Assistant Jennifer Brandt jbrandt@the-lynx-group.com 732-992-1536

OTHER CLINICAL HIGHLIGHTS Venlafaxine lowers endoxifen levels, reduces tamoxifen effectiveness Anticancer effects of metformin still cloudy More….

Eribulin plus trastuzumab an effective combination More….

Director, Creative & Design Robyn Jacobs Quality Control Director Barbara Marino Business Manager Blanche Marchitto

Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments.

This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care.

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EHC116

No. 3

HDAC inhibitor plus PARP inhibitor or cisplatin induce apoptosis of cancer cells More….

HER2 mutations may become new treatment targets More….

ADVANCED BREAST CANCER

Vice President of Finance Andrea Kelly

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TRIPLE-NEGATIVE BREAST CANCER

HER2 BREAST CANCER

Vice President, Director of Sales & Marketing Joe Chanley joe@greenhillhc.com

Vol. 4

HORMONE THERAPY

VBCC Editorial Board Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL

Ira Klein, MD, MBA Aetna Hartford, CT

Al B. Benson III, MD, FACP, FASCO Professor of Medicine Associate Director for Clinical Investigations, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL Past Chair, NCCN Board of Directors

Kevin B. Knopf, MD, MPH Medical Oncology, California Pacific Medical Center, Sutter Health Care, San Francisco, CA

Ted Okon, BS, MBA Executive Director Community Oncology Alliance Washington, DC Naimish Pandya, MD University of Maryland Baltimore, MD

Mark J. Krasna, MD Corporate Medical Director of Oncology Jersey Shore University Medical Center Neptune, NJ

Ed Pezalla, MD, MPH National Medical Director of Pharmacy Policy and Strategy Aetna, Hartford, CT

Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, NY

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC

Denise K. Pierce DK Pierce & Associates Zionsville, IN

Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA

Crystal Kuntz, MPA Astellas Pharma US Washington, DC

Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers Pittsburgh, PA

John L. Marshall, MD Chief, Hematology and Oncology Director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers Lombardi Comprehensive Cancer Center Georgetown University Medical Center Washington, DC

Arlene A. Forastiere, MD Senior Vice President Medical Affairs, eviti, Inc Philadelphia, PA Tracy Gosselin, RN, MSN Duke University Medical Center Durham, NC Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute New York, NY David Hom, MBA Solucia Farmington, CT Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL

Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX

Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT Marcus Neubauer, MD Medical Director, Oncology Services McKesson Specialty Health The Woodlands, TX

Jayson Slotnik, JD, MPH Partner, Health Policy Strategies, LLC, Washington, DC Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA G. Rhys Williams, ScD, MS Amgen, Thousand Oaks, CA

Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD

Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region, Portland, OR

Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA

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Burt Zweigenhaft, BS Chief Executive Officer, OncoMed Onco360, Great Neck, NY

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Chemotherapy

Neoadjuvant Systemic Therapy: Promising Experimental Model or Improved Standard of Care?

Neoadjuvant systemic therapy is a treatment strategy that has been used for more than 30 years but its role is still evolving. The concept emerged after anthracycline-containing combination regimens showed dramatic responses in large primary tumors: almost 90% of patients achieved at least a 50% reduction in measurable tumors, and approximately 10% achieved complete remissions (CRs).

When used earlier in the preoperative setting, anthracycline-based regimens became a means of improving the management of largely inoperable breast cancer. Eventually, in efforts led largely by Dr Hortobagyi, it was learned that clinical response to neoadjuvant chemotherapy would predict for overall survival (OS).

Dr Hortobagyi’s team at M.D. Anderson Cancer Center, and others, pioneered multidisciplinary strategies consisting of neoadjuvant chemotherapy followed by surgery and radiotherapy. Such strategies rapidly became the standard of care for patients with locally advanced breast cancer and with inflammatory breast cancer, improving local control rates to more than 80% and 5-year OS rates to more than 30%, he said.

“In the early 1980s, we described the concept of pathological CR and its correlation with favorable long-term overall survival,” he continued. A Cochrane review concluded that preoperative chemotherapy compared with adjuvant chemotherapy was associated with equivalent OS and disease-free survival (DFS), and increased breast conservation rates. Although local-regional recurrence rates were increased with neoadjuvant therapy, this was not seen when surgery was part of the management.

The Importance of Achieving pCR The achievement of a pathological CR (pCR) was associated with much better OS (hazard ratio [HR], 0.48) and DFS (HR, 0.48), the Cochrane investigators noted. But more recently, the impact of pCR on prognosis has been shown to vary according to the molecular subtypes that are now recognized. DFS is significantly better when pCR is achieved, in the case of luminal B/HER2-negative, nonluminal/HER2-positive, and triple-negative tumors; however, pCR is not associated with prognosis in luminal A tumors or in luminal B/HER2positive tumors, he said.

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Photo © SABCS/Todd Buchanan 2012

Gabriel N. Hortobagyi, MD, Delivers the...

“There is no individual pathological or molecular marker that can predict response to primary chemotherapy in an individual patient, although patients with estrogen receptor–negative, highgrade tumors and high S-phase fraction (or Ki67) are more likely to respond than [patients with] tumors with the opposite characteristics.”

—Gabriel N. Hortobagyi, MD, FACP

Dr Hortobagyi explained that “patients with hormone receptor–positive (luminal A and luminal B/HER2positive) tumors receive their primary systemic therapy (ie, endocrine treatment) after surgery. Therefore, pCR cannot possibly predict long-term outcomes. And patients with luminal B/ HER2-negative cancer have primary resistance to endocrine therapy, so pCR reflects entirely the benefit from systemic therapy (ie, chemotherapy).

In all other subtypes, pCR is highly predictive.”

Along with intrinsic subtype, a number of clinical and pathological factors predict pCR: tumor grade (high vs low), estrogen receptor (high vs low), HER2 status (high vs normal), histological type (ductal vs lobular), proliferation markers (high vs low), speed of clinical response (rapid vs slow), MDR1 gene expression (yes vs no), and extent of disease (stage III vs I).

“But there is no individual pathological or molecular marker that can predict response to primary chemotherapy in an individual patient,” Dr Hortobagyi emphasized, “although

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patients with estrogen receptor– negative, high-grade tumors and high S-phase fraction (or Ki67) are more likely to respond than [patients with] tumors with the opposite characteristics.”

A number of studies have attempted to correlate results in the neoadjuvant setting with outcomes, but more data are needed, he said. “We are awaiting with great interest the results of ALTTO, E5103, BETH, APHINITY, and other trials to determine whether promising results in the neoadjuvant setting uniformly translate into improved long-term outcomes,” he commented.

The Bottom Line on Neoadjuvant Systemic Therapy Dr Hortobagyi summarized the current state of neoadjuvant systemic therapy this way: • Does it downstage primary tumor and axillary lymph node involvement? Clearly, yes • Does it increase breast conservation rates? Clearly, yes • Does it affect local control? Not without optimal multidisciplinary planning • Does it affect survival? Maybe. The survival effect needs to be assessed in patients with HER2-positive and triple-negative breast cancer.

Is neoadjuvant chemotherapy an acceptable alternative outside of a clinical trial? It is the treatment of choice for patients with locally advanced and inflammatory breast cancer, and it is an acceptable and preferred alternative to surgery followed

by adjuvant chemotherapy for most patients with T2 and T3 tumors.

“Preoperative systemic therapy is optimal for all patients who are candidates for systemic therapy, and it should be tailored to the biological profile of the primary tumors. If the indication for systemic therapy is uncertain, surgical removal is preferable,” Dr Hortobagyi noted.

“Preoperative systemic therapy is not indicated,” he continued, “when systemic therapy is not indicated, primary and/or lymph node metastases cannot be measured and monitored, the patient is not compliant, and a multidisciplinary team is not available.”

Neoadjuvant chemotherapy is also “an excellent translational research tool” and, as such, will have some novel applications in the future.

Neoadjuvant chemotherapy is also “an excellent translational research tool” and, as such, will have some novel applications in the future, Dr Hortobagyi predicted. It will have a role in drug development; it will offer a means of monitoring biologic end points; and, when incorporated into randomized trials, it will justify or allow for the avoidance of randomized adjuvant trials. n

Dose-Dense Chemotherapy in Breast Cancer

By Audrey Andrews

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wo studies presented in San Antonio reached conflicting conclusions regarding the value of dose-dense chemotherapy in patients with early breast cancer.

The phase 3 UK TACT2 trial compared standard chemotherapy with epirubicin plus CMF (cyclophosphamide/methotrexate/fluorouracil) with accelerated (dose-dense) epirubicin in node-positive or in high-risk, node-negative early breast cancer.

The current report focused on the impact of accelerating epirubicin chemotherapy; the capecitabine/CMF comparison is premature.

The study included 4391 patients randomized between 2005 and 2008 to epirubicin (100 mg/m2 for 4 cycles) every 3 weeks or accelerated epirubicin (100 mg/m2 for 4 cycles plus peg­ filgrastim 6 mg on day 2) every 2 weeks, followed by classical CMF every 4 weeks for 4 cycles or capecitabine (2500 mg/m2 daily for 14 days) every 3 weeks for 4 cycles. Other adjuvant treatment for HER2-positive or hormone receptor−positive disease was given as needed.

At a median follow-up of 49 months, the primary end point—time to recurContinued on page 7

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Chemotherapy

Adjuvant Chemotherapy Reduces Local and Regional Tumor Recurrence, Especially for Patients with ER-Negative Breast Cancer

By Susan Reckling

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djuvant chemotherapy should be recommended for patients with completely resected, isolated local or regional recurrence (ILRR) of breast cancer, and the argument is strongest for women with estrogen receptor (ER)-positive tumor recurrences, according to the results of the international Chemotherapy as Adjuvant for Locally Recurrent Breast Cancer (CALOR) trial.

Stefan Aebi, MD, Head of Medical Oncology, Luzerner Kantonsspital, Lucerne, Switzerland, reported that, for patients with ILRR, adjuvant chemotherapy reduced the risk of recurrences by 41% and the risk of death by 59% in CALOR, which is reportedly the first randomized controlled trial to show a benefit of adjuvant chemotherapy in these patients.

Traditionally, the prognosis of women with ILRR has been poor, Dr

Aebi pointed out, with a disease-free survival of approximately 50% at 5 years. Surgery and radiation therapy represent the standards of care for this patient population, but the recent findings from the CALOR trial may suggest an emerging role for adjuvant chemotherapy in some of these women.

A heterogeneous group of 162 patients took part in the CALOR trial.

After mastectomy or breast-conserving surgery, the women were stratified by hormone receptor status of ILRR, site of tumor recurrence (ie, breast, chest wall, lymph nodes), and the use of previous chemotherapy.

Chemotherapy was by physician’s choice, but the suggested approach was a combination of at least 2 drugs for 3 to 6 months of treatment.

Radiation therapy was recommended for all the women, but was mandatory only for those with micro-

Dose-Dense Chemotherapy... rence (TTR)—was not significantly different for the 2 treatment strategies, reported David Cameron, MD, Pro­ fessor of Oncology, University of Edinburgh, Scotland.

The TTR rates were 90.9% with standard chemotherapy and 91.0% with accelerated epirubicin at 3 years, and 85.2% and 86.4%, respectively (P = .60), at 5 years.

Overall survival (OS) rates were similar―95.4% with standard chemotherapy and 94.4% with accelerated epirubicin at 3 years, and 89.3% and 88.8%, respectively, at 5 years (P = .23).

No subgroup benefited more from the dose-dense regimen than any other subgroup.

“There was no evidence of any improvement in disease outcomes,” Dr Cameron noted.

The dose-dense approach was associated with less myelosuppression (growth factors were mandatory), but more hand-foot toxicity.

Dose-Dense/Dose-Intense Regimen Superior to Conventional Chemotherapy In contrast, the phase 3 German AGO iddETC (intense dose-dense epirubicin/paclitaxel/cyclophosphamide) trial showed that an epirubi-

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“The 12% absolute difference at 5 years corresponds to a hazard ratio of 0.59, or a 41% relative reduction in the risk of tumor recurrence, which is statistically significant, with a P value of .045.”

—Stefan Aebi, MD

scopically involved margins.

At 4.9 years of median follow-up, the 5-year disease-free survival probability was 69% in the group that received chemotherapy compared with 57% for those who did not receive chemotherapy, Dr Aebi reported.

“The 12% absolute difference at 5 years corresponds to a hazard ratio of 0.59, or a 41% relative reduction in the risk of tumor recurrence, which is statistically significant, with a P value of .045,” he said.

Based on the disease-free survival data that were categorized by ER status, the efficacy of chemotherapy was “huge” for those with ER-negative tumor recurrences (hazard ratio, 0.32; P = .007). In contrast, the difference was marginal in the women with ERpositive tumors, Dr Aebi reported.

In terms of overall survival, at 5 years of median follow-up, the relative survival rate was 88% in the women who received chemotherapy compared with 76% in those who did not receive chemotherapy, corresponding to a relative risk reduction of 59%. The survival analysis based on ER status is still premature, Dr Aebi added. n

Continued from page 6

cin-based regimen that was dose-dense and dose-intense was superior to standard chemotherapy.

Volker J. Möbus, PhD, Head, De­ part­ ment of Obstetrics and Gyne­ cology, of the Klinikum Frankfurt Hoechst in Germany, reported, “At 10 years, recurrence-free survival and

“We observed no therapyrelated deaths or longterm toxicity….The iddETC regimen should be considered a standard regimen for high-risk breast cancer patients with nodepositive disease.”

—David Cameron, MD

overall survival continue to be significantly superior, with an absolute difference in overall survival of 10%.”

The iddETC trial enrolled 1284 patients with ≥4 positive lymph nodes (median, 8). In the experimental arm (iddETC), patients received 3 cycles each of epirubicin (150 mg/m2) every

2 weeks with growth factor support.

In the standard arm, they received 4 cycles of conventionally dosed epirubicin plus cyclophosphamide (90/600 mg/m2) followed by 4 cycles of paclitaxel (175 mg/m2), all in 3-week intervals without growth factor support.

At a median follow-up of 122 months, time to relapse, which was the primary end point, was reduced by 26% (P = .014) in the iddETC arm.

“We saw that iddETC improved disease-free survival irrespective of nodal status, HER2 status, and estrogen receptor status,” Dr Möbus said.

