Three-Year Outcomes After Neoadjuvant Chemotherapy With or Without Anthracycline Plus Dual HER2 Blockade in HER2-Positive Breast Cancer

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In a secondary analysis of the Dutch phase III TRAIN-2 trial reported in JAMA Oncology, Anna van der Voort, MD, and colleagues found similar 3-year event-free and overall survival in patients with HER2-positive breast cancer receiving neoadjuvant therapy with vs without an anthracycline plus dual HER2 blockade. The report noted that anthracycline use was associated with increased risk of cardiotoxicity.

The previously reported primary analysis of TRAIN-2 showed high pathologic complete response rates in the breast and axilla (ypT0/is, ypN0) after treatment with vs without anthracycline-containing vs nonanthracycline chemotherapy, both given with pertuzumab/trastuzumab (67% vs 68%). Anthracycline-containing chemotherapy was associated with more febrile neutropenia, hypokalemia, and grade ≥ 2 left-ventricular ejection fraction (LVEF) decline.

Anna van der Voort, MD

Anna van der Voort, MD

Study Details

In the open-label multicenter trial, 438 patients with stage II and III disease were randomly assigned between December 2013 and January 2016 to receive a nonanthracycline regimen of nine 3-week cycles of paclitaxel at 80 mg/m2 on days 1 and 8 and carboplatin at AUC 6 on day 1 or AUC 3 on days 1 and 8 (n = 219) or an anthracycline-containing regimen of three cycles of fluorouracil at 500 mg/m2, epirubicin at 90 mg/m2, and cyclophosphamide at 500 mg/m2 for 3 weeks followed by six cycles of paclitaxel and carboplatin in the same schedule (n = 219).

Both groups concurrently received trastuzumab at 6 mg/kg after a loading dose of 8 mg/kg and pertuzumab at 420 mg after a loading dose of 840 mg every 3 weeks. Adjuvant trastuzumab was given for 1 year.

Event-Free and Overall Survival

Follow-up analyses were performed on an intention-to-treat basis after a median follow-up of 48.8 months (interquartile range = 44.1–55.2 months). Event-free survival events occurred in 9.6% of patients in the nonanthracycline group vs 10.5% of the anthracycline group (hazard ratio [HR] = 0.90, 95% confidence interval [CI] = 0.50–1.63). Estimated 3-year event-free survival was 93.6% (95% CI = 90.4%–96.9%) in the nonanthracycline group vs 92.7% (95% CI = 89.3%–96.2%) in the anthracycline group. No significant differences between groups were observed in subgroup analyses, including according to hormone receptor and nodal status.

Death occurred in 3.7% of patients in the nonanthracycline group vs 4.1% of the anthracycline group (HR = 0.91, 95% CI = 0.35–2.36). Estimated 3-year overall survival was 98.2% (95% CI = 96.4%–100%) in the nonanthracycline group vs 97.7% (95% CI = 95.7%–99.7%) in the anthracycline group.


  • No significant differences in event-free or overall survival were observed between anthracycline-containing vs nonanthracycline regimens including dual HER2 blockade.
  • Anthracycline treatment was associated with increased cardiotoxicity.

Adverse Events

Most grade 3 or 4 adverse events occurred during neoadjuvant therapy and were reported previously in the primary analysis. Decline of LVEF of ≥ 10% from baseline and LVEF of < 50% at any time was more frequent in the anthracycline group (7.7% vs 3.2%, P = .04). Grade ≥ 2 LVEF decline was observed in 36.4% vs 22.5% of patients. At the final visit, grade 3 LVEF decline was present in 36 (46.2%) of 78 patients vs 16 (33.3%) of 48 patients. Two patients in the anthracycline group developed secondary acute leukemia at 111 and 1,067 days after the last chemotherapy administration, with both cases considered related to treatment.

The investigators concluded, “This follow-up analysis of the TRAIN-2 study shows similar 3-year event-free survival and overall survival estimates with or without anthracyclines in patients with stage II and III [HER2]-positive breast cancer. Anthracycline use is associated with increased risk of febrile neutropenia, cardiotoxic effects, and secondary malignant neoplasms.”

Gabe S. Sonke, MD, PhD, of the Department of Medical Oncology, Netherlands Cancer Institute, Amsterdam, is the corresponding author for the JAMA Oncology article.

Disclosure: The study was supported by Roche Netherlands. For full disclosures of the study authors, visit

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