Optimal Chemotherapy Combinations with Trastuzumab:

CONTINUING MEDICAL EDUCATION

E-Updates in HER1 and HER2 Targeting in Breast Cancer, Volume 2: Optimal Chemotherapy Combinations with Trastuzumab: Are Anthracyclines Obsolete?

Activity Release Date: July 15, 2008 Activity Expiration Date: July 15, 2009

About the Activity

This activity is based on a brief article developed as part of the E-Update Series and posted on the Web. It was developed from an identified educational need for information about practical management issues in the practice of medical, surgical, and radiation oncology. This activity has been developed and approved under the direction of Beam Institute.

Activity Learning Objectives

After completing this series of activities, the clinician should be able to: (1) Demonstrate knowledge of the latest biology of HER2-positive breast cancer and its clinical relevance to the every day practice of the community-based oncologist. (2) Appraise the evidence for the possible use of adjuvant trastuzumab for all HER2-positive breast cancers regardless of tumor characteristics. (3) Demonstrate knowledge of and use the most optimal chemotherapy combinations with trastuzumab. (4) Apply the knowledge of the current use of lapatinib in HER2-positive breast cancer and demonstrate an understanding of possible future use of lapatinib in HER2-positive breast cancer. Target Audience This activity targets physicians in the fields of oncology and hematology. Accreditation 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 Beam Institute and The Oncology Group. Beam Institute is accredited by the ACCME to provide continuing medical education for physicians. Continuing Education CreditAMA PRA Category 1 Credit™ Beam Institute designates this educational activity for a maximum of 2 AMA PRA Category 1 Credits™ . Physicians should only claim credit commensurate with the extent of their participation in the activity. Compliance Statement This activity is an independent educational activity under the direction of Beam Institute. The activity was planned and implemented in accordance with the Essential Areas and policies of the ACCME, the Ethical Opinions/Guidelines of the AMA, the FDA, the OIG, and the PhRMA Code on Interactions with Healthcare Professionals, thus assuring the highest degree of independence, fair balance, scientific rigor, and objectivity. However, Beam Institute, the Grantor, and CMPMedica shall in no way be liable for the currency of information or for any errors, omissions, or inaccuracies in the activity. Discussions concerning drugs, dosages, and procedures may reflect the clinical experience of the author(s) or may be derived from the professional literature or other sources and may suggest uses that are investigational in nature and not approved labeling or indications. Activity participants are encouraged to refer to primary references or full prescribing information resources. The opinions and recommendations presented herein are those of the author(s) and do not necessarily reflect the views of the provider or producer. Financial Disclosures Dr. Ellis has received grant support from Novartis and AstraZeneca; he has acted as a consultant for Novartis, AstraZeneca, GlaxoSmithKline, Pfizer, and Merck; and he has received lecture fees from Novartis, AstraZeneca, and GlaxoSmithKline. Dr. Abu-Khalaf has received clinical trial funding and support from Genentech. Dr. Harris has no financial relationships to disclose. Copyright Copyright owned by Beam Institute. Copyright 2008, all rights reserved. Contact Information We would like to hear your comments regarding this or other activities provided by Beam Institute. In addition, suggestions for future activities are welcome. Contact us at:

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Table of Contents

A Word From the Editor

Introduction

Role Of Anthracyclines in Her2 Positive Breast Cancer

Efficacy Of Anthracycline and Nonanthracycline Adjuvant Trastuzumab Clinical Trials

Cardiotoxicity of Anthracycline vs Nonanthracycline Adjuvant Trastuzumab Clinical Trials

Concurrent Anthracycline and Trastuzumab Neoadjuvant Therapy

Topoisomerase II as a Predictor of Anthracycline Benefit Her2 Positive Breast Cancer

Conclusion

Key Points

References

Dear Colleague:

We are pleased to introduce the third of four E-Updates that will be presented this year in the series entitled HER1 and HER2 Targeting in Breast Cancer. This clinically focused update concerns the optimal chemotherapy combinations with trastuzumab, a presentation that endeavors to determine whether anthracyclines are now obsolete in the setting of HER2+ disease. This is a particularly thorny issue for the clinician, so we are fortunate to have it addressed and analyzed by Dr. Maysa Abu-Khalaf, Assistant Professor of Medical and Gynecologic Oncology at the Yale Comprehensive Cancer Canter, and by her colleague, Dr. Lyndsay Harris, Director of the Breast Disease Unit at the Yale Comprehensive Cancer Center.