Deaths were reduced by 28% in the iddETC arm. The 10-year OS rates were 69% and 59%, respectively (P = .007). The most benefit was seen in patients with ≥10 positive nodes, where mortality was reduced by 34% (P = .016) and 10-year survival rates were 62% and 48%, respectively, Dr Cameron explained.

Epoetin Alfa Reduces the Need for Transfusions The iddETC arm was randomized to receive epoetin alfa as prophylaxis treatment against anemia, or no epoetin alfa, in an effort to determine the safety, efficacy, and the impact on clin-

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ical outcomes. Dose-dense regimens with growth factor support require red blood cell transfusions in up to 25% of patients, Dr Möbus noted.

Red blood cell transfusions were significantly lower among patients who received epoetin alfa (13% vs 28%; P <.001), and there was no increase in recurrences or deaths. There was no difference in relapse rates or OS; however, the use of epoetin alfa was as­ sociated with an increase in venous thromboembolism―13% versus 7%—a known consequence of these drugs.

“Epoetin alfa diminished the percentage of red blood cell transfusions, and primary prophylaxis avoided a decline in hemoglobin values. Negative impacts on recurrence-free and overall survival were not found,” Dr Möbus pointed out.

Dr Cameron concluded that iddETC is a feasible regimen with a manageable toxicity profile. “We observed no therapy-related deaths or longterm toxicity, such as congestive heart failure or peripheral neuropathy, and no increases in myelodysplastic syndrome or acute myeloid leukemia.

The iddETC regimen should be considered a standard regimen for highrisk breast cancer patients with node-positive disease.” n

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Chemotherapy

Risk of Leukemia after Chemotherapy Small, but Real

By Audrey Andrews

F

ewer than 0.5% of patients with breast cancer develop leukemia associated with chemotherapy, but this is 60% higher than the proportion documented in a previous analysis, according to a report based on the National Comprehensive Cancer Network (NCCN) database.

“Adjuvant chemotherapy was associated with a cumulative 10-year incidence of leukemia of about 0.5%, which appears to be higher than previously reported,” said Antonio Wolff, MD, Professor of Oncology at the Sidney Kimmel Comprehensive Can­ cer Center, Johns Hopkins Medicine, Baltimore, MD. There have been concerns that chemotherapy may induce second malignancies. Ten years ago, the National Surgical Adjuvant Breast and Bowel Project (NSABP) found a 0.27% risk of myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML) occurring 8 years after treatment with doxorubicin plus cyclophosphamide.

The greatest risk was seen among patients who received radiotherapy or growth factors.

In NSABP B-38, which was reported at the 2012 American Society of Clinical Oncology annual meeting, a 0.49% risk for patients with MDS and AML was found 5 years after treatment for breast cancer in patients who received growth factors.

To gauge the true risk, Dr Wolff and colleagues analyzed prospectively collected data on 20,533 patients with breast cancer who were followed for a median of 5.1 years.

Patients had stage I to III breast cancer and received treatment at 8 NCCN cancer centers between 1997 and 2008. Women who developed a recurrence were excluded.

Hematologic Malignancies Developed There were 51 cases of AML among the 20,533 patients, including 44 cases of myeloid leukemia and 7 cases of lymphoid leukemia.

“Leukemia risk was not limited to MDS and AML, and cases of high-risk lymphoid were observed,” Dr Wolff reported.

Because the hazard ratios (HRs) for the 2 types of malignancies were similar, these data sets were combined for final analysis. Most patients received 4 or 6 cycles of anthracycline and/or an alkylating agent, with or without a taxane.

Although many women today receive docetaxel plus cyclophosphamide and eliminate the anthracycline, this regimen was not well represented in this data set; therefore, its link to leukemia is unknown, he added.

“Adjuvant chemotherapy was associated with a cumulative 10-year incidence of leukemia of about 0.5%, which appears to be higher than previously reported.”

—Antonio Wolff, MD

The adjusted HR for the risk of leukemia was 1.29 for the receipt of radiation versus no radiation, but this increase did not reach statistical significance. The HR was 2.51 for any chemotherapy versus no chemotherapy (P = .007) and 1.59 for chemotherapy plus radiation versus one of these modalities alone (P = .127).

“We have to think carefully about treating women with a low risk of recurrence or with a biological subtype that is unlikely to benefit.”

—Eric P. Winer, MD However, in a stratified analysis that included women treated only with surgery, a trend was observed for an increased risk with radiotherapy only (HR, 2.73; P = .194), and significant differences were seen for chemotherapy only (HR, 5.68; P = .037) and chemotherapy plus radiation (HR, 5.64; P = .028). The risk for the combined modality was not significantly higher than that seen with chemotherapy alone, Dr Wolff reported.

“Radiation alone appears to be a risk factor, but may not add much to patients already treated with chemotherapy,” Dr Wolff concluded.

The cumulative incidences of leukemia for all the patients were 0.25% at 5 years and 0.46% at 10 years, and for the chemotherapy plus radiotherapy cohort, they were 0.32% and 0.51%, respectively.

The baseline incidence of leukemia in women this age (ie, the risk for the

general population) is not known, but Dr Wolff said the surgery-only cohort gives us an idea. Compared with surgery only, chemotherapy increased the risk, he noted, “but there are challenges in comparing this with baseline risk, because other factors, such as family history, could be in play.”

He further noted that because MDS was underreported until fairly recently, it may occur more frequently than suggested by this analysis, which did not find an increased risk.

More than 50% of the events emerged ≥5 years after chemotherapy was given. The median time to an event was 3.3 years overall, although it extended to 8 years in some cases.

Dr Wolff pointed out that although the latency period for anthracyclines is 1 to 3 years, it is much longer for cyclophosphamide. “Patients exposed to cyclophosphamide could be at risk at 10 years or more,” he estimated.

Eric P. Winer, MD, Professor of Medicine at Harvard Medical School, Boston, MA, emphasized that the risk of leukemia after chemotherapy is “quite small” and is actually less than 0.5%, considering that the general population has a baseline risk that is “greater than zero.”

Dr Winer indicated that when chemotherapy provides a benefit to the patient, the risk of leukemia is far less important than the risk of recurrence.

But he noted that many patients are unnecessarily treated with chemotherapy, because they derive no benefit, and for these patients any degree of leukemia risk is of concern.

“We have to think carefully about treating women with a low risk of recurrence or with a biological subtype that is unlikely to benefit,” Dr Winer emphasized. n

Radiation Therapy

Intraoperative Radiotherapy Fares Well Against EBRT

By Charles Bankhead

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ow-dose intraoperative radiation therapy has proved comparable with whole-breast irradiation for preventing breast cancer recurrence, according to the preliminary results of the large randomized Targeted Intraoperative Radiotherapy (TARGIT-A) trial.

After a median follow-up of 29

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months, the estimated 5-year absolute difference in relapses is 2.0% in favor of whole-breast irradiation. Although this numerically favors whole-breast irradiation, the difference is still within the 2.5% margin established for noninferiority.

In addition, a trend toward lower mortality has emerged in the intra-

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operative radiotherapy arm, driven by significantly lower non–breast cancer mortality, reported Jayant S. Vaidya, MBBS, MS, DNB, PhD, FRCS, a leader in breast surgery and oncology and a Consultant Surgeon at the Whittington, Royal Free, and University College London hospitals.

“The locoregional recurrence is

mainly driven by ipsilateral breast recurrence, and it is not seen in the largest subgroup of prepathology, PgR [progesterone receptor]-positive cases,” said Dr Vaidya. “Similarly, all recurrence is driven by ipsilateral breast recurrence, and there is no difference in the largest subgroup of Continued on page 9

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Radiation Therapy

Hypofractionation Validated for Breast Radiotherapy: Less Potential for Toxicity Shown

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en-year disease control in patients with nonmetastatic breast cancer did not differ significantly between patients treated with a reduced-dose hypofractionated radiation therapy compared with a standard protocol, according to a study presented at the meeting.

The 10-year locoregional recurrence rate was 4.3% in patients who received a 40-Gy radiation dose in 15 fractions and 5.5% in patients randomized to 50 Gy in 25 fractions.

Delivering a lower radiation dose in fewer fractions led to a significant reduction in the rate of adverse effects (AEs) to normal tissue, resulting in an absolute difference of 8.1% at 10 years, said John R. Yarnold, BSc, MBBS, MRCP, FRCR, Professor of Clinical Oncology, the Royal Marsden in London, and a senior investigator at the UK National Institute for Health Research.

“Patients can be safely and effectively treated to a lower total dose with fewer fractions than the historical standard of 50 Gy in 25 fractions,” said Dr Yarnold. “No detrimental effects of hypofractionation were identified in the subgroups studied.”

“These results support 40 Gy in 15 fractions as the United Kingdom standard for all patients with invasive breast cancer,” he maintained.

A companion trial that randomized patients to 3 radiation protocols showed an absolute difference of 4.1% in moderate or marked AEs at 10 years with a 39-Gy radiation dose administered in 13 fractions versus 50 Gy in 25 fractions. However, women receiving the lower dose had a 1% decrement in relapse-free survival compared with the standard-protocol group.

These findings came from the Standardisation of Breast Radiother­ apy (START) clinical trial program, comprising a pilot study and 2 randomized trials involving patients with early (T1-T3) breast cancer.

Started in 1999, the START A and B trials involved more than 4000 patients who were enrolled at 35 centers throughout the United Kingdom.

Both trials examined the relative safety and efficacy of hypofractionation versus the 50-Gy/25-fraction standard protocol for breast radiotherapy. Investigators hypothesized that a lower total dose of radiation delivered in fewer but larger fractions would reduce toxicity with no loss of disease control compared with the standard protocol. START B also evaluated the effects of administering the lower-dose protocol over a shorter time period.

After complete excision, patients in START A were randomized to 3

Photo © SABCS/Todd Buchanan 2012

By Charles Bankhead

“Patients can be safely and effectively treated to a lower total dose….These results support 40 Gy in 15 fractions as the United Kingdom standard for all patients with invasive breast cancer.”

—John R. Yarnold, BSc, MBBS, MRCP, FRCR

radiotherapy protocols: 50 Gy in 25 fractions over 5 weeks, 41.6 Gy in 13 fractions over 5 weeks, and 39 Gy in 13 fractions over 5 weeks. START B patients were randomized to radiation doses of 50 Gy in 25 fractions over 5 weeks or to 40 Gy in 13 fractions over 3 weeks.

Intraoperative Radiotherapy Fares Well... prepathology PgR-positive patients.

We saw no difference in the rate of distant recurrence.”

Dr Vaidya noted that primary breast cancer often develops in a multicentric manner, but recurrence is most often ipsilateral. As a result, focusing radiation therapy on the primary tumor site is a logical strategy, giving rise to the TARGIT-A protocol, which was developed at University College London.

The rationale for the approach is further supported by evidence from 2008 that irradiation of the wound bed inhibits proliferation, motility, and invasiveness that can be stimulated by wound fluid.

Using a portable radiation therapy machine, clinicians deliver an approximate 20-Gy dose directly to the wound bed after surgical excision. Patients with high-risk features receive supple-

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mental external beam radiation therapy (EBRT).

The TARGIT-A Trial Dr Vaidya reported findings from the ongoing TARGIT-A randomized trial comparing intraoperative radiotherapy and EBRT. The study population consists of 2020 women (aged ≥45 years) with unifocal early invasive breast cancer (preferably <3.5 cm). All patients had a median follow-up of 4 years (5 years for 1222 patients).

Preliminary results showed a 2.05 hazard ratio (HR) for recurrence for TARGIT versus for EBRT (P = .042).

A planned analysis of data stratified by hormone receptor status showed that the difference in recurrence rate owed primarily to the increased loco­ regional recurrence in patients with PgR-negative tumors and to delayed delivery of TARGIT (necessitating re-

Continued from page 8

opening of the wound cavity).

An analysis limited to the women with the PgR-positive tumors who re-

“The preferred treatment option is concurrent TARGIT [at the time of surgery] in progesterone receptor– positive patients. Add external beam radiotherapy if adverse prognostic factors are present.”

—Jayant S. Vaidya, MBBS, MS, DNB, PhD, FRCS

ceived TARGIT as planned produced a between-group difference of 0.18%

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The primary end point of both trials was locoregional recurrence; how­ ever, investigators in START A also examined the relative sensitivity of normal and malignant tissue to radiation fraction size.

The START A results confirmed that the rates of recurrence at 5 years did not differ significantly by radiotherapy protocol, and also that breast cancer and normal breast tissue have similar sensitivity to radiation fraction.

Dr Yarnold reported data from a median follow-up of 9.3 years in START A and 9.9 years in START B. The 10-year relapse rates in START A were 7.4% with 50 Gy, 6.3% with 41.6 Gy, and 8.8% with 39 Gy. Although still not significantly different, the results showed a trend toward a higher recurrence rate with the 39-Gy protocol.

The 10-year START B data showed a 23% reduction in the relative risk of relapse with the 40-Gy protocol. In addition, the lower dose was associated with fewer AEs for normal tissue, including lower rates of the individual effects that were evaluated, such as breast shrinkage, induration, and edema.

“These results are consistent with the hypothesis that small fractions are as gentle on breast tissue as on healthy tissues,” explained Dr Yarnold. n

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compared with the EBRT group.

In addition to recurrences, 88 deaths have occurred in the 2 treatment groups. The overall analysis yielded an HR of 0.70 in favor of TARGIT, representing a trend toward lower mortality. The estimated 5-year non– breast cancer mortality was 1.4% for the TARGIT group versus 3.5% in the EBRT group, which translated into a 53% reduction in the hazard in favor of TARGIT. With regard to applying TARGIT in clinical practice, Dr Vaidya emphasized careful patient selection.

“Patients should fulfill the eligibility criteria for the TARGIT-A trial,” Dr Vaidya said. “The preferred treatment option is concurrent TARGIT [at the time of surgery] in progesterone receptor–positive patients. Add external beam radiotherapy if adverse prognostic factors are present.” n

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HER2 Breast Cancer

HER2 Status Determined by Central Laboratory Testing May Be More Reliable than Routine Local Testing The new HERmark assay accurately assesses tumor status

By Susan Reckling

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etermining HER2 status utilizing novel central laboratory testing techniques has been shown to be more reliable than routine local HER2 testing, such as immunohistochemistry or in situ hybridization. This finding for patients with HER2-positive breast cancer may lead to future therapeutic applications for patients with HER2-negative breast cancer as well.

