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Weighing a Dose-Dense Option for Adjuvant Chemotherapy and Trastuzumab in Early-Stage Breast Cancer

Dana-Farber Cancer Institute, Brigham & Women's Hospital, Harvard Medical School, Boston, MA

The seminal trials of adjuvant trastuzumab all tested the hypothesis that adding trastuzumab to chemotherapy would improve outcomes compared with chemotherapy alone among women with HER-2–overexpressing breast cancer. Despite the profound similarity in the basic trial designs and the remarkable consistency of the trial results, the studies had many notable differences in the treatment program, including the eligibility criteria with regard to clinical characteristics and cardiac function, the concurrent or sequential use of chemotherapy and trastuzumab, the type and number of cycles of chemotherapy, and the duration of both chemotherapy and trastuzumab treatments.¹ Thus, the optimal chemotherapy/trastuzumab regimen for early stage breast cancer remains undefined.

Of the nearly 10,000 women who participated in the adjuvant trastuzumab trials, the vast majority received anthracycline-based regimens. Anthracyclines are a mainstay of treatment for early stage breast cancer, and retrospective analyses have suggested that the patients most likely to benefit from anthracycline treatment are those with HER-2–positive breast cancers. Both anthracycline-based chemotherapy and trastuzumab are associated with increased rates of congestive heart failure (CHF), raising concerns about combining these strategies in the treatment of HER-2–positive disease, and leading to the avoidance of simultaneous use of anthracyclines with trastuzumab in the adjuvant trials. The patients who did not receive anthracyclines in the adjuvant trastuzumab trials included only the small number of patients who received nonanthracycline regimens, such as cyclophosphamide, methotrexate, and fluorouracil (CMF), before enrolling in the Herceptin Adjuvant Trial (HERA) trial, and those enrolled in the "TCH" (docetaxel/carboplatin/trastuzumab) arm of the Breast Cancer International Research Group (BCIRG) 006 study.² That arm differed from the ACT ± trastuzumab arms of the BCIRG trial with respect to the timing of trastuzumab vis-à-vis chemotherapy, the number of chemotherapy cycles, the duration of concurrent trastuzumab and chemotherapy, and the type of chemotherapy (cyclophosphamide versus carboplatin, and anthracycline versus not).

Indeed, the approaches to the timing of trastuzumab and chemotherapy are important differences among the adjuvant trials. The duration of concurrent therapy ranged from none (HERA and North Central Cancer Treatment Group [NCCTG] N9831 sequential arm) to 9 weeks (Finland Herceptin [FinHer]) to 12 weeks (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-31/NCCTG N9831 concurrent arms and BCIRG AC T arm) to 18 weeks (BCIRG 006 TCH arm). Trastuzumab was initiated at the start of chemotherapy (FinHER and BCIRG 006 TCH arm), midway through chemotherapy (NSABP B-31/NCCTG N9831 and BCIRG 006 AC T arm), or after all chemotherapy was concluded (HERA and NCCTG N9831 sequential arm).

Amid all these vagaries, how is one to know the best regimen? The major considerations in selecting the best regimen are treatment efficacy and treatment safety, particularly cardiac safety, which is the toxicity of greatest concern when adding trastuzumab to adjuvant chemotherapy. Unpublished preliminary data from the NCCTG N9831 trial suggest that concurrent use of chemotherapy and trastuzumab are superior to sequential therapy,³ a finding that has led to widespread use of concurrent treatment programs in North American practice. Unpublished preliminary data from the BCIRG trial suggest comparable efficacy between TCH and AC TH, though the study was not powered to establish the equivalence of the two trastuzumab-based approaches.² Aside from these analyses, it is not possible to draw inferences regarding the most efficacious chemotherapy/trastuzumab regimen.

