A 7-year follow-up of the phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) protocol B-31 found that the cumulative difference in the rate of cardiac events was 3.1% between patients with HER2-positive, node-positive breast cancer who received trastuzumab (Herceptin) in addition to chemotherapy that included an anthracycline and taxane and those who did not receive trastuzumab. “The risk vs benefit of trastuzumab as given in this regimen remains strongly in favor of trastuzumab,” the investigators concluded in the Journal of Clinical Oncology.
Patients were randomly assigned to receive four cycles of AC (doxorubicin at 60 mg/m2 and cyclophosphamide at 600 mg/m2), followed by either four cycles of paclitaxel at 175 mg/m2 every 3 weeks or 12 weekly doses of paclitaxel at 80 mg/m2 (ACP), with or without weekly trastuzumab at 4 mg/kg loading dose, then 2 mg/kg (ACHP) for 52 weeks.
To be eligible for NSABP B-31, patients must have completed breast surgery and axillary dissection and have had no evidence of distant metastatic disease. Patients were not given trastuzumab if they developed symptomatic myocardial dysfunction during AC therapy, demonstrated an asymptomatic absolute decline in left-ventricular ejection fraction of more than 15% from baseline value after AC, or had a post-AC left-ventricular ejection fraction below the local institution’s lower limit of normal.
“As a result, the formal cardiac study was restricted to patients in either arm whose post-AC cardiac function met the criteria to allow initiation of trastuzumab,” the researchers noted. To be considered evaluable, patients must also have received at least one dose of post-AC therapy.
A cardiac event was defined as “a definite or probable cardiac death or congestive heart failure manifested by dyspnea with normal activity or at rest and associated with an absolute decrease in [left-ventricular ejection fraction] of greater than 10 percentage points from baseline to a value less than 55% or a decrease of more than 5% to a value below the lower limit of normal,” the authors noted. Among 944 patients who received trastuzumab, 37 (4%) experienced a cardiac event. Among 743 patients who did not receive trastuzumab, 10 (1.3%) experienced a cardiac event, for a difference of 2.7%.
The relative risk of a cardiac event was 3.30 among trastuzumab recipients vs control patients (95% CI = 1.63–6.66; P < .001), the researchers reported. Only two cardiac events occurred more than 2 years after the initiation of trastuzumab therapy, and one cardiac-related death occurred in each group of patients.
“Most patients in B-31 who discontinued trastuzumab as a result of symptomatic or asymptomatic [cardiac dysfunction] have recovered [left-ventricular ejection fraction] measurements ≥ 50%. In all, 36 patients (3.8% of the entire evaluable cohort) who discontinued trastuzumab for cardiac reasons have persistent [left-ventricular ejection fraction] values less than 50%,” the investigators reported.
While trastuzumab given concurrently with or after adjuvant chemotherapy has been shown to improve disease-free and overall survival patients with early-stage HER2-positve breast cancer, regimens including trastuzumab have been associated with cardiac dysfunction, especially when those regimens also include an anthracycline. “Given the demonstrated efficacy of trastuzumab, it is critical to identify risk factors that predispose patients to [cardiac dysfunction] and, conversely, to identify patients who may gain considerable clinical benefit from this regimen with minimal cardiac risk,” the researchers said.
On the basis of pretreatment risk factors for a cardiac event, the investigators developed a Cardiac Risk Score “that may provide a tool for estimating cardiac risk associated with the addition of trastuzumab to paclitaxel after AC. This model conforms closely with B-31 data but should be validated in other studies using similar chemotherapy regimens,” the researchers stated. They noted that cardiac history forms continue to be submitted annually on patients enrolled in B-31 and that a long-term quality-of-life and cardiac assessment for those remaining disease-free is underway.
“In summary, 7-year follow-up of NSABP B-31 demonstrates a striking and reassuring lack of longer-term cardiac events,” according to an editorial accompanying the study report. “Over the long run, we hope to see the development of highly efficacious adjuvant treatments for HER2-positive breast cancer with substantially less risk of toxicity than current standards,” the editorialists wrote. They noted that preliminary reports for “novel HER2-directed agents,” including trastuzumab emtansine (T-DM1) and trastuzumab combined with pertuzumab (Perjeta) or with lapatinib (Tykerb) “have suggested a low risk of cardiac toxicity.” ■
Romond EH, et al: J Clin Oncol 30:3792-3799, 2012.
Mayer EL, Lin NU: J Clin Oncol 30:3769-3772, 2012.