The accurate assessment of tumor HER2 status is critical in determin­­ ing appropriate therapy for patients with breast cancer, noted Denise A. Yardley, MD, Senior Investigator of the Breast Cancer Research Program at the Sarah Cannon Research Institute in Nashville, TN, who presented the results of a multicenter retrospective biomarker study.

Dr Yardley’s team compared the HERmark HER2 total protein expres-

sion (H2T) cancer assay with local (ie, site-reported) HER2 testing and central laboratory HER2 retesting of formalin-fixed, paraffin-embedded (FFPE) breast cancer tissues.

The HERmark Breast Cancer Assay The HERmark breast cancer assay is a novel method used to quantitatively measure the levels of HER2 expression (or H2T levels). The quantitative total HER2 measurements by the HERmark assay and the results of local (“real-world”) HER2 testing were correlated with tumor histopathologic characteristics and overall survival (OS) in a cohort of 192 FFPE breast cancer samples from patients, 90% of whom had not received HER2targeted therapy. The study sites were instructed to identify approximately 50% HER2-positive and 50% HER2negative breast cancer cases.

Dr Yardley emphasized that high H2T levels (>13.8) that were determined by the HERmark assay significantly correlated with poor OS (haz-

Using the HERmark assay may enrich the identification of both HER2-positive and HER2-negative breast cancers, thereby providing added clinical value to real-world local HER2 testing.

ard ratio [HR], 5.6; P <.001), whereas HER2-positive status that was determined by local testing only trended with OS (HR, 1.78; P = .098). The ob-

served discrepancy in OS based on different HER2 classification methods appeared to be a result of the misclassification of HER2 status as determined by local testing.

Of note, of the 24 triple-negative breast cancer cases that had been reported by local testing, 4 were reclassified as HER2-positive by using the HERmark assay.

The investigators emphasized that the results of this retrospective study confirmed previous reports that HER2 status that is determined by central laboratory testing is more reliable than local testing, real-world HER2 results.

In addition, quantitative H2T levels, determined via the HERmark assay, may enrich the identification of HER2positive as well as HER2-negative breast cancers and thus may provide added clinical value to real-world local HER2 testing. n

One Year of Trastuzumab Remains the Standard of Care

By Caroline Helwick

F

or patients with HER2-positive early breast cancer, 1 year of treatment with trastuzumab (Herceptin) remains the standard of care, according to the HERA trial and a subanalysis of the PHARE study.

The optimal duration of anti-HER2 adjuvant therapy has never been clearly established, and the issue continues to be studied in current trials, but for now, 1 year is the recommended treatment.

with adjuvant trastuzumab led to the drug’s approval.

In the current landmark analysis with 8 years of median follow-up, there was no evidence of long-term

HERA: Trastuzumab Shows Robust Effect at 8 Years The 8-year update of the HERA trial showed a sustained benefit for trastuzumab 8 years after patients were randomized, and it determined that 2 years of treatment were not better than 1 year.

The study was presented by Martine Piccart-Gebhart, MD, PhD, Associate Professor of Oncology at the Université Libre de Bruxelles and Head of the Department of Medicine at the Jules Bordet Institute in Brussels, Belgium.

Between 2001 and 2005, HERA randomized 5102 patients to 1 year of trastuzumab, 2 years of trastuzumab, or observation. The striking finding of a 50% reduction in recurrence risk

—Martine Piccart-Gebhart, MD, PhD

10

“There is still a gray zone, and efforts to determine the optimal duration should continue.”

benefit with the longer duration of treatment when trastuzumab was administered as sequential treatment after chemotherapy, Dr PiccartGebhart reported.

“One year of trastuzumab remains the standard of care as part of adjuvant therapy for patients with HER2positive early breast cancer,” she noted. Disease-free survival (DFS) at 8 years was 75.8% with 2 years of trastuzumab and 76.0% with 1 year (hazard ratio [HR], 0.99; P = .86). Overall survival (OS) rates were 86.4% and 87.6%, respectively (P = .63). The same pat-

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tern held true for both hormone receptor–positive and hormone receptor– negative subgroups, although there was a hint of greater benefit after 2 years of treatment with trastuzumab in the hormone receptor–negative cohort—raising a hypothesis that will be further explored, Dr Piccart-Gebhart explained.

HERA also determined the overall benefit of trastuzumab versus observation at 8 years, showing that a robust treatment effect could still be observed despite 52% of the observation arm crossing over to receive trastuzumab, she added.

The HR favoring trastuzumab was 0.76 for both DFS (P <.001) and OS (P = .005). Rather than attenuating because of crossover, the OS benefit has actually increased since the previous analysis 4 years ago.

It is likely that the true effect of 1 year of trastuzumab is even greater because of the contamination of the crossover, the investigators suggested.

Six Months Probably Not Sufficient Whether 6 months of trastuzumab is as effective as 1 year of therapy was not answered by the HERA trial. This

was the question evaluated in the PHARE trial, which randomized 3480 patients to 6 or 12 months of maintenance trastuzumab. The study was designed to test noninferiority of the shorter regimen.

PHARE failed to show noninferiority for 6 months of trastuzumab versus 1 year, also validating 1 year as the proper duration of this treatment, reported Xavier Pivot, MD, PhD, of the University Hospital of Besançon, France.

After 42.5 months of median follow-up, disease-related events occurred in 10.4% of the patients treated for 1 year and 13.0% of those treated for 6 months, yielding a 28% increased risk with the shorter treatment.

The DFS rate was significantly better with 1 year of the drug at all time points; at the end of the study, 4-year DFS was 87.8% with 1 year of treatment versus 84.9% with 6 months of treatment.

“The results were inconclusive for the noninferiority analysis, and there was a trend favoring the standard 12 months of treatment,” Dr Pivot said.

Subgroup analyses suggested that the overall results were driven by Continued on page 11

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HER2 Breast Cancer

Results of Immunohistochemistry and In Situ Hybridization Reliable Indicators of HER2-Positive Status

By Susan Reckling

T

he incidence of false-negative immunohistochemistry (IHC) is only 1% in patients with primary breast cancer, according to a prospective multicenter Canadian study presented at the meeting. This is good news in relation to standardized testing utilizing IHC and in situ hybridization techniques for the accurate diagnosis of patients expressing HER2.

Overexpression and amplification of HER2 is present in 15% to 20% of all patients with breast cancer and is associated with a higher-grade cancer and an increased risk of tumor recurrence, according to Wedad Hanna, MBBCh, MD, Professor of Anatomic Pathology, Department of Laboratory Medicine and Pathobiology, and Affiliate Sci­ entist, Odette Cancer Research Pro­ gram, Sunnybrook Research Institute, University of Toronto, Ontario.

HER2-positive status is predictive of response not only to trastuzumab (Herceptin) but also to newer agents, such as pertuzumab (Perjeta) and trastuzumab emtansine (T-DM1).

Trastuzumab is also beneficial in the management of ductal carcinoma in situ (DCIS).

One of the challenges in testing for HER2 is that tissue from one area of the breast may test positive for HER2 while tissue from a different site may test negative, Dr Hanna noted.

Investigators in this study evaluated breast resection specimens obtained in 2010 and 2011, focusing on resection specimens that were scored 0 or 1+ via IHC. A score of 0 to 1+ is considered to be HER2-negative.

The final analysis included 711 cases, including 162 patients with grade 1 tumors, 320 with grade 2 tu-

mors, and 225 patients with grade 3 tumors (4 patients were not assigned a grade). Only 7 of the 711 patients (0.98%) undergoing IHC and in situ hybridization had a false-negative result, Dr Hanna reported.

HER2-positive status is predictive of response not only to trastuzumab but also to newer agents, such as pertuzumab and trastuzumab emtansine.

The results of this study confirmed previously published Canadian guide­ lines recommending initial IHC test-

ing of all invasive carcinomas followed by in situ hybridization on equivocal cases.

Ironically, Dr Hanna served as a cochairperson for the committee that developed the Canadian guidelines.

She suggested that HER2 testing should be considered in all patients with DCIS, and that HER2-positive patients should receive more aggressive treatment than those with HER2negative disease.

Dr Hanna further emphasized the validity of these results, noting that study cohorts were represented by patients who did not receive any additional treatment beyond surgery and, therefore, exemplify the natural course of the disease. In addition, she maintained that the testing was robust in that all tumors were tested with IHC and in situ hybridization. n

HER2 Mutations May Become New Treatment Targets

S

ome patients who test HER2 negative by conventional tests may still benefit from anti-HER2 agents. This is the conclusion of a study that examined HER2 mutations in detail which was presented by Ron Bose, MD, PhD, Assistant Professor, Oncology Division, Department of Medicine, Washington University School of Medicine in St Louis, MO. In a genetic analysis of 1500 women, 25 had HER2 mutations in the absence

One Year of...

Continued from page 10

worse outcomes in patients with estrogen receptor–negative tumors who received sequential systemic therapy and who had a 57% increased risk for an event with 6 months of trastuzumab. Breast cancer experts said that the results establish 1 year of trastuzumab as the standard of care, but findings from ongoing and future studies are still awaited.

The relative benefit of 6 months versus 1 year of trastuzumab will be evaluated by the PERSEPHONE trial (which is also evaluating sequential

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of gene amplification, which is the hallmark of HER2-positive breast cancer, Dr Bose reported.

These genes seemed to be impor­ tant, he added. Many of the variants were “activating events” that drove tumor growth in laboratory models.

“The activating mutations are turning on HER2’s functioning and will probably result in abnormal, unregulated HER2 signaling, which is like­ ­­­ly driving the cancer cell,” Dr Bose

and concurrent trastuzumab) and the HELLENIC trial (concurrent therapy).

The SHORT-HER and SOLD trials are evaluating 9 weeks versus 12 months of trastuzumab given in conjunction with a taxane, similar to the FinHER trial, which found a benefit for 9 weeks of treatment.

Dr Piccart-Gebhart noted, “PHARE doesn’t really tell us that giving 12 months [of trastuzumab] is superior to 6 months. There is still a gray zone, and efforts to determine the optimal duration should continue.” n

explained.

The mutations appeared in 2 regions of the HER2 gene. The first cluster of mutations was in the extracellular domain, at amino acid (aa) 309-310 (exon 8). The second cluster of mutations was at aa 755-781, which is in the kinase domain (exons 19-20) along with aa 835-896 (exons 21-22).

The investigators further evaluated 13 of the variants, examining enzyme activity, tissue cultures, and tumor growth in mice. They found that many variants were susceptible to currently approved drugs, including trastuzumab (Herceptin) and lapatinib (Tykerb; a tyrosine kinase inhibitor [TKI]). But all of the variants were susceptible to the investigational TKI neratinib, which has prompted a clinical trial of neratinib in stage IV patients who have HER2 mutations.

The press briefing moderator C. Kent Osborne, MD, Professor of Medicine and Cellular and Structural Biology, and Director of the Smith Breast Center at Baylor College of Medicine in Houston, TX, said the study “has limited usefulness right now,” but it is important, because it offers elucidation about heretofore unappreciated genetic mutations that

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Photo © SABCS/Todd Buchanan 2012

By Caroline Helwick

“The activating mutations are turning on HER2’s functioning and will probably result in abnormal, unregulated HER2 signaling, which is likely driving the cancer cell.”

—Ron Bose, MD, PhD may have a role in breast cancer and that can be targeted. It is possible that these mutations exist in other subtypes of breast cancer as well, Dr Osborne noted. n

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Advanced Breast Cancer

Overall Survival Trend Seen with Eribulin versus Capecitabine

By Audrey Andrews

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ease. Half the population had received only 1 previous regimen for advanced disease and 28% had received only 2 previous regimens.

Almost all patients (84%-88%) had visceral disease; 66% had HER2negative, approximately 40% had estrogen receptor (ER)-negative, and 27% had triple-negative tumors.

Patients were randomly assigned to receive eribulin 1.4 mg/m2 on days 1 and 8 every 21 days or capecitabine 1250 mg/m2 twice daily on days 1 to 14, every 21 days. Strati­fication was by geographic region and HER2 status.

The coprimary end points were OS and progression-free survival (PFS).

Improved Overall Survival Trend Shown The median OS was 15.9 months with eribulin and 14.5 months with capecitabine, for a 12% reduction in risk that trended toward, but did not meet, statistical significance (P = .056).

Photo © SABCS/Bahram Mark Sobhani 2012

trend toward improved overall survival (OS) with eribu­ lin mesylate (Halaven) was demonstrated in the global phase 3 clinical trial comparing this newer agent with capecitabine (Xeloda) in patients with previously treated metastatic breast cancer.

“We did not show a statistically significant superiority of eribulin over capecitabine, which was our goal, but eribulin demonstrated a trend favoring an overall survival benefit over capecitabine, a widely accepted and used standard therapy in this setting,” said Peter A. Kaufman, MD, Associate Professor of Medicine at Dartmouth in Lebanon, NH. “Eribulin is the only chemotherapeutic agent with a demonstrated survival benefit for patients with heavily pretreated metastatic breast cancer,” Dr Kaufman noted. The drug has a novel mechanism of action that is distinct from most other tubulin-targeted agents.

In the previous phase 3 Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus E7389 (EMBRACE) trial, treatment with eribulin improved OS by 2.5 months versus current treatments (physician’s choice) in patients who were previously treated for metastatic disease (Cortes J, et al. Lancet.

2011;377:914-923). This study led to the US Food and Drug Administration approval of eribulin for patients with metastatic breast cancer who have received at least 2 previous chemotherapy regimens that included an anthracycline and a taxane.

The global, randomized, openlabel, multicenter, phase 3 trial (Study 301) examined whether eribulin would be effective earlier in the treatment course for patients with locally advanced or metastatic disease. Eribulin was compared with capecitabine, which is widely used in all lines of therapy for metastatic breast cancer and is approved in patients whose disease is resistant to paclitaxel (Taxol) and to an anthracycline-containing regimen.

The study included 1102 patients with locally advanced or metastatic breast cancer who had received ≤3 previous chemotherapy regimens (≤2 regimens for advanced disease) and who had received previous therapy with an anthracycline and a taxane in the neoadjuvant or adjuvant setting or for locally advanced or metastatic dis-

“We did not show a statistically significant superiority of eribulin over capecitabine, which was our goal, but eribulin demonstrated a trend favoring an overall survival benefit over capecitabine, a widely accepted and used standard therapy in this setting.”