Among other key clinical considerations, the authors describe the cardiotoxicity risk factors that must be recognized and considered when considering therapy with adjuvant trastuzumab.

The fourth and final E-Update in this series will present the current and future roles of lapatinib in HER2 breast cancer. We hope that taken together these four updates focused on HER2-directed therapy will improve the clinicians understanding of how to maximize the benefits of HER2 targeting in breast cancer and minimize side effects and serious toxicities.

Sincerely,

Matthew J. Ellis, MB, BChir, PhD, FRCP Director, Breast Cancer Program Anheuser Busch Tenured Associate Professor of Medicine Washington University School of Medicine St. Louis, Missouri

INTRODUCTION

HER2 (human epidermal growth factor receptor 2) is a 185 kDa member of the erb-B receptor tyrosine kinase family and is overexpressed in 25% to 30% of breast cancer patients. HER2 overexpression is an adverse prognostic factor in early breast cancer, and is associated with an increased risk of distant relapse and death.[1] The presence of HER2 on the cell surface makes it a logical target for antibody therapy, leading to the development of trastuzumab (Herceptin) - a humanized monoclonal antibody against the extracellular domain of the HER2 protein. Trastuzumab was first approved in 1998 for first-line treatment of HER2 positive metastatic breast cancer in combination with paclitaxel.[2] Trastuzumab has been found to improve survival for women with metastatic breast cancer, and subsequently, adjuvant trials showed substantial benefits for patients with early-stage HER2 positive breast cancer. This review focuses on discussing the efficacy and cardiotoxicity of anthracycline and trastuzumab combination regimens compared to nonanthracycline and trastuzumab regimens.

ROLE OF ANTHRACYCLINES IN HER2 POSITIVE BREAST CANCER

Data from multiple clinical trials have indicated that patients with HER2 positive tumors may benefit from adjuvant anthracycline therapy. The National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-11 randomized patients with lymph node-positive, hormone receptor-negative breast cancer to treatment with melphalan and fluorouracil with or without doxorubicin. In a retrospective analysis after a mean time on study of 13.5 years, the clinical benefit from doxorubicin was statistically significant in patients with HER2-positive tumors with an improved DFS (relative risk [RR] = 0.60; P =.001), OS (RR = 0.66; P =.01), relapse-free survival (RFS; RR = 0.58; P =.002), and distant DFS (RR = 0.61; P =.003). There was no benefit to the addition of doxorubicin in the HER2 negative subset.[3]

The relationship between HER2 status and responsiveness to adjuvant anthracycline-containing therapy was evaluated in premenopausal women with node-positive breast cancer enrolled in the MA-5 trial led by the National Cancer Institute of Canada. In this study, patients were randomly assigned to treatment with cyclophosphamide, epirubicin, and fluorouracil (CEF), or classic cyclophosphamide, methotrexate, and 5-fluorouracil (CMF). At median follow-up times of 5 and 10 years, outcomes were superior for those receiving CEF.[4,5] In addition, 639 formalin-fixed paraffin-embedded specimens, obtained from 710 premenopausal subjects from this trial, were analyzed for HER2 status. For those with HER2-positive tumors, CEF was superior to CMF, with hazard ratios (HRs) of 0.52 (P = .003) and 0.65 (P = .06) for RFS and OS, respectively. There was no observed difference between CEF and CMF in patients with HER2-negative disease.[6]

