Neoadjuvant Chemotherapy With vs Without Anthracyclines Plus Dual HER2 Inhibitors in HER2-Positive Breast Cancer


Key Points

  • Pathologic complete response rates were no different with neoadjuvant therapy with vs without anthracycline.
  • Febrile neutropenia was more common in the anthracycline group. 

In the Dutch Breast Cancer Research Group’s phase III TRAIN-2 trial reported in The Lancet Oncology, van Ramshorst et al found no difference in pathologic complete response rate with neoadjuvant chemotherapy with vs without an anthracycline plus dual HER2 blockade in women with HER2-positive breast cancer. The nonanthracycline regimen was associated with less febrile neutropenia.

Study Details

In the open-label trial, 418 evaluable patients with previously untreated stage II to III HER2-positive breast cancer from 37 sites in the Netherlands were randomly assigned between December 2013 and January 2016 to receive fluorouracil (500 mg/m²), epirubicin (90 mg/m²), and cyclophosphamide (500 mg/m²) every 3 weeks for 3 cycles followed by paclitaxel (80 mg/m² on days 1 and 8) and carboplatin (AUC = 6 on day 1) every 3 weeks for 6 cycles (n = 212) or 9 cycles of paclitaxel and carboplatin at the same dose and schedule as in the anthracycline group (n = 206), with both groups receiving trastuzumab (Herceptin; 6 mg/kg, loading dose 8 mg/kg) and pertuzumab (Perjeta; 420 mg, loading dose 840 mg) concurrently with all chemotherapy cycles. Random allocation was stratified by tumor stage, nodal stage, estrogen receptor status, and age.

The primary endpoint was the proportion of patients achieving a pathologic complete response in breast and axilla (ypT0/is ypN0). Follow-up for long-term outcomes is ongoing.

Study Findings

Median follow-up was 19 months. Pathologic complete response was observed in 67% of patients in the anthracycline group vs 68% of the nonanthracycline group (odds ratio [OR] = 1.07, P = .95). Rates were 89% vs 84% in patients with hormone receptor–negative disease (OR = 0.71, 95% confidence interval [CI] = 0.30–1.68) and 51% vs 55% (OR = 1.17, 95% CI = 0.71–1.95) among patients who were estrogen receptor– and/or progesterone receptor–positive. The test for interaction between treatment group and hormone receptor status was not significant (P = .32).

Serious adverse events were reported in 28% of the anthracycline group and 22% of the nonanthracycline group. Among the most common adverse events, grade ≥ 3 neutropenia occurred in 60% vs 54%, grade ≥ 3 diarrhea in 12% vs 18%, and grade ≥ 2 peripheral neuropathy in 30% vs 31%. Grade ≥ 3 febrile neutropenia occurred in 10% vs 1% (P < .0001). Symptomatic left-ventricular systolic dysfunction occurred in 1% vs 0%. One death was considered possibly treatment-related, due to pulmonary embolism in a patient in the anthracycline group.  

The investigators concluded, “In view of the high proportion of pathological complete responses recorded in both groups and the fact that febrile neutropenia was more frequent in the anthracycline group, omitting anthracyclines from neoadjuvant treatment regimens might be a preferred approach in the presence of dual HER2 blockade in patients with early HER2-positive breast cancer. Long-term follow-up is required to confirm these results.”

The study was supported by Roche Netherlands.

Gabe S. Sonke, MD, of the Department of Medical Oncology, Netherlands Cancer Institute, is the corresponding author for The Lancet Oncology article.

Disclosure: See study authors’ full disclosures at

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