—Peter A. Kaufman, MD

“There was an early separation of the curve and a trend, but it’s not statistically significant,” Dr Kaufman noted.

The OS rate was 64.4% with eribulin

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Figure Overall Survival, by Receptor Status: Eribulin versus Capecitabine Hazard ratio (95% confidence interval)

Subgroup Overall

Eribulin Capecitabine Median, months

0.879 (0.77-1.003)

15.9

14.5

Positive

0.965 (0.688-1.355)

14.3

17.1

Negative (N = 755)

0.838 (0.715-0.983)

15.9

13.5

Positive

0.897 (0.737-1.093)

18.2

16.8

Negative (N = 449)

0.779 (0.635-0.955)

14.4

10.5

Yes (N = 284)

0.702 (0.545-0.906)

14.4

9.4

No

0.927 (0.795-1.081)

17.5

16.6

HER2 status

ER status

Triple negative

0.2

0.5 Favors eribulin

1.0

2 5 Favors capecitabine

Intention-to-treat population. ER indicates estrogen receptor.

Adapted with permission from Kaufman PA, et al. A phase III, open-label, randomized, multicenter study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with anthracyclines and taxanes. Presented at San Antonio Breast Cancer Symposium; December 4-8, 2012; San Antonio, CA.

versus 58.0% with capecitabine at 1 year (P = .035); 32.8% versus 29.8%, respectively, at 2 years (P = .324); and 17.8% versus 14.5%, respectively, at 3 years (P = .175), he reported at an oral session and at a press briefing, where the results were highlighted.

Median PFS was 4.1 months with eribulin and 4.2 months with capecitabine (hazard ratio [HR], 1.079; P = .305).

The assessments were similar by independent and investigator reviews.

The objective response rates were 11% and 12%, respectively, by independent review and 16% and 20%, respectively, by investigator review.

The clinical benefit rates were 26% and 27%, respectively, by independent review and 33% and 34%, respectively, by investigator review.

Study medication exposure was similar between the arms. The median duration of treatment was 4.1 months with eribulin and 3.9 months with capecitabine. The median numbers of treatment cycles were 6 and 5, respectively, and the relative dose intensities were 87% and 86%, respectively, Dr Kaufman reported.

Some Subgroups May Benefit More “Prespecified exploratory analyses suggested that particular patient subgroups may derive greater therapeu-

tic benefit with eribulin, and this may warrant further study,” Dr Kaufman said. Trends favoring eribulin over capecitabine were observed in 3 subsets of patients (Figure): • Triple-negative: HR, 0.702 (95% confidence interval [CI], 0.5450.906); median OS, 14.4 months versus 9.4 months, respectively • ER-negative: HR, 0.779 (95% CI, 0.635-0.955); median OS, 14.4 months versus 10.5 months, respectively • HER2-negative: HR, 0.838 (95% CI, 0.715-0.983); median OS, 15.9 months versus 13.5 months, respectively.

Of note, in the triple-negative subset of 284 patients, who typically have aggressive disease, the median OS was 14.4 months with eribulin compared with 9.4 months with capecitabine, Dr Kaufman said.

The median OS was 14.4 months versus 10.5 months for ER-negative patients; and 15.9 months versus 13.5 months, respectively, for HER2negative patients.

Adverse Event Profile The adverse event profiles of the 2 drugs were consistent with their previously known side effects. There was a higher incidence of neutropenia with eribulin than with capecitabine, but febrile neutropenia occurred in only 2% of patients receiving eribulin (vs <1% in patients taking capecit-

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Advanced Breast Cancer

Eribulin Plus Trastuzumab an Effective Combination Response achieved by 55% of patients with HER2-positive advanced disease

By Caroline Helwick

—Linda T. Vahdat, MD

the results of a study using eribulin as a first-line treatment for patients with metastatic breast cancer who were HER2-positive. The results were striking for the combination of eribulin and trastuzumab in this patient population, Dr Vahdat said.

Objective responses were observed in 22 (55%) of the 40 patients, the disease control rate was 92%, and the duration of response in the 22 re-

Study Details The focus of the current trial was to explore the antitumor activity and the safety of eribulin in combination with trastuzumab as first-line therapy for HER2-positive advanced breast cancer. As of October 2012, 40 of the 52 planned patients had received at least 1 dose of eribulin and could be evaluated for this preliminary analysis.

The median age of the patients was 58 years; 80% were white; 67% had estrogen receptor (ER)-positive disease; 75% had Eastern Cooperative

Overall Survival Trend... abine), “which is low and acceptable,” Dr Kaufman said.

As expected, capecitabine was associated with more hand-foot syndrome than treatment with eribulin and slightly more diarrhea, nausea, and vomiting. The researchers are currently compiling data from the quality-of-life analysis, which should help guide future studies of eribulin in patients with metastatic breast

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Continued from page 12

cancer, he noted.

“Although we did not meet our primary end points, this is still the first study demonstrating the activity of eribulin in earlier lines of treatment of metastatic breast cancer,” Dr Kaufman said. “Eribulin is an active therapy in this setting, and overall it has potentially comparable activity to capecitabine, which is a widely used treatment in this patient population.” n

Figure 1 Progression-Free Survival

Event-free Probability probability Event-free

1.0 1.0

Censored Censored

0.8 0.8 0.6 0.6

0.4 0.4 0.2 0.2

Median 9.2 (6.70, 19.06) MedianTime time,(Months): months=(range): 9.2 (6.70-19.06)

25%Quantile quartile, months= (range): (3.48-7.06) 25% (Months): 6.0 (3.48,6.0 7.06)

75% quartile, months (range): 19.1 (9.17-19.06)

75% Quantile (Months): = 19.1 (9.17, 19.06)

0.0 0.0

12 14 16 18 20 00 22 44 66 8

8 10 10 12 14 16 18 20

Survival Timemonths (Months) Survival time, Copyright © Lynda T. Vahdat, MD. Used with permission.

Figure 2 Percentage Change from Baseline 20 20

20

0 0

0

-20 –20

–20

-40 –40

–40

-60 –60

–60

-80 –80

–80

Percentage Change from Baseline

“This combination performed terrifically....These preliminary results suggest that the combination of eribulin plus trastuzumab appears to have considerable activity with an acceptable toxicity profile as first-line therapy for HER2positive locally advanced or metastatic breast cancer.”

sponders was 204 days (range, 141541 days). For all patients receiving treatment with eribulin, the median progression-free survival (PFS) was 9.2 months (Figure 1).

“This combination performed terrifically,” Dr Vahdat said in an interview. “These are preliminary data, but what is really shocking is that only 1 patient out of 40 progressed. Look at the waterfall plot [Figure 2]. We usually see progression in 30% to 40% of patients. This appears to be a great combination.”

The approval of eribulin in the United States, Europe, Japan, and other countries was based on the Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice Versus E7389 (EMBRACE), a phase 3, open-label trial in which women with locally recurrent or metastatic breast cancer were randomly allocated to eribulin or to treatment of their physician’s choice (Cortes J, et al. Lancet.

2011;377:914-923).

Overall survival was significantly improved with eribulin—13.1 months versus 10.6 months with physician’s choice of treatment, a 19% risk reduction (P = .041).

Percentage from Baseline Change Change from baseline, %

E

ribulin mesylate (Halaven) is currently used in patients with metastatic breast cancer whose disease has progressed on other treatments, but the drug may be useful in earlier lines of therapy. Eribulin is especially promising when paired with trastuzumab (Herceptin), according to a phase 2 clinical trial presented at the meeting.

Linda T. Vahdat, MD, Professor of Medicine, Director of the Breast Cancer Research Program, Chief of the Solid Tumor Service, Weill Cornell Medical College, New York, reported

-100 –100 –100 -120 –120 –120 1 1 6 6 11 1116 1621 2126 2631 3136 3641

1 6 11 16 21 26 31 36 41 Patients Patient Patient CR CR CR

PR PR PR

SD SD SD

PD PD PD

NE NE NE

CR indicates complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, nonevaluable.

Copyright © Lynda T. Vahdat, MD. Used with permission.

Oncology Group performance status of 0; 40% had received previous therapy with trastuzumab; and 52% had metastasis to the liver, 42% to the lungs, and 35% to the bone. The median time from their original diagnosis was 2.4 years.

A total of 4 patients experienced treatment-related serious adverse events during the study. Febrile neutropenia occurred in 7.5% of patients; neutropenia in 5%; and anemia, fatigue, and peripheral neuropathy in 2.5% each. Dose reductions, interruptions, and discontinuation of therapy resulting from treatmentemergent adverse events occurred in 20%, 22.5%, and 12.5% of patients, respectively. Of the 40 total patients, 15% were receiving growth factor support.

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For the 55% of patients who responded, the median duration of response was 6.7 months (with no difference between ER-positive and ER-negative patients). The median PFS was 9.2 months overall, increasing to 19.1 months among patients in the highest PFS quartile, Dr Vahdat reported.

“These preliminary results suggest that the combination of eribulin plus trastuzumab appears to have considerable activity with an acceptable toxicity profile as first-line therapy for HER2-positive locally advanced or metastatic breast cancer. The study has completed enrollment, and we expect final results by the end of next year,” she concluded. n

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Prognostic Tests

Gene-Based Test Identifies Breast Cancer with Low... clinical trials of adjuvant endocrine therapy for patients with ER-positive and HER2-negative tumors.

The EndoPredict Test “The EndoPredict score identifies early and late recurrences and offers independent prognostic information beyond what can be achieved with all common clinical parameters,” he said.

“Proliferation genes add prognostic information for identifying early recurrences, whereas genes associated with estrogen receptor signaling are important for late events,” he explained.

ER-positive breast cancers remain at risk for late metastasis beyond 5 years, whereas most ER-negative tumors do not. Consequently, ER-positive cancer is associated with higher breast cancer– specific mortality after 5 to 10 years of follow-up, Dr Dubsky said.

The risk for late metastatic recurrence increases with nodal positivity and tumor size. Several molecular tests have been developed as aids to clinical decision-making, but no test with published data has outperformed the combination of hormone receptor status, HER2 status, and the proliferation factor Ki67.

EndoPredict is an RNA-based ge-

Study Results The primary objectives of the study were to evaluate the test’s ability to predict the risk for late metastasis and to determine whether the test plus the clinical variables of tumor size and nodal status improved prediction of late metastasis.

In addition, the investigators explored the contributions of genes associated with ER signaling and differentiation from pro­ liferation in early and late metastases.

The test classified 49% of the patients as low risk. After 5 years of follow-up, patients who did not have low-risk scores had almost a 3-fold greater risk for distant metastasis compared with the low-risk group (hazard ratio [HR], 2.80; P <.001).

Beyond 5 years, the risk remained significantly increased in patients who were not classified as low risk (HR, 2.91; P = .002).

Multivariate analyses showed that the gene test was a predictor of early distant recurrence (HR, 1.20; P <.001) and late metastases (HR, 1.28; P =

Photo © SABCS/Todd Buchanan 2012

Exploratory investigation of individual genes included in the panel revealed various effects on pathogenesis.

“The EndoPredict score identifies early and late recurrences and offers independent prognostic information beyond what can be achieved with all common clinical parameters.”

—Peter C. Dubsky, MD netic test consisting of 8 cancer-related genes (BIRC5, UBE2C, DHCR7, RBBP8, IL6ST, AZGP1, MGP, and STC2) and 3 reference genes. Dr Dubsky presented results from a retrospective validation study involving 1702 patients from 2

Continued from cover

.001). Nodal status was the strongest predictor of early and late metastases (HR, 2.15; P <.001; HR, 2.45; P <.001, respectively). Age, tumor size, Ki67 level, tumor grade, and treatment assignment did not predict metastasis.

The EPclin Score The investigators also evaluated the prognostic performance of the EPclin score—a combination of the EndoPredict and the clinical risk factors of nodal status and tumor size— with regard to the risk of metastasis beyond 5 years.

The addition of the gene-based test significantly improved the prognostic value of all common clinical parameters that were evaluated. The EPclin score demonstrated better performance than any other clinical parameters that were added to the EndoPredict test.

“The EPclin score identified a lowrisk subgroup containing 64% of all patients at risk after 5 years,” said Dr Dubsky. “Results showed that 98% of these women remained free of distant metastases 10 years after diagnosis.

The risks and side effects of extended therapy should be weighed against this projected outcome.” n

Breast Cancer Index Predicts Late Recurrences in Patients with ER-Positive Breast Cancer Helps to select appropriate treatment type

By Audrey Andrews

T

he Breast Cancer Index (BCI), a polymerase chain reaction– based assay, can predict late recurrences in estrogen receptor (ER)positive patients, according to results from the translational arm of the Arimidex, Tamoxifen, Alone or in Combination (TransATAC) trial population.

The BCI performed on primary tumors in node-negative ER-positive patients, who are traditionally considered a “good-risk” group, identifies subgroups with a high risk of recurrence, and its prognostic power works independent of traditional clinical characteristics, such as number of nodes, tumor grade, age, and so forth, reported Dennis C. Sgroi, MD, Asso­ ciate Professor, Dana-Farber/Harvard Can­ cer Center, Harvard Medical School.

“At the point of diagnosis, BCI identified 2 groups: those at low risk of

14

early recurrence who are adequately treated with endocrine therapy alone, and those at high risk of early recurrence who do not benefit adequately from simple endocrine therapy and who should be considered for additional therapy,” Dr Sgroi reported.

“And at the point of 5-year follow-up, for patients who are disease-free, it identified 2 groups: those at low risk of late recurrence who do not need subsequent therapy, and those at significant risk of late recurrence who should be considered for additional or alternative systemic adjuvant therapy,” he continued.

Dr Sgroi noted that residual risk of recurrence remains a substantial concern for patients with ER-positive breast cancer. Current multigene signatures have significant prognostic performance in predicting early recurrences (ie, up to 5 years after diagnosis); however, such signatures

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have limited performance in predicting the risk of late recurrence (ie, >5 years), he noted.

The BCI consists of 2 biomarkers: the HOXB13:IL17BR gene-expression ratio and a set of cell cycle–related genes that

“The BCI demonstrated sustained significant prognostic performance, while the IHC4 and Oncotype DX Recurrence Score lost their prognostic ability.”