A pooled meta-analysis of eight large randomized controlled clinical trials that compared anthracycline-based with nonanthracycline-based adjuvant chemotherapy regimens in the treatment of early breast cancer and reported efficacy data according to HER2 status, examined interaction between HER2 status and the benefit of adjuvant anthracycline therapy. In HER2 positive disease (n = 1,536 patients), anthracyclines were superior to nonanthracycline-based regimens in terms of disease-free (pooled HR of relapse = 0.71; 95% confidence interval [CI] = 0.61 to 0.83; P < .001) and overall (pooled HR of death from any cause = 0.73; 95% CI = 0.62 to 0.85; P < .001) survival. In HER2 negative disease (n = 3,818 patients), anthracyclines did not improve disease-free (HR = 1.00; 95% CI = 0.90 to 1.11; P = .75) or overall (HR = 1.03; 95% CI = 0.92 to 1.16; P = .60) survival. The test for interaction between HER2 status and receipt of anthracyclines was significant for both DFS was 13.7 (P < .001), and for overall survival, it was 12.6 (P < .001).[7]

EFFICACY OF ANTHRACYCLINE AND NONANTHRACYCLINE ADJUVANT TRASTUZUMAB CLINICAL TRIALS

Given the positive outcomes of trastuzumab in the metastatic setting, several clinical trials were designed to evaluate the efficacy of adjuvant trastuzumab in patients with early-stage HER2 positive breast cancer. The first interim analyses of The National Surgical Adjuvant Breast and Bowel Project (NSABP) trial B-31, the North Central Cancer Treatment Group (NCCTG) Intergroup trial N9831, and Herceptin Adjuvant (HERA) trial were presented at the 41st Annual Meeting of the American Society of Clinical Oncology (ASCO) in May 2005.[8,9] With a median follow-up of 12 to 28 months, these trials showed that the addition of trastuzumab to standard chemotherapy was associated with an approximate 50% decrease in the risk of breast cancer relapse, and the NSABP B-31 and NCCTG N9831 joint analysis showed an approximate 33% decrease in the risk of death from breast cancer.

National Surgical Adjuvant Breast and Bowel Project [NSABP] trial B-31 and North Central Cancer Treatment Group N9831

The NSABP B-31 study compared doxorubicin and cyclophosphamide, followed by paclitaxel every 3 weeks (group 1) with the doxorubicin and cyclophosphamide and subsequently paclitaxel every 3 weeks plus 52 weeks of trastuzumab beginning with the first dose of paclitaxel (group 2). The N9831 compared three regimens: doxorubicin and cyclophosphamide followed by weekly paclitaxel (group A), the same regimen followed by 52 weeks of trastuzumab after paclitaxel (group B), and the same regimen plus 52 weeks of trastuzumab initiated concomitantly with paclitaxel (group C). The studies were amended to include a joint analysis comparing groups 1 and A (the control group) with groups 2 and C (the trastuzumab group). Group B was excluded because trastuzumab was not given concurrently with paclitaxel. By March 15, 2005, 394 events (recurrent, second primary cancer, or death before recurrence) had been reported, triggering the first scheduled interim analysis. Of these, 133 were in the trastuzumab group and 261 in the control group (HR = 0.48; P < .0001). The absolute difference in disease-free survival (DFS) between the trastuzumab group and the control group was 12% at 3 years. Trastuzumab therapy was associated with a 33% reduction in the risk of death (P = .015).

The addition of trastuzumab to paclitaxel after a regimen of doxorubicin and cyclophosphamide reduced the rates of recurrence by half among women with HER2-positive breast cancer. The absolute decreases in distant recurrence were 8.8 percentage points after 3 years and 15.9 percentage points after 4 years, although the latter value had a wide confidence interval (11.1 to 20.8 percentage points). The reduction was similar among women with hormone-receptor–negative tumors and women with hormone-receptor–positive tumors. No subgroups of patients that did not appear to benefit from trastuzumab therapy were identified. The addition of trastuzumab reduced the mortality rate by one third (P = .015).

