The TRAIN-2 study was a multicenter, open-label, randomized phase III trial that sought to determine whether the addition of anthracyclines to the combination of the ERRB2/HER2-targeted agents (trastuzumab and pertuzumab) improved pathological complete response compared with a carboplatin-taxane regimen.

A 3-year follow-up secondary analysis of the TRAIN-2 study was conducted to determine the effect of an anthracycline-free regimen compared with an anthracycline-containing regimen on event-free survival (EFS) and overall survival (OS) in women with stage II or III ERRB2/HER2 BC receiving dual ERRB2/HER2 blockade with trastuzumab and pertuzumab. EFS was defined as the time from randomization to disease progression resulting in inoperabililty, recurrence, secondary primary malignant neoplasms, or death by any cause. OS was the time from randomization to death from any cause.

Treatment regimens consisted of three cycles of fluorouracil (500 mg/m2), epirubicin (90 mg/m2), and cyclophosphamide (500 mg/m2), followed by six cycles of paclitaxel and carboplatin or nine cycles of paclitaxel (80 mg/m2 Days 1 and 8) and carboplatin (area under the concentration-time curve, 6 mg/mL/min). Both groups received trastuzumab (6 mg/kg; loading dose 8 mg/kg) and pertuzumab (420 mg IV; loading dose 840 mg) every 3 weeks.

A total of 438 women were randomized into the two groups (219 each group). Median follow-up was 48.8 months. Approximately one-third of patients had stage III disease.

It should be noted that TRAIN-2 was not powered to detect treatment differences in the secondary endpoints, which included EFS, OS, recurrence-free survival, and BC-specific survival. However, study investigators found that 10.5% of patients in the anthracycline group compared with 9.6% of women in the nonanthracycline group experienced an event. Of these events, the estimated 3-year EFS was 92.7% in the anthracycline group and 93.6% in the nonanthracycline group. In the nonanthracycline group, 97.3% of patients completed 1 year of trastuzumab treatment compared with 89.0% of the anthracycline group. Cardiotoxicity occurred in 6.9% of patients on adjuvant trastuzumab who were treated with an anthracycline, resulting in discontinuation of the ERRB2/HER2-targeted agent; none of the patients in the nonanthracycline group discontinued treatment due to adverse cardiac effects.

The 3-year OS was 97.7% in the anthracycline group and 98.2% in the nonanthracycline group. Subgroup analyses did not reveal a difference in outcomes in the anthracycline versus nonanthracycline group when hormone receptor status, lymph-node status, tumor stage, and disease stage or grade were taken into account.

A decline in left ventricular function of >10% from baseline or <50% at any time occurred more commonly in the anthracycline group compared with the nonanthracycline group (7.7% vs. 3.2%, respectively). Two patients in the anthracycline-treated group developed secondary acute leukemia, which was considered to be chemotherapy-related.

This study provides further evidence for pharmacists that in women with ERRB2/HER2-positive BC, anthracycline-free regimens containing dual ERRB2 blockade appear to offer similar benefits in EFS and OS as do anthracyclines/dual ERRB2 blockade regimens, but with fewer adverse events.

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