—Dennis C. Sgroi, MD form the molecular grade index.

Investigators compared the prognostic performance of the BCI with the 21gene Recurrence Score and the immunohistochemical (IHC)4 score in 665 patients from the translational arm of the TransATAC trial who were fol-

lowed for a median of 10 years.

The index distinguished 3 risk groups—BCI-low (58%), which constituted the reference; BCI-intermediate (25%); and BCI-high (17%). Patients falling into the BCI-intermediate category had nearly a 3-fold increased risk for recurrence at 10 years compared with a 5-fold risk in the BCI-high group (P <.001).

The 5-year rate of late recurrence was approximately 13% for the BCIintermediate and BCI-high groups compared with 3.5% for the BCI-low group.

The BCI-high group also had more than an 8-fold risk of early recurrence, with 18% of the patients relapsing within 5 years. The BCI-intermediate group rate of patients relapsing by 5 years was 5.6%.

In a multivariate analysis, the BCI outperformed the other 2 tests. “The BCI demonstrated sustained significant prognostic performance, while the IHC4 and Oncotype DX Recurrence Score lost their prognostic ability,” Dr Sgroi added. n

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Prognostic Tests

Molecular Profiling in Early Invasive Breast Cancer

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By Caroline Helwick

n making decisions about adjuvant chemotherapy, biologic subtype has replaced nodal status and tumor size as parameters to consider, although subtype—and tests that define them—are still insufficient for the provision of optimal care, said Antonio C. Wolff, MD, Professor of Oncology at Johns Hopkins University School of Medicine, Baltimore. Dr Wolff spoke at an educational session devoted to molecular profiling.

Phenotype, based on estrogen receptor (ER) and HER2 status, has a strong negative predictive value, but only a modest positive predictive value for treatment benefit. “We still need traditional measures such as nodal status and tumor size,” he maintained.

In the past decade, microarray expression has revealed 4 intrinsic breast cancer subtypes—basal-type (largely triple-negative); HER2-positive; luminal A (mostly ER-positive and low grade by Ki67 index); and luminal B (mostly ER-positive and high grade).

Much of the prognostic variation occurs within these 4 groups, and treatment decisions are now largely based on the characteristics associated with them, Dr Wolff said.

It is becoming clear that tumor-cell proliferation is critical in these subtypes, especially in the luminal groups, and that proliferation is associated with response to chemotherapy.

Gene-Expression Profiling Studies suggest that the adoption of gene-expression profiling has altered the use of chemotherapy. Based on 2012 findings from 7375 patients, the use of these assays grew from 15% in 2006 to 27% in 2008 and the use of chemotherapy declined from 54% to 47%.

Patients with large node-negative or any node-positive cancer were 11-fold less likely to receive chemotherapy; those with small node-negative cancers were 11-fold more likely to receive chemotherapy.

“I think that clinicians are mostly ordering tests for tumors they are not so sure about. They have a sense of what they are going to do with a given patient when they order the test, and, in most cases, the test results will be used to confirm their decision,” Dr Wolff said.

“Molecular assays must not yet override results with standard assays.”

Future Profiles Efforts are under way to molecularly refine the classification system for tumors. The Cancer Genome Atlas (TCGA) of molecular “portraits” is elucidating phenotype, ge­notype, epi-

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genetics, and proteomic features (eg, copy number variations). “The question is what to do with this information,” Dr Wolff said. “One of the challenges is that the TCGA dataset is still

not correlated with clinical outcomes.

As we move toward the concept of precision medicine, we need this.”

Because of the heterogeneity of tumors, many questions are yet to be

answered. He predicted that the field will move from qualitative, descriptive prognosis toward a quantitative prognosis based on individualized therapies. n

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SUPPLEMENT

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www.ValueBasedCancerCare.com

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Sentinel Node Management

Sentinel Node Surgery Correctly Stages Lymph Nodes Following Neoadjuvant Chemotherapy

By Audrey Andrews

A

xillary lymph node dissection (ALND) may not be necessary after neoadjuvant chemotherapy in most patients, according to investigators who found that sentinel lymph node (SLN) dissection correctly staged more than 90% of patients.

A study of the American College of Surgeons Oncology Group, ACOSOG Z1071, evaluated whether SLN surgery may sufficiently substitute for ALND as a less invasive procedure.

“We showed that sentinel lymph node surgery correctly identified the nodal status in 91.2% of patients who were node-positive at presentation and who underwent neoadjuvant chemotherapy,” said Judy C. Boughey, MD, Associate Professor of Surgery, Department of Surgery, Mayo Clinic in Rochester, MN. A number of factors helped to reduce the chance of false-negative results with SLN surgery. Dr Boughey said she would “feel safe incorporating sentinel node surgery in clinical practice in cases where patients have a good clinical response to chemotherapy, undergo sentinel node mapping with standardization of the technique, and have 3 or more sentinel nodes identified. I feel the false-negative rate

is acceptable in that group.”

SLN dissection is routinely used for patients initially diagnosed with nodenegative disease. The study evaluated whether SLN dissection could be safely used in patients with node-positive breast cancer, who at this time typically undergo ALND instead.

negative nodes,” Dr Boughey pointed out. “Our hypothesis was that sentinel node surgery is an accurate method of axillary staging in these patients.”

The goal was to have a false-negative detection rate of ≤10%, she noted.

Patients Underwent Both Procedures The study included 756 patients with node-positive breast cancer who received neoadjuvant chemotherapy, of whom 637 underwent both SLN dissection and ALND. SLN surgery correctly identified the nodal status in 91.2% of the patients, including 40% who were ultimately node negative and 60% with residual nodal disease. Of the 382 patients with residual disease, ALND confirmed that 326 were indeed sentinel node positive, whereas 56 patients were sentinel node negative but node positive according to the axillary dissection. Sentinel node surgery, therefore, correctly identified the nodal status in 91.2% of the patients in this study, Dr Boughey reported.

“Surgery is a useful tool for the detection of residual nodal disease in women with node-positive disease receiving neoadjuvant chemotherapy, but surgical technique is important for minimizing the false-negative rate.”

—Judy C. Boughey, MD

“The question is whether removal of the lymph nodes with an axillary dissection is needed, or whether less invasive surgery would reliably identify patients who still have disease in the lymph nodes and which patients have

False-Negative Rates Lower in Some Groups The rate of false negatives among

Black Women Less Likely to Receive Sentinel Node Dissection Therapy

B

lack women and other racial minorities are less likely than white women to receive sentinel lymph node (SLN) dissection as the standard of care for clinically nodenegative breast cancer, and this has negative consequences, an analysis of the Surveillance, Epidemiology and End Results (SEER)/Medicare database suggested.

Dalliah M. Black, MD, FACS, As­ sistant Professor of Surgical Oncol­ogy, M.D. Anderson Cancer Center, Houston, reported that the use of SLN surgery was approximately 12% to 14% less for black women who received treatment between 2002 and 2007, when this procedure became preferred over axillary lymph node completion.

The disparity was independent of patient age, tumor characteristics, type of cancer surgery, and other factors.

16

Although as a retrospective analysis, the differences are not easy to explain, Dr Black believes that socioeconomic factors may play a role. Other breast cancer specialists agreed that race may be a surrogate for socioeconomic level, which has been shown to be associated with disparities in access to care.

The study examined 31,274 women in the SEER/Medicare database who were diagnosed with nonmetastatic, invasive breast cancer from 2002 through 2007. The overall rate of SLN dissection was 62% among black patients, 65% among other nonwhite patients, and 74% among white patients (P <.001 for all), Dr Black reported.

For both racial groups, the use of SLN surgery increased over the study period. By 2007, when the approach was recommended as preferred in the guidelines of the National Com­ pre­ hensive Cancer Network, the rates

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The finding that lymphedema rates were equally low for black patients and for white patients who received SLN dissection “suggests that when black patients had the appropriate surgery, they were not at an increased risk of lymphedema.”

Photo © SABCS/Todd Buchanan 2012

By Caroline Helwick

supplement

—Dalliah M. Black, MD, FACS

were 70% for black women and 83% for white women, she added.

patients with at least 2 sentinel nodes examined was 12.6%, which is higher than their stated goal. They then looked at factors that might have affected this rate, and they found some differences.

The rate was lower (10.8%) when both blue dye and radiolabeled colloid were used and when at least 3 sentinel nodes were examined. Of the 78 patients with clinical N1 disease who had only 1 sentinel node examined, the false-negative rate climbed to 31.5%.

When histologic changes were present, the false-negative rate was 10.8%; when histology was unknown, the rate was 13.5%. Dr Boughey therefore emphasized that knowledge of the tumor’s histology could boost the accuracy of the procedure. When a clip was placed in the lymph nodes at diagnosis, the false-negative rate dropped to 7.4%. There was no significant difference according to clinical tumor stage.

“Sentinel lymph node surgery is a useful tool for the detection of residual nodal disease in women with node-positive disease receiving neoadjuvant chemotherapy, but surgical technique is important for minimizing the false-negative rate,” Dr Boughey advised. n

This difference remained stable, regard­-less of whether the women ultimately received a lumpectomy only or a mastectomy.

The disparity impacted negatively on the occurrence of lymphedema, Dr Black continued. At 5 years, the incidence of lymphedema was 18% among black women who underwent axillary dissection rather than SLN dissection, 12.2% among white women who underwent axillary dissection, 8.8% for black women who received SLN dissection, and 6.8% for white women who had SLN dissection.

Axillary dissection and black race were both independent predictors of an elevated risk of lymphedema (P <.001). The finding that lymphedema rates were equally low for black patients and for white patients who received SLN dissection “suggests that when black patients had the appropriate surgery, they were not at an increased risk of lymphedema,” she said. n

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Hormone Therapy

Letrozole Superior to Tamoxifen for a Subtype of Breast Cancer

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comparison of letrozole (Fem­ ara) with tamoxifen (Nolva­ dex) demonstrated that the former may be superior for the treatment of postmenopausal estrogen receptor (ER)-positive patients who have lobular carcinoma, according to a subanalysis of patients in the phase 3 BIG 1-98 trial. This subanalysis further showed that for the 2 histologic subtypes of breast cancer, luminal B tumors were more responsive to treatment than luminal A tumors.

“The magnitude of benefit of adjuvant letrozole varies by histology and estrogen receptor subgroup. Let­ rozole is associated with statistically significant reductions in disease-free survival [DFS] and overall survival [OS] events for both lobular and ductal carcinoma, but the magnitude of benefit is higher for patients diagnosed with lobular carcinoma,” said Otto Metzger-Filho, MD, a research fellow at the Division of Women’s Cancer, Dana-Farber Can­ cer Institute, Boston.

The BIG 1-98 trial compared 5 years of treatment with tamoxifen or with letrozole or their sequences in post-

Photo © SABCS/Todd Buchanan 2012

By Audrey Andrews

“The magnitude of benefit of adjuvant letrozole varies by histology and estrogen receptor subgroup. Letrozole is associated with statistically significant reductions in disease-free survival and overall survival events for both lobular and ductal carcinoma, but the magnitude of benefit is higher for patients diagnosed with lobular carcinoma.”

—Otto Metzger-Filho, MD

menopausal women with ER-positive early breast cancer. The 3660 patients receiving single-agent treatment were divided by invasive lobular or ductal carcinoma. Lobular and ductal tumors were classified into luminal A and luminal B subtypes using a Ki-67 (proliferation index) cutoff of 14%.

Among the 2500 women with ductal carcinoma, 45% had luminal A tumors and 56% had luminal B tumors.

Of the 324 women with lobular carcinoma, 73% had luminal A and 27% had luminal B tumors.

Treatment and Histology Affected Outcomes In the multivariate analysis of DFS, which was adjusted for classic clinicopathologic features, significant interactions were found between treatment and histology. All hazard ratios (HRs) favored letrozole over tamoxifen, but the 0.33 HR for lobular luminal B tumors was the most “impressive,” Dr Metzger-Filho said.

The HRs for other tumor subtypes were 0.49 for lobular luminal A tumors, 0.64 for ductal luminal B tu-

mors, and 0.95 for ductal luminal A tumors. The treatment interactions were highly significant according to histology (ie, ductal carcinoma vs lobular carcinoma; P = .006) and by subtype (ie, luminal A vs luminal B; P = .01).

At 5 years, 89% of patients with lobular tumors who received letrozole showed DFS versus 75% of patients with lobular tumors who received tamoxifen (HR, 0.48); the 8-year DFS was 82% versus 66%, respectively (P = .03).

OS was also significantly favoring letrozole, with an HR of 0.39 for lobular carcinoma and 0.69 for ductal carcinoma. The 8-year OS rates were 88% and 84%, respectively, Dr Metzger-Filho said.

Commenting on these findings, Frankie A. Holmes, MD, oncologist/ hematologist at Texas Oncology in Houston, and cochair of the Breast Cancer Research Committee at the US Oncology Network, said she viewed the findings as “practice changing.”

She added, “It’s good to see some data, especially for the treatment of an ‘orphan cancer.’” Approximately 10% of patients with breast cancer have a lobular tumor. n

Benefit of Higher Doses of Fulvestrant Confirmed

By Caroline Helwick

A

lthough many clinicians are already prescribing fulvestrant (Faslodex) at a dose of 500 mg, a phase 3 study presented at the meeting confirmed the superiority of this dose over 250 mg.

Three years ago, the first results of the randomized, multicenter, phase 3 CONFIRM trial showed a significantly better progression-free survival (PFS) with 500 mg in women with estrogen receptor (ER)-positive metastatic breast cancer. The final analysis shows an overall survival (OS) advantage as well, although in the unadjusted analysis, the difference did not achieve statistical significance, reported Angelo Di Leo, MD, PhD, Head of Sandro Pitigliani Medical Oncol­ ogy Unit, Department of Oncology, Hospital of Prato, Istituto Toscani Tumori, in Italy.

“These results are consistent with the previously reported PFS and OS data,” Dr Di Leo said. “Based on the results of the present trial, whenever fulvestrant is considered for the treat-

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ment of menopausal patients with ER-positive advanced breast cancer, the recommended dose is 500 mg.”

Women are typically considered for fulvestrant after they have failed treatment with tamoxifen (Nolvadex) and aromatase inhibitors.