Herceptin Adjuvant (HERA) trial

The Herceptin Adjuvant (HERA) (Breast International Group [BIG] 01-01) trial is an international, intergroup, open-label, phase 3 randomized trial involving women with HER2-positive (overexpressing or amplified) early-stage invasive breast cancer who completed locoregional therapy (surgery with or without radiotherapy) and a minimum of four courses of chemotherapy (administered as adjuvant treatment postoperatively among 89% of the women, or as neoadjuvant treatment preoperatively among 5% of the women, or as both adjuvant and neoadjuvant chemotherapy among 6% of the women). This international, multicenter, randomized trial compared 1 or 2 years of trastuzumab given every 3 weeks with observation in patients with HER2-positive and either node-negative or node-positive breast cancer who had completed locoregional therapy and at least four cycles of neoadjuvant or adjuvant chemotherapy. Data were available for 1,694 women randomly assigned to 2 years of treatment with trastuzumab, 1,694 women assigned to 1 year of trastuzumab, and 1,693 women assigned to observation. At the first planned interim analysis (median follow-up of 12 months and a maximum of 36 months), 347 events (recurrence of breast cancer, contralateral breast cancer, second nonbreast malignant disease, or death) were observed: 127 events in the trastuzumab group and 220 in the observation group. The unadjusted hazard ratio for an event in the trastuzumab group, as compared with the observation group, was 0.54 (95% CI, 0.43 to 0.67; P <.0001 by the log-rank test, crossing the interim analysis boundary), representing an absolute benefit in terms of disease-free survival at 2 years of 8.4 percentage points. Overall survival in the two groups was not significantly different (29 deaths with trastuzumab vs. 37 with observation).

Breast Cancer International Research Group 006

The Breast Cancer International Research Group (BCIRG) 006 phase III adjuvant trial randomized patients with HER2 positive, node-positive, or high-risk node-negative breast cancer to receive 4 cycles of doxorubicin 60 mg/m2 plus cyclophosphamide 600 mg/m2 (AC), followed by docetaxel 100 mg/m2 (AC→T), and finally 4 cycles of AC followed by docetaxel 100 mg/m2 plus trastuzumab every 3 weeks for 1 year (AC→TH), or 6 cycles of docetaxel 75 mg/m2 plus carboplatin at an area under the curve of 6 followed by trastuzumab every 3 weeks for 1 year (TCH). Data presented from the first interim analysis at a median follow-up of 23 months indicated a clinical benefit in terms of disease-free survival (DFS) as well as acceptable safety parameters with the trastuzumab-containing regimens, although overall survival (OS) data were still immature. The results of a second interim analysis of the BCIRG 006 trial were presented by Dr. Dennis Slamon at the 29th Annual San Antonio Breast Cancer Symposium at a median follow-up of 36 months.[10]

The second interim analysis confirmed earlier data that reported a significant clinical benefit with trastuzumab in terms of DFS in both the AC→TH (HR = 0.61; P < .0001) and TCH (HR 0.67; P = .0003) arms compared to the AC→T arm. When compared to the AC→T arm, projected 4-year DFS was significantly improved in both the AC→TH (83% vs. 77%; HR 0.61 [95% CI, 0.48-0.76]; P < .0001) and TCH (82% vs. 77%; HR 0.67 [95% CI, 0.54-0.83]; P = .0003) arms. The absolute difference in DFS benefit was 6% for the AC→TH arm and 5% for the TCH arm, although no significant difference in efficacy was seen between the trastuzumab-containing arms (P = .42). Compared to the AC→T arm, the 4-year OS rate was higher in the AC→TH (92% vs. 86%; HR 0.59 [95% CI, 0.42-0.85]; P = .004) and TCH (91% vs. 86%; HR 0.66 [95% CI, 0.47-0.93]; P = .017) arms, although no significant difference was seen between the AC→TH and TCH arms in terms of OS (P = .58).

