Follow-up Analysis Found Similar Survival Rates of Chemotherapy With or Without Anthracyclines for ERBB2-Positive Breast Cancer

A 3-year follow-up analysis of event-free and overall survival revealed similar results for patients with stage II or III ERBB2-positive breast cancer treated with either neoadjuvant anthracycline and nonanthracycline treatment regimens.

The 3-year follow-up analysis of the TRAIN-2 study (NCT01996267) found similar event-free survival (EFS) and overall survival (OS) after neoadjuvant chemotherapy with or without anthracyclines for patients with stage II or III ERBB2-positive breast cancer, according to data published in JAMA Oncology.

The randomized, open-label phase 3 trial investigated both an anthracycline-free and anthracycline-containing chemotherapy regimen with dual ERBB2 blockade in patients with this type of breast cancer.

“This follow-up analysis of the TRAIN-2 study shows similar 3-year EFS and OS with or without anthracyclines in patients with stage II and III ERBB2-positive breast cancer,” wrote the investigators. “Anthracycline use was associated with an increased risk of febrile neutropenia, cardiotoxic effects, and secondary malignant neoplasms.”

A total of 438 women were enrolled and randomized 1:1 evenly (n = 219 per group) to either the anthracycline group or nonanthracycline group.

Patients in the anthracycline group received 3 cycles of fluorouracil at 500 mg/m2, epirubicin at 90 mg/m2, and cyclophosphamide at 500 mg/m2, followed by 6 cycles of paclitaxel 80 mg/m2 on days 1 and 8 and carboplatin at area under the concentration-time curve (AUC) 6 mg/mL/min on day 1 or AUC 3 mg/mL/min on days 1 and 8. Patients in the nonantracycline group received 9 cycles of paclitaxel and carboplatin. Every 3 weeks, both groups received trastuzumab (Herceptin) at 6 mg/kg (loading dose 8 mg/kg) and pertuzumab (Perjeta) at 420 mg intravenously.

Similar rates of EFS were observed between both groups, with 23 occurring in the anthracycline group compared with 21 in the nonanthracycline group (HR, 0.90; 95% CI, 0.50-1.63).

The 3-year EFS rates were 92.7% (95% CI, 89.3%-96.2%) and 93.6% (95% CI, 90.4%-96.9%) in the anthracycline and nonanthracycline groups, respectively. For 3-year OS, the anthracycline group had a rate of 97.7% (95% CI, 95.7%-99.7%) compared with 98.2% (95% CI, 96.4%-100%) in the nonanthracycline group.

The investigative team continued with the results, explaining that “Left ventricular ejection fraction decline was more common in the anthracycline group and 2 patients treated with anthracyclines developed acute leukemia.”

The trial was conducted across 37 hospitals in the Netherlands from December 9, 2013, to January 14, 2016. The follow-up analyses were conducted in the intention-to-treat population at a median follow-up of 48.8 months.

The main limitation of the research centers around its inability to detect differences in EFS and OS. Because of this, the results presented were descriptive. More, the 9 cycles of neoadjuvant chemotherapy differ from the commonly used 6 cycles of anthracycline-free regimens.

On the heels of the results from the TRAIN-2 study, the investigative team launched the multicenter, phase 2 TRAIN-3 trial (NCT03820063) to investigate the hypothesis that “patients who achieve complete radiologic remission after 3 or 6 cycles of anthracycline-free chemotherapy combined with dual ERBB2 blockade are candidates for early surgery without compromising long-term outcome.”

“These results add to the literature on omitting anthracyclines in patients with early-stage ERBB2-positive breast cancer,” concluded the investigators.


van der Voort A, van Ramshorst MS, van Werkhoven ED, et al. Three-Year Follow-up of Neoadjuvant Chemotherapy With or Without Anthracyclines in the Presence of Dual ERBB2 Blockade in Patients With ERBB2-Positive Breast Cancer: A Secondary Analysis of the TRAIN-2 Randomized, Phase 3 Trial. JAMA Oncol. Published May 20, 2021. doi:10.1001/jamaoncol.2021.1371