Although fulvestrant has been available for more than 10 years, clinicians have not widely embraced it. Some specialists contend that the drug was suboptimally dosed at 250 mg, the US Food and Drug Administration–approved dose, and speculate that outcomes might be more robust if higher doses were used, which the analysis of the CONFIRM trial sought to determine. The analysis was conducted when 75% of the patients had died.

The study involved 736 women with ER-positive metastatic breast cancer who had progressed or recurred after treatment with another antiestrogen drug. Patients were randomized to 1 of the 2 doses of fulvestrant and followed until disease progression or until death.

“It is interesting to highlight the concept that the 2 survival analyses are perfectly consistent….that there is an increased benefit in terms of survival for patients who receive 500 mg of fulvestrant.”

—Angelo Di Leo, MD, PhD

At the final analysis, a 1-month improvement in the median PFS was observed with the higher-dose group (6.5 months vs 5.5 months, respectively; P = .006), and the median OS improved from 22.3 months to 26.4 months, which was a 19% reduction in risk (P = .016).

Dr Di Leo said that the P value came from an unadjusted exploratory analysis that lacked the statistical power to reflect true differences between the

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arms; however, he emphasized that a clear trend toward improved survival has emerged between the earlier analysis and the final analysis.

“It is interesting to highlight the concept that the 2 survival analyses are perfectly consistent,” he said.

“They are leading to the same conclusion, and that conclusion is that there is an increased benefit in terms of survival for patients who receive 500 mg of fulvestrant.”

During treatment and follow-up, 35 patients in the 500-mg fulvestrant arm had at least 1 serious adverse event compared with 27 patients who received 250 mg. A serious adverse event leading to death occurred in 5 patients in the 500-mg fulvestrant arm compared with 6 patients in the 250mg fulvestrant arm.

These safety results do not support any clinically relevant difference between 250 mg and 500 mg of fulvestrant, and “they are consistent with the previously reported safety profile of fulvestrant 500 mg,” Dr Di Leo said. n

www.ValueBasedCancerCare.com

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Emerging Therapies

Investigational CDK Inhibitor Extends Remission Time

By Audrey Andrews

tor Richard S. Finn, MD, Assistant Professor of Hematology/Oncology, University of California, Los Angeles (UCLA), and a researcher at Jonsson Comprehensive Cancer Center at UCLA. “The results confirm the preclinical observations made with PD991 in breast cancer models.”

In the first part of the current phase 2 clinical trial, the investigators randomly assigned 66 postmenopausal women with metastatic ER-positive breast cancer to letrozole alone or to letrozole plus PD991. In the second part of the study, 99 patients were screened for genomic alterations that may enhance the effect of the drug, specifically cyclin D1 amplification and/or p16 loss.

PD991 is given orally for 3 weeks on and 1 week off.

San Antonio, TX—The addition of an oral investigational agent to letrozole (Femara) for the treatment of estrogen receptor (ER)-positive metastatic breast cancer more than tripled the time spent in remission compared with endocrine therapy alone, according to a study reported at the CTRCAACR San Antonio Breast Cancer Symposium.

The agent, PD 0332991 (known as PD991), is a novel selective inhibitor of cyclin-dependent kinase (CDK) 4/6 that disables tumor-cell progression. In preclinical studies, PD991 inhibited cell growth and suppressed DNA replication. Preclinical studies also suggested the compound was synergistic when combined with tamoxifen (Nolvadex).

“Based on these observations, a phase 1/2 study was initiated, and we saw a dramatic improvement in progression-free survival [PFS] that was statistically and clinically meaningful with the addition of PD991 to letrozole,” said lead investiga-

Patients Go 2 Years without Progression Median PFS was 26.1 months in the combination arm versus 7.5 months with letrozole alone (P <.001).

Response rates were 45% with the combination and 31% with letrozole alone. The clinical benefit rates, which includes disease stability for 24 weeks, were 70% versus 44%, respectively, in the 2 cohorts.

“These are some of the best results I have seen for quite a while. The patients were gaining almost 2 years of time before disease progression.”

—Peter Ravdin, MD, PhD After retrospectively analyzing the biomarkers for cyclin D1 amplification or for p16 loss, the researchers found that ER positivity was the only biomarker that was predictive of whether patients would benefit from taking PD991.

The combination was well toler­

ated, although neutropenia, leukopenia, anemia, and fatigue were observed more often with the combination; however, there were no cases of febrile neutropenia.

“These conditions were uncomplicated and were managed with dose modifications and reductions,” Dr Finn noted. “Growth factors were not required.”

Peter Ravdin, MD, PhD, Director of the Breast Health Clinic at the Cancer Therapy and Research Center of the University of Texas Health Science Center, San Antonio, told Value-Based Cancer Care, “These are some of the best results I have seen for quite a while. The patients were gaining almost 2 years of time before disease progression, which is really very striking.”

Although other CDK inhibitors are in development, PD991 stands out as the most effective so far, Dr Ravdin added. The tolerability appears good, but he cautioned that it is too early to be sure, because the study is based on a population of less than 200 patients. n

Hormone Therapy

in the 15-year risk for recurrence and death compared with placebo.

Further analysis of the ATLAS trial now shows that 10 years of treatment with the drug is even more effective.

Because tamoxifen has a “carryover effect” and remains protective for years after treatment is stopped, the main benefit of extended duration did not emerge until after 10 years, Mr Gray reported.

ATLAS enrolled 6846 women with ER-positive breast cancer between 1996 and 2005. Women who had taken tamoxifen for 5 years were then randomly assigned to continue treatment for another 5 years or to stop treatment immediately.

After 8 years of follow-up, there were 1328 breast cancer recurrences and 728 deaths after recurrence. The duration of tamoxifen treatment had little effect on recurrence or deaths for the first 9 years after diagnosis, but after 10 years the extended treatment led to a 25% lower recurrence rate (P = .002) and a 29% lower breast cancer mortality rate (P = .01) compared with stopping treatment at 5 years, Mr Gray said.

When 10 years of treatment with

18

Photo © SABCS/Todd Buchanan 2012

ATLAS: Ten Years of Tamoxifen Superior to 5...

“With these new results, we see statistically fewer recurrences when patients take tamoxifen for 10 years rather than 5, and it is highly significant for breast cancer mortality and overall mortality.”

—Richard Gray, MSc tamoxifen was compared with placebo from the start, mortality from breast cancer was essentially halved, he added.

The absolute mortality gain was 12%, or 1 life saved for every 8 women, Mr Gray noted.

Peter Ravdin, MD, PhD, Director of the Breast Health Clinic at the Cancer Therapy and Research Center of the

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University of Texas Health Science Center, San Antonio, commented on the findings. He noted that the results of ATLAS are most relevant to premenopausal women, because they typically receive tamoxifen and not aromatase inhibitors.

In this patient subset, “we usually stop tamoxifen at 5 years, but now we will be telling them there is evidence that 10 years is superior to 5. I am going to be comfortable doing that,” he said.

Although treatment with tamoxifen is not without its risk—0.4% of women died of endometrial cancer after 10 years of treatment with tamoxifen in the trial—the risk is “so low that it is statistically hard to discern in trials of younger women,” Dr Ravdin pointed out. “But it is always important to weigh risks and benefits.”

Therefore, for women at minimal risk of relapse—such as those with small, grade 1 tumors—it is rational to stop tamoxifen after 5 years of use, he maintained. “But some women will have difficulty with the idea of continuing beyond 5 years, and, in many cases, the amount of benefit is

Continued from cover

at a glance ➤ New evidence shows that 10 years of tamoxifen therapy improves outcomes compared with 5 years in patients with ER-positive early breast cancer ➤ After 10 years, recurrence rate is reduced by 25% and breast cancer–related mortality by 29% versus only 5 years of tamoxifen ➤ Compared with placebo, 10 years of tamoxifen reduces breast cancer mortality by approximately 50% ➤ For women with positive nodes and bigger tumors, continuation of tamoxifen should be strongly considered

small enough that discontinuation is the right decision,” Dr Ravdin noted.

“Women with a relatively high risk of relapse, such as those with positive nodes and bigger tumors, will definitely be strong candidates for continuation of therapy,” he said. n

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THIRD ANNUAL

Association for Value-Based Cancer Care Conference Influencing the Patient-Impact Factor

This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

May 2-5, 2013 • Westin Diplomat • Hollywood, Florida CONFERENCE CO-CHAIRS

AGENDA* THURSDAY, MAY 2, 2013 8:00 am - 5:00 pm

Registration

FRIDAY, MAY 3, 2013

Craig K. Deligdish, MD Hematologist/Oncologist Oncology Resource Networks

Gary M. Owens, MD President Gary Owens Associates

Burt Zweigenhaft, BS President and CEO OncoMed

PROGRAM OVERVIEW

Following on the success of our Second Annual Conference, AVBCC will be coming to Hollywood, Florida, on May 2-5, 2013. We continue to be guided by the expertise of leaders in these fields providing attendees with a thorough understanding of the evolution of the value equation as it relates to cancer therapies. Our goal is to be able to assist them in implementing, improving, and sustaining their organizations and institutions, while improving access for patients and ultimately quality patient care.

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

8:15 am - 9:15 am

Session 1: Welcome, Introductions, and Opening Remarks Conference Co-Chairs - Craig K. Deligdish, MD; Gary M. Owens, MD; Burt Zweigenhaft, BS

9:15 am - 10:15 am

Keynote Address

10:15 am - 10:30 am

Break

10:30 am - 11:45 am

Session 2: Trends in Treatment Decision-Making: Pathways and Stakeholder Collaborations Marcus Neubauer, MD; Michael Kolodziej, MD

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 2:00 pm

Session 3: Cost of Cure: When, How, and How Much?

John Fox, MD; John Hennessy

2:00 pm - 2:45 pm

Session 4: Where Is Oncology Care Headed in the Future?

Jayson Slotnick, JD, MPH (Moderator); Barbara L. McAneny, MD

2:45 pm - 3:30 pm

Session 5: What Will the Cancer Delivery System Look Like in 2015?

Ted Okon; John D. Sprandio, MD

3:30 pm - 3:45 pm

Break

3:45 pm - 4:30 pm

Session 6: Employers and Oncology Care F. Randy Vogenberg, PhD, RPh (Moderator); Bridget Eber, PharmD; Patricia Goldsmith; Darin Hinderman

4:30 pm - 5:15 pm

Session 7: Advanced Care Directives: Palliative Care, Hospice, Ethics J. Russell Hoverman, MD, PhD; Thomas Smith, MD, FACP, FASCO

5:15 pm - 5:45 pm

Summary/Wrap-Up of Day 1

This conference is intended for medical oncologists, practice managers/administrators, and managed care professionals. Stakeholders in a position to impact cancer patient care, such as advanced practice nurses, pharmacists, and medical directors, are also invited to join this exciting forum.

6:00 pm - 8:00 pm

Cocktail Reception in the Exhibit Hall

7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

DESIGNATION OF CREDIT STATEMENTS

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 8: The Role of Government in the Future of Oncology Care Jayson Slotnick, JD, MPH

9:15 am - 10:00 am

Session 9: Medicaid: A Healthcare Delivery System Review Matthew Brow

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 10: Payer, Government, and Industry Insights: Balancing Cost and Quality Kip Piper

11:00 am - 11:45 am

Session 11: National Coalition for Cancer Survivorship: Medication Nonadherence Issues Pat McKercher; Lillie Shockney, RN, BS, MAS

LEARNING OBJECTIVES

Upon completion of this activity, the participant will be able to: • Discuss the current trends and challenges facing all stakeholders in optimizing value in cancer care delivery.

• Define the barriers associated with cost, quality, and access as they relate to healthcare reform and what solutions are currently being considered.

• Compare and contrast the different approaches/tools providers and payers are utilizing to manage and deliver care collaboratively.

• Examine the current trends in personalized care and companion diagnostics.

• Analyze the patient issues around cost, quality, and access to care.

TARGET AUDIENCE

SPONSORS

This activity is jointly sponsored by the Florida Society of Clinical Oncology, Medical Learning Institute Inc, Association for Value-Based Cancer Care, Inc., Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENT

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

SATURDAY, MAY 4, 2013

PHYSICIAN CREDIT DESIGNATION

The Medical Learning Institute Inc designates this live activity for a maximum of 17.25 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

REGISTERED NURSE DESIGNATION

12:00 pm - 1:00 pm

Exclusive Lunch Symposium/Product Theater

1:15 pm - 3:00 pm

Session 12: Meet the Experts Networking Roundtable Session

3:00 pm - 3:45 pm

Session 13: Personalized Medicine, Companion Diagnostics, Molecular Profiling, Genome Sequencing—The Impact on Cost, Treatment, and the Value Proposition Mark S. Boguski, MD, PhD; Gary Palmer, MD, JD, MBA, MPH

3:45 pm - 4:15 pm

Summary/Wrap-Up of Day 2

4:30 pm - 6:30 pm

Cocktail Reception in the Exhibit Hall

Medical Learning Institute Inc. Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 17.25 contact hours.

SUNDAY, MAY 5, 2013 7:00 am - 8:00 am

Simultaneous Symposia/Product Theaters

REGISTERED PHARMACY DESIGNATION

8:15 am - 8:30 am

Opening Remarks

8:30 am - 9:15 am

Session 14: Cancer Rehabilitation: The Next Frontier in Survivorship Care Julie Silver, MD

9:15 am - 10:00 am

Session 15: Current and Future Considerations for the Oncology Practice Manager Dawn Holcombe, MBA, FACMPE, ACHE; Leonard Natelson

10:00 am - 10:15 am

Break

10:15 am - 11:00 am

Session 16: Access to Drugs—Shortages, Biosimilars Douglas Burgoyne, PharmD; James T. Kenney, Jr., RPh, MBA

11:00 am - 11:45 am

Session 17: Perspectives from Oncology Group Practices—Successes, Issues, and Challenges Thomas Marsland, MD; David Eagle, MD

11:45 am - 12:00 pm

Summary and Conclusion of Conference

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 17.25 contact hours (1.725 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE $375.00 until March 15, 2013 REGISTRATION $425.00 after March 15, 2013 REGISTER TODAY AT

www.regonline.com/avbcc2013

*Agenda is subject to change.

AVBCCKsize20413

Triple-Negative Breast Cancer

Targetable Pathways Revealed for Triple-Negative...

