Long Term Follow-Up of National Surgical Adjuvant Breast and Bowel Project Trial B-31: How Well Can We Predict Cardiac Toxicity With Trastuzumab?

Theintroductionofadjuvant trastuzumabhasdramaticallyreduced recurrence rates and improved survival among women with stage I to III human epidermal growth factor receptor 2 (HER2) –positive breast cancer. Although the majority of trials have evaluated the use of trastuzumab administered sequentially after an anthracycline-based regimen, other regimens have also been evaluated, including the regimen of docetaxel, carboplatin, and trastuzumab (TCH). The motivation for testing a nonanthracycline-based regimen was founded largely on concerns about both shortand long-term cardiotoxicity. Indeed, in the pivotal trial that was conducted in the first-line metastatic setting, 27% of patients receiving concurrent doxorubicin, cyclophosphamide, and trastuzumab developed either symptomatic or asymptomatic cardiac dysfunction, compared with 13% of patients who received paclitaxel with trastuzumab. Fortunately, rates of early cardiac dysfunction in the large adjuvant trastuzumab trials have been substantially lower than might have been predicted from the metastatic data. In the Herceptin Adjuvant (HERA) study that evaluated a sequential regimen of trastuzumab monotherapy after completion of chemotherapy, the rate of severe congestive heart failure (CHF) was 0.8%, and 3.6% of individuals experienced a significant decrease in left ventricular ejection fraction (LVEF) at a median follow-up of 3.6 years. In the North Central Cancer Treatment Group (NCCTG) N9831 study, among patients who received doxorubicin and cyclophosphamide followed by concurrent trastuzumab-paclitaxel (ACTH), the cumulative incidence of cardiac events was 3.3% at 3 years. In two phase II trials that explored dose-dense doxorubicin and cyclophosphamide preceding trastuzumab-based regimens, the rates of cardiac toxicity were also low at short-term follow-up. However, there remain valid concerns about the impact of trastuzumab on longer term cardiac outcomes. As highlighted in a recent editorial, the long-term sequelae of trastuzumab-associated CHF and the clinical meaning of the asymptomatic drops in LVEF are still incompletely characterized. If the superiority of TCH compared with ACTH were unquestioned, then there would be little debate. However, the Breast Cancer International Research Group (BCIRG) 006 trial was neither designed nor adequately powered to directly compare these two regimens, and the 3% absolute difference in disease-free survival favoring ACTH raises the possibility that the two regimens may not have equivalent efficacy. Given these issues, how can oncologists provide the most balanced recommendations, and how can patients make the most informed decisions, taking into account both efficacy and toxicity on an individual patient-by-patient basis? Although the role of anthracyclines in the treatment of HER2positive breast cancer continues to be debated, rightly or wrongly, clinicians and patients are voting with their feet. Nationally, the use of anthracycline-based trastuzumab regimens has declined precipitously in recent years. In 2008, among the Medicare population, taxane-based trastuzumab regimens were administered five times more frequently than anthracycline-based regimens. Even among patients younger than age 65 years in an insurance claims database (64% younger than age 55 years), taxane-based trastuzumab regimens were employed approximately twice as often as anthracycline-based regimens (S. Giordano, personal communication, June 2012). Although we are not aware of large-scale studies examining the factors underlying this shift, it is reasonable to postulate that concerns about toxicity, and in particular, cardiac toxicity, are likely a major driver. In the article that accompanies this editorial, Romond et al present results of a 7-year follow-up of cardiac function in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31 clinical trial. The trial randomly assigned patients with node-positive, HER2-positive primary breast cancer to receive either anthracyclineand taxane-based chemotherapy alone or with trastuzumab, with the trastuzumab initiated concurrently with commencement of the taxane. A cardiac event was defined as cardiac death or symptomatic CHF with concomitant decline in LVEF. The cumulative incidence of cardiac event at 7 years was 4.0% in the trastuzumab arm and 1.3% in the nontrastuzumab arm, a 2.7% absolute difference. Notably, only two of the 37 cardiac events in the trastuzumab arm occurred beyond 2 years of follow-up; overall, LVEF recovered to 50% or greater in more than half of patients (58%). Only one cardiac death has been observed to date in either arm of the trial. The authors also report the outcomes of JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 30 NUMBER 31 NOVEMBER 1 2012