Given the importance of cardiac toxicity, it is worth examining the methodologies used in the trials to assess cardiac safety. The landmark trials differed with respect to required cardiac function at baseline ( 50% before treatment in the BCIRG, NSABP and NCCTG trials; 55% after chemotherapy in the HERA trial) and differed in cardiac surveillance and definitions of cardiac toxicity.⁴ In the limited available follow-up, the incidence of symptomatic heart failure among trastuzumab-treated patients has ranged from 0.5 to 4.1%. Predictors of CHF include older patient age, pre-existing hypertension, borderline-normal baseline left ventricular ejection fraction, and cumulative anthracycline exposure.^5,6 A higher percentage of patients develop asymptomatic declines in ejection fraction of unclear long-term significance. Preliminary data suggest that the nonanthracycline TCH regimen may have a lower absolute risk by 1% to 2% than seen with AC TH. However, the differences in the design and patient selection in the extant clinical trials make it difficult to determine which treatment strategy would be associated with the lowest risk of (CHF) for an individual patient.

Does the world need additional trastuzumab-based adjuvant chemotherapy regimens? Arguably, yes. While there is clear motivation for exploring nonanthracycline alternatives, there also remains considerable interest in finding safe, anthracycline-based trastuzumab regimens based on the historical role of anthracyclines in treating HER-2–positive breast cancer. Furthermore, there has been interest in gauging whether the widely utilized dose-dense, every 2 week adjuvant chemotherapy regimen might translate into better results with trastuzumab than the reported experience with every 3 week chemotherapy employed in many of the adjuvant trastuzumab trials, owing to either improved safety or activity, or both.

This background motivated Dang et al⁷ from Memorial Sloan-Kettering toinvestigate the feasibility and toxicity of adding trastuzumab to the dose-dense AC paclitaxel backbone. As developed in Cancer and Leukemia Group B (CALGB) 9741,⁸ administration of AC T every 2 weeks with granulocyte colony-stimulating factor (G-CSF) support improved disease-free and overall survival compared to every 3 week chemotherapy administration. For their feasibility study, the Memorial group delivered four cycles of AC followed by four cycles of paclitaxel, each given every 2 weeks. Weekly trastuzumab was initiated concurrently with paclitaxel, and after conclusion of chemotherapy, was continued for the remainder of a year. The study sought to determine cardiac safety of this dose-dense ACTH regimen, with early stopping rules designed to close the study in the event of a higher-than-expected rate of heart failure. The planned study size of 64 patients thus provided an approximate 60% probability of finding the regimen safe, with a true cardiac event rate of 4%. In the report, 91% of patients on study were able to complete the prescribed therapy, with general toxicities as expected for the dose-dense regimen. The authors describe no significant declines in ejection fraction during the AC phase of the treatment, and median left ventricular ejection fraction (LVEF) for the group was stable throughout the trastuzumab treatment. One patient developed symptomatic heart failure, requiring cessation of trastuzumab therapy. The overall cardiac event rate was 1.4% (95% CI, 0% to 7.4%); no cardiac deaths were observed. Five of 70 patients had asymptomatic declines in LVEF; two were able to restart trastuzumab at time of LVEF recovery, and three remained off protocol due to persistent LVEF decline. Two additional patients were hospitalized for cardiac events (dysrhythmia, pericarditis) of uncertain relationship to treatment. The authors conclude that dose-dense AC TH is safe and feasible. The question is: should we be routinely administering it to patients?

For several reasons, we believe that caution is still warranted before widespread use of dose-dense AC TH. This modestly sized feasibility study of 70 patients was underpowered to declare that dose-dense AC TH has an incidence of CHF as low as other anthracycline-based treatments, where cardiac risk has been defined from experience treating at least ten times as many patients. As a consequence of the limited number of patients, the authors note that the study lacked the power to exclude a true heart failure rate of 6% to 8%, and the small study size makes it hard to measure what impact dose-dense AC TH might have on treatment feasibility or cancer recurrence compared to other regimens.