Dozens of genes were found to be amplified, deleted, or mutated. Ap­ proximately 90% of all patients had an aberration in at least 1 of the following 5 common pathways: PI3K/ mTOR (involved in signaling and

Genetic Analysis of 114 Tumors Dr Balko and colleagues conducted a genetic analysis of this residual tumor tissue to look for genetic aberrations that might be targeted by specific therapies. Their study includ-

“These data provide a ‘targetable’ catalogue of the alterations present in the residual disease of triplenegative after neoadjuvant chemotherapy, and support genomically driven adjuvant trials in this patient population.”

Photo © SABCS/Todd Buchanan 2012

are currently available or are being developed to target these markers.

Currently, the treatment of patients with triple-negative breast cancer is more of a hit-and-miss situation, Dr Balko said. No biomarkers have been established—such as HER2 for trastuzumab (Herceptin)— that could enhance the treatment of these patients.

“Neoadjuvant chemotherapy is increasingly used in patients with triplenegative breast cancer. It can induce a pathologic complete response in about 30% of patients, which portends a favorable prognosis, while those patients with residual disease in the breast at surgical resection exhibit worse outcomes,” Dr Balko pointed out.

“There are currently no targeted therapeutic options for triple-negative patients with residual disease after neoadjuvant chemotherapy to be used in the adjuvant setting. We hypothesized that molecular analysis of the residual disease would identify genetic alterations that are ultimately responsible for disease recurrence and could be targeted with clinically available medications,” he noted.

—Justin Balko, PharmD, PhD

ed tissue samples from 114 women, which were analyzed by 3 methods.

With next-generation sequencing, the researchers were able to ultimately look for 182 oncogenes and tumor suppressor genes in 81 samples.

cellular death), DNA repair genes (eg, BRCA1 and BRCA2), RAS/MAP kinase pathway (cellular proliferation, differentiation, and death), cell cycle genes, and growth factor receptors, such as the epidermal growth

Continued from cover

factor receptor, which is important in lung cancer.

The most common aberration was p53, a well-known oncogene, which was found in 90% of the triple-negative tissue samples, Dr Balko reported.

Some combinations of these genetic variants heralded a worse prognosis than others. In a univariate analysis of 62 patients, the presence of the MEK kinase gene plus amplification of the MYC oncogene had a synergistic effect. Women with these 2 aberrations were more likely to relapse than women with only 1 of the variants.

“In addition, we identified novel JAK2 amplifications in about 10% of the patients, which may be therapeutically targetable,” Dr Balko said.

The JAK2 inhibitor ruxolitinib (Jakafi) is approved for the treatment of patients with myelofibrosis, and a number of other JAK2 inhibitors are in clinical trials.

“These data provide a ‘targetable’ catalogue of the alterations present in the residual disease of triple-negative after neoadjuvant chemotherapy, and support genomically driven adjuvant trials in this patient population,” Dr Balko concluded. n

HDAC Inhibitor plus PARP Inhibitor or Cisplatin Induce Apoptosis of Triple-Negative Breast Cancer Cells

By Caroline Helwick

H

istone deacetylase (HDAC) inhibitors may have a future in the targeted treatment of triple-negative breast cancer, if the results of in vitro studies can be replicated clinically.

HDAC inhibitors are cytostatic agents that have been shown to limit the proliferation of tumor cells in culture. In the case of triple-negative tumors, research is showing that exposure to an HDAC inhibitor indirectly impairs the ability of these cells to repair damaged DNA, and at the same time it sensitizes them to 2 agents that are frequently used in the treatment of triple-negative disease—a PARP inhibitor and cisplatin (Platinol).

Kapil N. Bhalla, MD, FACP, Chief of Personalized Cancer Medicine at the University of Kansas Cancer Center in Kansas City, explained that the prospect for HDAC inhibitors in this tumor subtype arose from the

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likelihood that heat shock protein 90 (hsp90), the highly conserved and abundant cell chaperone, is involved in carcinogenesis.

“If you have a patient with triple-negative breast cancer who does not have a BRCA1 mutation, you could consider a clinical trial using an HDAC inhibitor in combination with a PARP inhibitor and cisplatin.”

—Kapil N. Bhalla, MD, FACP Dr Bhalla and colleagues previously reported that treatment with an HDAC inhibitor renders hsp90 inac-

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tive, thereby impeding the DNA damage response that involves the ATRBRCA1-Chk1 signaling pathway (these are hsp90 client proteins).

HDAC inhibition creates an environment within cells that is not unlike that seen in breast cancer cells with BRCA1 mutations.

“In the present study, we determined that treatment with vorinostat [Zolinza] or panobinostat induced hyperacetylation and inhibition of chaperone function of nuclear hsp90, leading to proteasomal degradation and the depletion of ATR, Chk1, and BRCA1,” he said. This ultimately stopped the DNA repair process.

Dr Bhalla and colleagues also investigated whether the pan-HDAC inhibitors vorinostat or panobinostat could sensitize triple-negative breast cancer cells to PARP inhibition. They found that either agent, when given together with the PARP inhibitor ABT888, was

a lethal combination to triple-negative cells, regardless of whether the cells contained the BRCA1 mutation.

These findings indicate that treatment with pan-HDAC inhibitors creates “BRCAness,” and that in combination with a PARP inhibitor or cisplatin, it synergistically induces apoptosis in triple-negative breast cancer cells.

“These studies support the rationale of testing the efficacy of a treatment regimen that includes a PARP inhibitor combined with a pan-HDAC inhibitor and cisplatin against triple-negative breast cancers,” Dr Bhalla noted.

Dr Bhalla foresees the clinical application of his research. “If you have a patient with triple-negative breast cancer who does not have a BRCA1 mutation, you could consider a clinical trial using an HDAC inhibitor in combination with a PARP inhibitor and cisplatin,” he advised. n

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Other Clinical Highlights

Venlafaxine Lowers Endoxifen Levels, Reduces Tamoxifen Effectiveness

By Caroline Helwick

T

he antidepressant venlafaxine (Effexor) is often prescribed to patients with breast cancer who are taking tamoxifen (Nolvadex) to help reduce the side effect of hot flashes. But according to research presented at the meeting, venlafaxine may reduce the effectiveness of tamoxifen.

The findings came from a multicenter prospective pharmacologic study that looked at paired blood samples from 30 women who were taking tamoxifen for at least 4 weeks and were initiated treatment with venlafaxine for the treatment of hot flashes. Blood samples were taken before starting venlafaxine and 8 to 16 weeks afterward.

Genotyping was done for alleles associated with no, reduced, and ultrarapid metabolism. The goal was to determine whether venlafaxine altered the pharmacokinetics of tamoxifen and to determine the distribution of the cytochrome (CY) P2D6 metabolizers in this population.

CYP2D6 is the rate-limiting enzyme that is responsible for the metabolic activation of tamoxifen to endoxifen.

Among women taking tamoxifen, those who are extensive metabolizers of CYP2D6 have higher endoxifen concentrations, have more vasomotor symptoms, and are more likely to discontinue tamoxifen compared with those who are poor metabolizers.

“The data regarding CYP2D6 genotype and cancer recurrence has been mixed,” said lead investigator Matthew P. Goetz, MD, an oncologist with the Mayo Clinic in Rochester, MN. “Venlafaxine is a weak CYP2D6 inhibitor not known to alter tamoxifen pharmacokinetics and is commonly recommended for tamoxifen-induced hot flashes.”

The women with tamoxifen-induced vasomotor symptoms requiring venlafaxine were comprised predominantly of CYP2D6 extensive and ultrarapid metabolizers. Venlafaxine significantly decreased endoxifen concentrations. Across all genetic sub-

groups, levels were depressed by a median of approximately 1.6 ng/mL over time (P = .04). Limited evidence suggests that at least 6 ng/mL is need-

“Given previous data linking low endoxifen concentrations with recurrence, venlafaxine should be used with caution in tamoxifen-treated patients.”

—Matthew P. Goetz, MD

ed. In the study, 3 women with low CYP2D6 activity had levels drop below that.

Dr Goetz acknowledged that the amount of endoxifen that is needed for benefit is still unknown, and that the effect of venlafaxine on breast can-

cer outcomes remains unknown.

“The bottom line,” he said, “is that there is a decrease. It’s small, but it’s statistically significant. The question really is, ‘Are there subgroups of patients in which this is important?’”

Dr Goetz concluded that although the optimal concentration of endoxifen is currently unknown, “given previous data linking low endoxifen concen­ trations with recurrence, ven­la­faxine should be used with caution in tamoxifen-treated patients.”

Hiltrud Brauch, DPhil, PhD, Deputy Head and Coordinator of the Oncology Program at the Dr Margarete FischerBosch-Institute of Clinical Pharma­ cology in Stuttgart, Germany, led a 2009 study showing that variations in CYP2D6 have an effect on disease-free and event-free survival in patients taking tamoxifen.

“Poor metabolizers do not benefit from tamoxifen as well as extensive metabolizers,” Dr Brauch said. “The long and the short of it is that this matters to women.” n

More Evidence Links Vitamin D Deficiency to Worse Outcomes in Breast Cancer Helps to select appropriate treatment type

M

ore evidence is accumulating that vitamin D levels play a role in breast cancer outcomes. Investigators from the United Kingdom reported that postmenopausal women with sufficient vitamin D levels were significantly less likely to develop bone metastases when taking zoledronic acid (Zometa) compared with women with lower vitamin D levels.

“Patients with a sufficient level of vitamin D had a better prognosis,” said Robert Coleman, MBBS, MD, FRCP, Professor, Department of Oncology, the University of Sheffield, England, and an Associate Director of the National Institute for Health Research Cancer Research Network in the United Kingdom. He called the findings “quite surprising.”

However, markers of bone turnover were not associated with risk, Dr Coleman added.

The findings came from an analysis of tissue samples from 872 partici-

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“Clinicians should be measuring vitamin D [and] replenishing it appropriately.

But whether vitamin D as an intervention will change outcome, I don’t know.”

—Robert Coleman, MBBS, MD, FRCP pants of the large AZURE trial, which evaluated the efficacy of zoledronic acid in 3360 patients with early breast cancer. This subgroup analysis included 606 premenopausal women and 266 postmenopausal women.

AZURE showed little benefit in adding zoledronic acid to chemotherapy, but in a prespecified analysis, the postmenopausal women had a significantly lower risk of recurrence, in the bone and in distant sites, compared

with premenopausal women. The current investigation sought to explore this, and looked at baseline levels of 2 markers of bone turnover (CTX and P1NP) as well as 25-hydroxyvitamin (25[OH])D as a marker of bone and general health.

The 25(OH)D level was deemed “insufficient” at ≤30 ng/mg and “sufficient” above this level. A striking finding was that only 10.3% of women had sufficient vitamin D levels, Dr Coleman reported.

Vitamin D Level Linked to Recurrence Although neither of the 2 bone turnover markers predicted outcomes, there were “quite surprising differ­ ences” in recurrence based on 25(OH) D levels, he said.

A low vitamin D level predicted the development of bone metastases, with a hazard ratio (HR) of 0.11 (P = .025).

A low vitamin D level appeared to predict for distant recurrence as well,

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with an HR of 0.56, but this did not reach statistical significance.

Dr Coleman suggested that the findings have clinical implications.

“Clinicians should be measuring vitamin D [and] replenishing it appropriately,” he noted. “But whether vitamin D as an intervention will change outcome, I don’t know.”

Carol A. Lange, PhD, coleader of the Women’s Cancer Research Pro­ gram, Professor of the Departments of Medicine and Pharmacology, Tickle Family Land Grant Endowed Chair in Breast Cancer Research, and Director, Cancer Biology Training Grant of the University of Minnesota, Minneapolis, who moderated the session, agreed that “it’s a really good idea” to keep vitamin D levels in the sufficient range, noting that this is an inexpensive and apparently safe intervention.

Current studies are attempting to further elucidate the mechanism underlying vitamin D’s potential antitumor effects, Dr Lange said.—CH n

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Other Clinical Highlights

Evidence Still Cloudy for Anticancer Effects with Metformin

By Caroline Helwick

O

bservational studies have sug­ gested that the antidiabetes agent metformin (Glucophage) may have anticancer effects. New studies have attempted to confirm this, but the results and their meaning still remain unclear.

Reviewing several studies presented at the meeting, Michael N. Pollak, MD, the Alexander Goldfarb Research Chair in Cancer Research and the Di­rec­tor, Division of Cancer Prevention, De­ partment of Oncology, McGill Uni­ versity, Montreal, Canada, said that there are many unanswered questions, but that “some of those questions have become clearer.”

The rationale for investigating antitumor effects that may be attributed to metformin stemmed first from the observation that diabetic patients receiving the drug were less likely to devel-

op breast cancer than diabetic patients who did not receive metformin.

Laboratory studies have pointed to multiple mechanisms by which metformin may inhibit tumor growth or proliferation, but preclinical models do not accurately reflect the metformin concentrations achieved in humans, Dr Pollak said.

In a study presented at the meeting, Italian investigators evaluated cancer-cell apoptosis in 88 patients with breast cancer who were randomized to metformin or to placebo for 4 weeks before surgery for early breast cancer. Apoptosis was similar between the groups at baseline, but it increased significantly in both arms before surgery. An interaction was seen between apoptosis (by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling

[TUNEL] assay) and homeostasis model assessment, a measure of insulin resistance.

Patients who were not insulin resistant had a TUNEL level of 10% with metformin versus 6% with placebo (P = .05). In contrast, women with insulin resistance had a median TUNEL value of 6% with metformin and 9% with placebo (P = .3). Proliferation by Ki67 was also correlated with TUNEL at baseline and surgery, according to Giancarlo Pruneri, MD, Assistant Professor, Division of Pathology, European Institute of Oncology, Milan School of Medicine, Italy.

A small presurgical study from Columbia University showed no effect of metformin on tumor proliferation. The mean Ki67 values did not change significantly according to metformin exposure.

Positive Effects of Metformin in Breast Cancer However, a small Canadian study showed metformin to be potentially beneficial in 38 nondiabetic women with early breast cancer who took the drug for 2 weeks or longer before diagnostic core biopsy. The neoadjuvant use of metformin was associated with a significant reduction in Ki67 activity (P = .016) and with a significant increase in TUNEL (P = .037).