Four-year DFS stratified by lymph node status indicated a benefit from trastuzumab in the 310 evaluable patients with node-negative disease in the AC→TH arm (94% vs. 86%; HR 0.32 [95% CI, 0.17-0.62]; P = .0007) and the 309 evaluable patients in the TCH arm (93% vs. 86%; HR 0.47 [95% CI, 0.26-0.83]; P = .0096) compared to the 309 evaluable patients in the AC→T arm. Similarly, benefit in 4-year OS was seen in the 309 evaluable patients with node-negative disease in the AC→TH arm (97% vs. 93%; HR 0.16 [95% CI, 0.04-0.73]; P = .018) and the 307 evaluable patients in the TCH arm (98% vs. 93%; HR 0.42 [95% CI, 0.15-1.2]; P = .106) compared to the 307 evaluable patients in the AC→T arm. In all patient subpopulations, the trastuzumab-containing regimen was favored over the control regimen for both DFS and OS. According to the data presented in the BCIRG 006 second interim analysis, the addition of trastuzumab to chemotherapy is superior to chemotherapy alone in the adjuvant setting in patients with HER2 positive early-stage breast cancer, and the use of nonanthracycline combinations might yield comparable efficacy with superior safety.

Finland Herceptin (FinHER) trial

The FinHER trial randomized 232 patients who had high-risk node-negative or node-positive HER2 positive breast cancers assessed by centralized chromogenic in situ hybridization (CISH) to receive 9 weeks of trastuzumab combined with docetaxel or vinorelbine versus the same chemotherapy given without trastuzumab.[11] The chemotherapy regimens included 3-weekly cycles of docetaxel (100 mg/m2) versus 8 weekly cycles of vinorelbine (25 mg/m2 on days 1, 8, and 15), followed by 5-fluorouracil (600 mg/m2), epirubicin (60 mg/m2), and cyclophosphamide (600 mg/m2) every 3 weeks. At the time of analysis, the median follow-up times were 37 and 35 months in the trastuzumab and control groups, respectively. This study showed a significant reduction in distant recurrence (HR 0.29; 95% CI: 0.13–0.64; P = .002), an improved 3-year DFS (HR 0.42; 95% CI: 0.21–0.83; P = .01), and a nonstatistically significant trend toward improved OS (HR 0.41; 95% CI: 0.16–1.08; P = .07) favoring the patients treated with trastuzumab.

CARDIOTOXICITY OF ANTHRACYCLINE VS NONANTHRACYCLINE ADJUVANT TRASTUZUMAB CLINICAL TRIALS

Anthracyclines have been reported to result in type I cardiotoxicity, which follows a dose-dependent relationship, and that after a threshold of damage takes place, myocyte death occurs, making it irreversible. Various authors have reported a continuum of increasing risk as the cumulative amount of administered drug is increased above 400 mg/m2.[12-14] Delayed onset cardiotoxicity has been subclassified as early subacute cardiotoxicity occurring < 1 year after completing treatment or late cardiotoxicicty occurring > 1 year after cessation of treatment.[15] Delayed cardiotoxicity has been reported in approximately 5% of patients treated with doxorubicin.[16] Late cardiotoxicicty may not be apart until years to decades after anthracycline administration and usually occurs in patients who developed early subacute cardiotoxicity.[15]

In contrast, trastuzumab-related type II cardiotoxicity is not dose related, and it is usually reversible.[17] HER-2 is believed to play a critical role in the developing embryonic postnatal heart, and it is hypothesized that HER-2 continues to have an important function in adults in modifying the cardiac response to stress.[18, 19] A two-hit model of trastuzumab-induced cardiotoxicity has been proposed in which trastuzumab results in a loss of HER2-mediated signaling and thus interferes with the heart's ability to respond to stress.[20] When faced with subsequent cardiac stress, such as either hemodynamic overload or anthracyclines cardiotoxicity, the HER2-deficient hearts are more susceptible to the cardiotoxic effects of the stressor and the risk of irreversible loss of cardiac myocytes is increased. The nature and severity of the cardiac stress in addition to underlying cardiac risk factors are believed to be important factors that may influence the extent of the cardiac injury.