Secondly, the patient selection in this trial likely contributed to a low risk of heart failure. By raising the baseline entry bar for LVEF to 55% or greater, the investigators surely lowered the chance of CHF. In this respect, their findings are similar to the results observed in the HERA trial, which reported that almost any standard chemotherapy regimen can safely be followed by trastuzumab if the ejection fraction remains above 55%.⁶ The young patient population (median age 49 years) and robust baseline ejection fraction (median, 68%) undoubtedly contributed to low rates of CHF. Indeed, models developed by the NSABP suggested that the risk of heart failure for the "average" patient in the Memorial study would be less than 2% –good news for patients, but a challenge when trying to compare these trial results with data derived from treatment of larger, more diverse patient populations.⁹ For older patients, or those with lower baseline ejection fractions or higher numbers of comorbid conditions, it is unclear whether dose-dense AC TH is safe.

Is dose-dense chemotherapy relevant for HER-2–positive breast cancer in the trastuzumab era? We await retrospective analyses from CALGB 9741 to clarify how chemotherapy scheduling in the pretrastuzumab era affected different tumor subsets defined by ER and HER-2 status. Data suggest that the schedule of paclitaxel may be less critical in the trastuzumab era. In the metastatic setting, CALGB 9840 compared paclitaxel weekly or every 3 weeks.¹⁰ In a subset of patients with HER-2–positive breast cancer assigned to paclitaxel plus trastuzumab, the paclitaxel schedule did not alter the efficacy of trastuzumab treatment. Similar findings, albeit indirect, are noted in the adjuvant setting. Comparisons between NCCTG N9831, where paclitaxel was given weekly with trastuzumab, and NSABP B-31, where paclitaxel was given every 3 weeks with trastuzumab, do not suggest major differences in recurrence rates or hazard ratios.¹¹ It may be that trastuzumab is sufficiently potent in treating HER-2–positive breast cancer that it "trumps" the impact of chemotherapy agent or schedule selection.

Not to be overlooked is the brief duration–8 weeks–of overlap between trastuzumab and chemotherapy with dose-dense AC TH. While the HERA trial demonstrated advantage for trastuzumab in the absence of any overlap with chemotherapy,¹² concurrent treatment may be preferable. The substantial survival advantage seen in the FinHER, NSABP/NCCTG, and BCIRG trials were all accomplished with a minimum of 9, and in most cases 12 to 18, weeks of concurrent therapy. It is also of interest that longer, 6-month durations of combined chemotherapy plus trastuzumab administration in the neoadjuvant setting have yielded remarkably high rates of complete pathological response in HER-2–positive breast cancers.¹³ Forthcoming national and international neoadjuvant trials of anti–HER-2 therapy from the CALGB and the Breast International Group are structured around a minimum of 12 weeks of concurrent chemotherapy and trastuzumab. Because these favorable results from the collective adjuvant and neoadjuvant experience might result from longer periods of concurrent therapy, the short 8-week exposure to concurrent paclitaxel/trastuzumab therapy produced by the dose-dense schedule should be considered investigational.

As with all adjuvant treatments, the goal of adjuvant trastuzumab-based therapy is to tailor the right therapy for the patient and for her tumor. As refinements in patient selection and advances in tumor biology move forward, it would be desirable to optimize chemotherapy and trastuzumab treatments in a more individualized fashion, taking into consideration traditional clinical factors, treatment-associated risks, and ultimately the intrinsic sensitivity of the tumor to established agents. The study by Dang et al⁷ provides a glimpse into both the opportunities and the challenges of integrating rapidly emerging treatments into existing standards of care. Ongoing data analyses and future prospective trials will define which trastuzumab-based adjuvant chemotherapy would be optimal for patients with HER-2–positive breast cancer. For the moment, the trastuzumab and chemotherapy combinations defined in the large, phase III studies remain the preferred regimens.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Harold J. Burstein, Genentech support to institution Expert Testimony: None Other Remuneration: None

AUTHOR CONTRIBUTIONS

Conception and design: Erica L. Mayer, Harold J. Burstein

Data analysis and interpretation: Erica L. Mayer, Harold J. Burstein

Manuscript writing: Erica L. Mayer, Harold J. Burstein

Final approval of manuscript: Erica L. Mayer, Harold J. Burstein

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