Other markers of tumor proliferation were also reduced significantly, according to Ryan J. O. Dowling, PhD, Division of Signalling Biology, Ontario Cancer Institute, Canada, and colleagues, who noted that changes in insulin levels and Akt signaling suggest that metformin has clinically important insulin-dependent effects on tumor growth. n

New Meta-Analysis: Complete Response to Neoadjuvant Therapy in Breast Cancer Predictor of Long-Term Benefit

By Audrey Andrews

A

new meta-analysis confirmed that patients with breast cancer who achieve a pathologic complete response (pCR) to neoadjuvant therapy have a more favorable outcome than those who do not.

Patients who achieved a pCR had a 52% reduction in the probability of an event and a 64% reduction in the probability of death (P <.001 for both), as was shown in the meta-analysis of the Collaborative Trials in Neoadjuvant Breast Cancer (CTNeoBC). “pCR is a proposed surrogate end point for predicting long-term clinical benefit on end points such as disease-free survival, event-free survival [EFS], or overall survival [OS].

A meta-analysis has been needed to establish the magnitude of pCR improvement on a trial level that results in improved disease-free survival,” said lead investigator Patricia Cortazar, MD, Clinical Team Leader for the Breast Oncology Group of the US Food and Drug Administration.

The analysis included 12 neoadjuvant randomized controlled trials in which pCR was clearly defined, all the necessary data were collected, and data on EFS and OS with long-term follow-up were available.

The studies used various definitions of pCR, including: • ypT0ypN0: absence of invasive cancer in the breast and axillary

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nodes, and absence of ductal carcinoma in situ (DCIS) • ypT0/isypN0: absence of invasive cancer in the breast and axillary nodes; DCIS is allowed • ypT0/is: absence of invasive cancer in the breast; DCIS is allowed regardless of nodal involvement.

Major Findings The analysis showed that pCR was positively associated with more favorable long-term outcomes, including EFS and OS. The more favorable outcomes after pCR occurred regardless of whether DCIS was present or absent. For consistency, a standard pCR definition should be used in future trials, preferably ypT0ypN0 or ypT0/isypN0.

By breast subtype, a larger association with EFS was observed in patients with aggressive tumor subtypes; the association was smaller in patients with less aggressive tumors.

The magnitude of pCR improvement that predicts long-term clinical benefit (ie, EFS and OS improvement) could not be established, possibly as a result of low pCR rates, heterogeneous populations, and the lack of targeted therapies in most trials.

Larger pCR differences between treatment arms are needed to translate into long-term outcome and may vary according to breast cancer subtype.

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Overall, the percentage of patients achieving a pCR was 13% by using the ypT0ypN0 definition, 18% by ypT0/isypN0, and 22% by ypT0/is.

Eradication of tumor from the breast and from the lymph nodes was better associated with improved EFS and with OS than with eradication from the breast alone.

Patients who achieved a pCR had a 52% reduction in the probability of an event and a 64% reduction in the probability of death.

“The absolute magnitude of improvement in pCR rate needed to impact long-term outcome may be greater than the observed difference in these trials, and may vary according to breast cancer subtype.”

—Patricia Cortazar, MD

The achievement of pCR was variable by tumor subtype, being infrequent in patients with low-grade hormone receptor (HR)-positive tumors (7%) and more frequent among highgrade HR-positive (16%), triple-neg-

ative (34%), HR-positive and HER2positive (30%), and HR-negative and HER2-positive (50%) tumors.

“Patients with more aggressive tumor subtypes who achieved pCRs had greater EFS compared with patients who did not achieve pCRs,” Dr Cortazar noted.

Among HER2-positive patients, the achievement of pCR was associated with significant reductions in risk; within certain subgroups, this was enhanced with treatment with trastuz­ umab (Herceptin). In HER2-positive and HER2-negative patients, hazard ratios associated with pCR were 0.35 without trastuzumab and 0.15 (P <.001 for both) with trastuzumab.

In addition, the triple-negative subgroup greatly benefited from attaining a pCR, with a hazard ratio of 0.24 (P <.001), Dr Cortazar added.

Of note, the magnitude of pCR improvement in the randomized trials did not predict the EFS and OS effects.

“This meta-analysis did not establish the magnitude of increase in pCR rate needed to predict the superiority of one regimen over another in terms of EFS or OS,” she said. “The absolute magnitude of improvement in pCR rate needed to impact longterm outcome may be greater than the observed difference in these trials, and may vary according to breast cancer subtype.” n

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HALAVEN® (eribulin mesylate) Injection BRIEF SUMMARY – See package insert for full prescribing information.

2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.

Recommended dose delays • Do not administer HALAVEN on Day 1 or Day 8 for any of the following: – ANC <1,000/mm3 – Platelets <75,000/mm 3 – Grade 3 or 4 non-hematological toxicities.

• The Day 8 dose may be delayed for a maximum of 1 week.

– If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose.

– If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate the next cycle no sooner than 2 weeks later.

Recommended dose reductions • If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a reduced dose as set out in Table 1.

• Do not re-escalate HALAVEN dose after it has been reduced.

Table 1 Recommended Dose Reductions Recommended Event Description HALAVEN Dose Permanently reduce the 1.4 mg/m2 HALAVEN dose for any of the following: ANC <500/mm3 for >7 days ANC <1,000 /mm3 with fever or infection Platelets <25,000/mm3 1.1 mg/m2 Platelets <50,000/mm3 requiring transfusion Non-hematologic Grade 3 or 4 toxicities Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicity Occurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2 0.7 mg/m2 Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 Discontinue HALAVEN ANC = absolute neutrophil count.

Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

5 WARNINGS AND PRECAUTIONS 5.1 Neutropenia Severe neutropenia (ANC <500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with alanine aminotransferase or aspartate aminotransferase >3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin >1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.

Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3.

5.2 Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1. Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.

5.3 Embryo-Fetal Toxicity There are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.

5.4 QT Prolongation In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome.

6 ADVERSE REACTIONS The following adverse reactions are discussed in detail in other sections of the labeling: • Neutropenia • Peripheral neuropathy • QT interval prolongation The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%).

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).

The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.

Table 2 Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1 MedDRA ver 10.0 HALAVEN (n=503) Control Group (n=247) All Grades ≥ Grade 3 All Grades ≥ Grade 3 a Blood and Lymphatic System Disorders Neutropenia 82% 57% 53% 23% Anemia 58% 2% 55% 4% Nervous system disorders 35% 8% 16% 2% Peripheral neuropathyb Headache 19% <1% 12% <1% General disorders and administrative site conditions Asthenia/Fatigue 54% 10% 40% 11% Mucosal inflammation 9% 1% 10% 2% Pyrexia 21% <1% 13% <1% Gastrointestinal disorders Constipation 25% 1% 21% 1% Diarrhea 18% 0 18% 0 Nausea 35% 1% 28% 3% Vomiting 18% 1% 18% 1% Musculoskeletal and connective tissue disorders Arthralgia/Myalgia 22% <1% 12% 1% Back pain 16% 1% 7% 2% Bone pain 12% 2% 9% 2% Pain in extremity 11% 1% 10% 1% Investigations Weight decreased 21% 1% 14% <1% Metabolism and nutrition disorders Anorexia 20% 1% 13% 1% Respiratory, thoracic, and mediastinal disorders Cough 14% 0 9% 0 Dyspnea 16% 4% 13% 4% Skin and subcutaneous tissue disorders 10% NAc Alopecia 45% NAc

Table 2 (cont'd) MedDRA ver 10.0

HALAVEN (n=503) Control Group (n=247) All Grades ≥ Grade 3 All Grades ≥ Grade 3 Infections and Infestations Urinary Tract Infection 10% 1% 5% 0 a Based upon laboratory data. b Includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. c Not applicable; (grading system does not specify > Grade 2 for alopecia).

Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of patients who received HALAVEN. Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.

Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN. Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the HALAVENtreated group: • Eye Disorders: increased lacrimation • Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth • General Disorders and Administration Site Conditions: peripheral edema • Infections and Infestations: upper respiratory tract infection • Metabolism and Nutrition Disorders: hypokalemia • Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness • Nervous System Disorders: dysgeusia, dizziness • Psychiatric Disorders: insomnia, depression • Skin and Subcutaneous Tissue Disorders: rash 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category D There are no adequate and well-controlled studies with HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen.

Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose.

Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption.

8.3 Nursing Mothers It is not known whether HALAVEN is excreted into human milk. No studies in humans or animals were conducted to determine if HALAVEN is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from HALAVEN, a decision should be made whether to discontinue nursing or to discontinue HALAVEN taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have not been established.

8.6 Hepatic Impairment Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C).

8.7 Renal Impairment For patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of HALAVEN was not studied in patients with severe renal impairment (CrCl <30 mL/min).

10 OVERDOSAGE Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day.

There is no known antidote for HALAVEN overdose.

12 CLINICAL PHARMACOLOGY 12.3 Pharmacokinetics Specific Populations Hepatic Impairment A study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=5) hepatic impairment.

Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function.

Renal Impairment No formal PK trials were conducted with HALAVEN in patients with renal impairment. Available data suggests that geometric mean dose-normalized systemic exposure is similar for patients with mild renal impairment (CrCl 50-80 mL/min) relative to patients with normal renal function. However, for patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dosenormalized systemic exposure increased 2-fold compared to patients with normal renal function.

12.6 Cardiac Electrophysiology The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies have not been conducted with eribulin mesylate.

Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay.

The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling • Advise patients to contact their health care provider for a fever of 100.5°F or greater or other signs or symptoms of infection such as chills, cough, or burning or pain on urination.

• Advise women of childbearing potential to avoid pregnancy and to use effective contraception during treatment with HALAVEN. –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– HALAVEN® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2012 Eisai Inc. All rights reserved. Printed in USA / March 2012 ERI 346

ERIBPUS-4306_M04_A_SIZE_Brief_Summary.indd 1

3/28/12 3:08 PM

After 2 prior lines of MBC chemotherapy,

DISCOVER OVERALL SURVIVAL HALAVEN: The FIRST and ONLY single-agent therapy proven to significantly extend OVERALL SURVIVAL after 2 prior lines of MBC therapy1-9

UPDATED OVERALL SURVIVAL (OS) ANALYSIS (UNPLANNED): MEDIAN OS, MONTHS (95% CI)1,10,a

P R O P O R T I O N O F PAT I E N T S A L I V E

1.0

The updated OS analysis was consistent with the primary analysis1 The primary analysis, conducted when ~50% of events (deaths) had been observed, demonstrated a median OS for Halaven vs TPC of 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months (95% CI: 9.3, 12.5), HR*=0.81 (95% CI: 0.66, 0.99) (P=0.041)1,10 Results from an updated, unplanned survival analysis of the Phase III, randomized, open-label, multicenter, multinational EMBRACE† trial of Halaven versus TPC in patients with metastatic breast cancer (MBC) (N=762), conducted when 77% of events (deaths) had been observed. The primary endpoint was OS. Patients were randomized (2:1) to receive either Halaven 1.4 mg/m2 IV for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization. At baseline, all patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen. All patients received prior anthracycline- and taxanebased chemotherapy, unless contraindicated. Therapies in the TPC arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxanes [included paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracyclines, 10% other chemotherapy), and 3% hormonal therapy.

0.9 0.8

Halaven

0.5

Treatment of Physician’s Choice

0.4

(n=254)

0.3

10.6

0.2

(9.2, 12.0)

0.1

Deaths=203

0.0 6

Number of patients at risk

508 254

406 178

QT Prolongation

• Patients should be monitored closely for signs of peripheral motor and sensory neuropathy • Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4 in 0.4% of patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less • Neuropathy lasting more than 1 year occurred in 5% of patients. Twenty-two percent of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days) • Peripheral neuropathy (5%) was the most common adverse reaction resulting in discontinuation

Please see accompanying brief summary of Halaven full Prescribing Information.

To learn more about Halaven, visit www.halaven.com

HALAVEN® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2012 Eisai Inc. All rights reserved.

Printed in USA/August 2012 HALA0042 R1

18

24

30

36

274 106

142 61

54 26

11 5

0 Halaven 0 TPC

CI=confidence interval; Treatment of Physician’s Choice (Control arm)=TPC. Conducted in the intent-to-treat (ITT) population.

Halaven is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Peripheral Neuropathy

12

TIME (MONTHS)

Pregnancy Category D

• Monitor complete blood counts prior to each dose, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days • Severe neutropenia (ANC <500/mm3) lasting more than 1 week occurred in 12% (62/503) of patients. Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels • Grade 3 and Grade 4 neutropenia occurred in 28% and 29%, respectively, of patients who received Halaven. Febrile neutropenia occurred in 5% of patients and two patients (0.4%) died from complications

IN MEDIAN OS

Deaths=386

Indication

Neutropenia

INCREASE

(12.1, 14.4)

0.6

0

a

Important Safety Information

25% (2.6 month)

(n=508)

13.2

0.7

• Halaven is expected to cause fetal harm when administered to a pregnant woman and patients should be advised of these risks • In an uncontrolled ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias; concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities • Correct hypokalemia or hypomagnesemia prior to initiating Halaven and monitor electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment

• For patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic and/or moderate (CrCl 30-50 mL/min) renal impairment, a reduction in starting dose is recommended

Most Common Adverse Reactions

• Most common adverse reactions (≥25%) reported in patients receiving Halaven were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%) • The most common serious adverse reactions reported in patients receiving Halaven were febrile neutropenia (4%) and neutropenia (2%) References: 1. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2012. 2. Saad ED et al. J Clin Oncol.

2010;28(11):1958-1962. 3. Slamon DJ et al. N Engl J Med. 2001;344(11):783-792. 4. Geyer CE et al. N Engl J Med. 2006;355(26):2733-2743. 5. von Minckwitz G et al. J Clin Oncol. 2009;27(12):1999-2006. 6. Miller K et al. N Engl J Med. 2007;357(26):2666-2676. 7. Robert NJ et al. J Clin Oncol. 2011;29(10):1252-1260. 8. Sparano JA et al.

J Clin Oncol. 2010;28(20):3256-3263. 9. Jones SE et al. J Clin Oncol. 2005;23(24):5542-5551. 10. Cortes J et al.

Lancet. 2011;377(9769):914-923.

*HR=hazard ratio. † EMBRACE=Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice versus E7389 (Eribulin).