National Surgical Adjuvant Breast and Bowel Project [NSABP] trial B-31

North Central Cancer Treatment Group N9831

In both trials, LVEF was assessed before entry, after the completion of doxorubicin and cyclophosphamide therapy, and 6, 9, and 18 months after randomization. Trial B-31 required multiple gated acquisition scanning, whereas trial N9831 allowed multiple-gated acquisition scanning or echocardiography. The initiation of trastuzumab required an LVEF after doxorubicin and cyclophosphamide therapy that met or exceeded the lower limit of normal and a decrease of less than 16 percentage points from baseline. Patients in whom clinically significant cardiac symptoms developed while they were receiving doxorubicin and cyclophosphamide were excluded from subsequent trastuzumab therapy. The 6- and 9-month cardiac assessments were used to determine whether trastuzumab should be continued in patients without cardiac symptoms. If the LVEF had declined 16 or more percentage points from baseline or 10 to 15 percentage points from baseline to below the lower limit of normal range, trastuzumab was withheld for 4 weeks, at which time the LVEF was reassessed. If the LVEF remained below these levels or if the patient had symptomatic cardiac dysfunction while receiving trastuzumab, administration of the antibody was permanently discontinued.

In trial B-31, of the patients remained free of cardiac symptoms during doxorubicin and cyclophosphamide therapy and had LVEF values that met requirements for the initiation of trastuzumab therapy, the cumulative incidence of New York Heart Association class III or IV congestive heart failure or death from cardiac causes at 3 years was 0.8% in the control group (4 patients had congestive heart failure, and 1 died from cardiac causes) and 4.1% in the trastuzumab group (31 patients had congestive heart failure). Of the 31 women in the trastuzumab group who had congestive heart failure, 27 have been followed for at least 6 months after the onset of heart failure, and only 1 reported persistent symptoms of heart failure at the most recent follow-up visit. In trial N9831, the 3-year cumulative incidence of New York Heart Association class III or IV congestive heart failure or death from cardiac causes was 0% in the control group and 2.9% in the trastuzumab group (20 patients had congestive heart failure, 1 of whom died of cardiomyopathy).

In both studies, the cumulative 3-year incidence of congestive heart failure increased by about 3 percentage points with the addition of trastuzumab.

The 3-year cumulative incidence of class III or IV congestive heart failure or death from cardiac causes in the trastuzumab group was 4.1% in trial B-31 and 2.9% in trial N9831.

Herceptin Adjuvant (HERA) trial

Only patients who, after completion of all chemotherapy and radiotherapy, had a normal left ventricular ejection fraction (LVEF) (55% as measured on echocardiography or multiple gated acquisition [MUGA] scanning) were eligible for enrollment on the HERA trial. Cardiac exclusion criteria included a history of documented congestive heart failure, coronary artery disease with previous Q-wave myocardial infarction, angina pectoris requiring medication, uncontrolled hypertension, clinically significant valvular disease, and unstable arrhythmias.

Cardiac monitoring in the trastuzumab group and the observation group included responses to a cardiac questionnaire, physical examination, 12-lead electrocardiogram, and an assessment of LVEF by echocardiography or MUGA scanning at baseline and 3, 6, 12, 18, 24, 30, 36, and 60 months after randomization

There was one cardiac death in the observation group, and nine patients (0.54%) in the trastuzumab group who had severe congestive heart failure (P = .002). Symptomatic congestive heart failure, including the nine severe cases occurred in 1.7% of patients in the trastuzumab group and 0.06% of patients in the observation group (P < .001), a decrease in LVEF of at least 10 percentage points from baseline or more to below an LVEF of 50% was noted on at least one assessment among 7.1% of patients in the trastuzumab group and among 2.2% of those in the observation group ( P < .001).

