van Ramshorst MS, et al. - Researchers conducted the TRAIN-2 study (an open-label, randomized, controlled, phase 3 trial) in 37 hospitals in the Netherlands to determine if the addition of anthracyclines would improve pathological complete response vs a carboplatin–taxane regimen, when given in combination with the HER2-targeted agents trastuzumab and pertuzumab. They recorded a pathological complete response in the anthracycline group as well as in the non-anthracycline group. As compared to the non-anthracycline group, grade 3 or worse febrile neutropenia was more common in the anthracycline group. In patients with early HER2-positive breast cancer, omitting anthracyclines from neoadjuvant treatment regimens might be a preferred approach in the presence of dual HER2 blockade.

Methods

• Patients aged 18 years or older with previously untreated, histologically confirmed stage II–III HER2-positive breast cancer were enrolled.
• For this investigation, researchers randomly allocated patients utilizing central randomization software (1:1 ratio) with minimization without a random component, stratified by tumor stage, nodal stage, estrogen receptor status, and age, to receive 5-fluorouracil (500 mg/m²), epirubicin (90 mg/m²), and cyclophosphamide (500 mg/m²) every 3 weeks for three cycles followed by paclitaxel (80 mg/m² on days 1 and 8) and carboplatin (area under the concentration–time curve [AUC] 6 mg/mL per min on day 1 or optionally, as per hospital preference, AUC 3 mg/mL per min on days 1 and 8) every 3 weeks for six cycles, or to receive nine cycles of paclitaxel and carboplatin at the same dose and schedule as in the anthracycline group.
• Study participants in both groups received trastuzumab (6 mg/kg, loading dose 8 mg/kg) and pertuzumab (420 mg, loading dose 840 mg) concurrently with all chemotherapy cycles.
• The proportion of patients who achieved a pathological complete response in breast and axilla (ypT0/is ypN0) in the intention-to-treat population was the primary endpoint.
• According to actual treatment received, safety was analyzed in patients who received at least one treatment cycle.

Results

• Four hundred thirty-eight subjects were enlisted and randomly assigned to the two treatment groups (219 patients to each group), of whom 418 were evaluable for the primary endpoint (212 in the anthracycline group and 206 in the non-anthracycline group) between December 9, 2013 and January 14, 2016.
• It was observed that the median follow-up for all patients was 19 months (IQR 16–23 months).
• They recorded a pathological complete response in 141 (67%, 95% CI 60–73) of 212 patients in the anthracycline group and in 140 (68%, 61–74) of 206 in the non-anthracycline group (p=0.95).
• One patient randomly allocated to the non-anthracycline group did receive anthracyclines and was thus involved in the anthracycline group for safety analyses; therefore, for the safety analyses there were 220 patients in the anthracycline group and 218 in the non-anthracycline group.
• They reported serious adverse events in 61 (28%) of 220 patients in the anthracycline group and in 49 (22%) of 218 in the non-anthracycline group.
• Grade 3 or worse neutropenia (in 131 [60%] of 220 patients in the anthracycline group vs 118 [54%] of 218 in the non-anthracycline group), grade 3 or worse diarrhea (26 [12%] vs 37 [18%]), and grade 2 or worse peripheral neuropathy (66 [30%] vs 68 [31%]) were the most common adverse events of any cause, with no substantial differences between the groups.
• As compared to the non-anthracycline group (23 [10%] vs three [1%], p < 0.0001), grade 3 or worse febrile neutropenia was more common in the anthracycline group.
• In both groups (two [1%] of 220 vs 0 of 218), symptomatic left ventricular systolic dysfunction was rare.
• Due to pulmonary embolism, one patient in the anthracycline group died which was possibly treatment related.