Breast Cancer International Research Group 006

The safety, particularly cardiac safety, of both experimental regimens was acceptable, although there was a lower incidence of grade 3/4 congestive heart failure in the TCH arm compared to the AC→TH arm (0.4% vs. 2%; P = .0015). There were no cardiac deaths reported, but there were significantly more grade 3/4 congestive heart failure events in the 1,068 evaluable patients in the AC→TH arm compared to the 1,056 evaluable patients in the TCH arm and the 1,050 evaluable patients in the AC→T arm (2% vs. 0.4% and 0.4%). There was a significant difference in CHF events with AC→TH compared to TCH (P = .0015). Comparison of patients with > 10% relative left ventricular ejection fraction (LVEF) decline also showed significantly more LVEF dysfunction in the 1,042 evaluable patients in the AC→TH arm compared to the 1,030 evaluable patients in the TCH arm and the 1,014 evaluable patients in the AC→T arm (18% vs. 9% and 10%; P < .0001). The TCH arm was statistically indistinguishable from the AC→T arm in terms of LVEF dysfunction (P = .5).

Finland Herceptin (FinHER) trial

One patient had cardiac infarction and three had cardiac failure; none of these four patients had received trastuzumab. Left ventricular ejection fractions were preserved in women who received trastuzumab. Trastuzumab-treated women had slightly better ejection fractions than those who did not receive trastuzumab; in an ANCOVA model, the estimated difference 12 months after the completion of chemotherapy was 1.7 percentage points (95% CI, 0.1 to 3.5 percentage points; P = .06), and at 36 months it was 3.0 percentage points (0.7 to 5.4 percentage points, P = .01). In this model, vinorelbine and docetaxel had similar estimated effects on the ejection fraction at both times (P = .50). Four women treated with trastuzumab (3.5%) and seven who were not (6%) had one or more measurements of ejection fraction more than 15 percentage points less than the pretreatment value. A decrease by more than 10 percentage points, resulting in an ejection fraction of less than 50%, occurred in three patients, none of whom had received trastuzumab.

CONCURRENT ANTHRACYCLINE AND TRASTUZUMAB NEOADJUVANT THERAPY

Forty-two patients with HER2-positive disease with operable breast cancer were randomly assigned to either four cycles of paclitaxel followed by four cycles of fluorouracil, epirubicin, and cyclophosphamide or to the same chemotherapy with simultaneous weekly trastuzumab for 24 weeks.[21] The planned sample size was 164 patients. However, after 34 patients had completed therapy, the trial was stopped because of superiority of trastuzumab plus chemotherapy. pCR rates were 25% and 66.7% for chemotherapy (n = 16) and trastuzumab plus chemotherapy (n = 18), respectively (P = .02). The decision was based on the calculation that, if the study continued to 164 patients, there was a 95% probability that trastuzumab plus chemotherapy would be superior. Although no clinical congestive heart failure was observed, a more than 10% decrease in the cardiac ejection fraction was observed in five and seven patients in the chemotherapy and trastuzumab plus chemotherapy arms, respectively. Left ventricular ejection fraction returned to baseline values in those patients who had follow-up cardiac studies, except for one patient for whom the ejection fraction remains in the low normal range.

TOPOISOMERASE II AS A PREDICTOR OF ANTHRACYCLINE BENEFIT HER2 POSITIVE BREAST CANCER.

Topoisomerase IIa (topo IIa) is a DNA-modifying enzyme that binds to the double helix in order to release torsional stress and create double-strand breaks that allow replication to occur. Anthracyclines interfere by binding covalently with topo IIa after double-strand breaks have occurred, inducing lethal cellular damage by inhibition of religation. Increase in topo IIa expression is associated with sensitivity to these agents, both in cell lines and tumors due to increased substrate on which the drug may act.[22,23] Topo IIa occurs in the same amplicon on chromosome 17 (CEP 17) as HER2 and has been shown to be altered by amplification, point mutation, and deletion in breast cancers that overexpress the oncogene.[24-26]

The role of topo IIα amplification as a predictive marker of response to anthracyclines in breast cancer has been evaluated in retrospective studies. Di Leo et al stated that the superiority of anthracyclines over CMF in HER-2 amplified patients could be confined to the subgroup of topo IIα amplified tumors.[27] In contrast, Knoop et al reported a nonstatistically significant improvement in RFS for the small number of patients with topo IIα deleted tumors.[28] In addition, the predictive value of topo IIα was evaluated in premenopausal women with node-positive breast cancer randomized in the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) MA.5 trial to CEF vs. CMF.[29] In this study both topo IIα amplification and deletion predicted benefit from CEF vs. CMF for both disease-free (HR=0.48 [95%CI: 0.21-0.83]) and overall survival (HR=0.38 [95%CI: 0.18-0.80]). In the BCIRG 06 trial, the correlation between response to anthracyclines and topo IIα abberations was prospectively evaluated. Patients with topo IIα amplification had better disease-free survival after adjuvant therapy in both the trastuzumab-containing arm without anthracycline and in the nontrastuzumab-containing arm which included an anthracycline.[30]

CONCLUSION

Several clinical trials have demonstrated that trastuzumab significantly improves outcomes in patients with HER2-positive early-stage breast cancer. These trials have shown that the cardiotoxicity of adjuvant trastuzumab is overall acceptable; however, it appears to be more frequent in the anthracycline and trastuzumab regimens compared to the nonanthracycline and trastuzumab regimens. Therefore a nonanthracycline- and trastuzumab-based regimen, such as TCH, may be considered as an appropriate alternative to patients who have cardiac risk factors.

There are significant differences in the methods in which topo II α has been measured in the various published reports, which may explain in part the differences in its reported predictive role from anthracycline therapy. In addition, the data suggesting that both topo IIα amplification and deletion-predicted benefit from anthracyclines raises the possibility that topo II α is not a actual predictor of response to anthracycline therapy but rather the allelic imbalance of topo IIα may be a surrogate for tumor aneuploidy. Therefore, the role of topo II αs' role in predicting increased benefit from anthracyclines remains to be established and should not be used in clinical practice at this time.

KEY POINTS

Data from multiple clinical trials have indicated that patients with HER2 positive tumors may benefit from adjuvant anthracycline therapy. However, it is unclear if there will be a continued benefit from anthracycline in the setting adjuvant trastuzumab therapy, or more specifically in combination with taxanes as suggested by the results of BCIRG 006. Anthracycline and trastuzumab regimens should still be considered standard treatment for patients with early stage HER2 positive breast cancer until the additional 5-year follow up of the adjuvant trastuzumab clinical trials becomes available.

Although the overall risk of cardiotoxicity in the adjuvant trastuzumab appears to be acceptable, the risk is smaller with the nonanthracycline and trastuzumab regimens, which should be considered as an alternative for patients with cardiac risk factors. For example in the setting of a patient with a borderline baseline ejection (in the range of 50% to 55%) or who is otherwise thought to be at greater risk of cardiomyopathy (diabetes, hypertension, or valvular heart disease for example). In these “at risk” cases concurrent chemotherapy and trastuzumab may be preferable to trastuzumab alone as trastuzumab maintenance may not be sustainable due to a drop in the EF. The FinHER trial suggests that even brief trastuzumab exposure concurrently with chemotherapy has substantial benefits.

Concurrent neoadjuvant trastuzumab and epirubicin therapy increased pCR and appeared to have acceptable short-term cardiotoxicity. However, treatment with this regimen is not recommended outside a clinical trial.

Baseline and serial monitoring of cardiac function, and close management of cardiac risk factors such as hypertension, diabetes, and hyperlipidemia is strongly recommended during and following treatment of patients receiving anthracycline and/or trastuzumab therapy.

There are significant differences in the methods in which topo II α has been measured in the various published reports, which may explain in part the differences in its reported predictive role from anthracycline therapy. Therefore, it should not be used to select an anthracycline vs. nonanthracycline therapy for patients outside a clinical trial at this time.

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