Three-Year Follow-up of Neoadjuvant Chemotherapy With or Without Anthracyclines in the Presence of Dual<i>ERBB2</i>Blockade in Patients With<i>ERBB2</i>-Positive Breast Cancer
Authors: Anna van der Voort, Mette S. van Ramshorst, Erik D. van Werkhoven, Ingrid A. Mandjes, Inge Kemper, Annelie J. Vulink, Irma M. Oving, Aafke H. Honkoop, Lidwine W. Tick, Agnes J. van de Wouw, Caroline M. Mandigers, Laurence J. van Warmerdam, Jelle Wesseling, Marie-Jeanne T. Vrancken Peeters, Sabine C. Linn, Gabe S. Sonke
Journal: JAMA Oncology (2021)

<h3>Importance</h3> Primary analysis of the TRAIN-2 study showed high pathologic complete response rates after neoadjuvant chemotherapy with or without anthracyclines plus dual<i>ERBB2</i>(formerly<i>HER2</i>) blockade. <h3>Objective</h3> To evaluate 3-year event-free survival (EFS) and overall survival (OS) of an anthracycline-free and anthracycline-containing regimen with dual<i>ERBB2</i>blockade in patients with stage II and III<i>ERBB2</i>-positive breast cancer. <h3>Design, Setting, and Participants</h3> A total of 438 patients with stage II and III<i>ERBB2</i>-positive breast cancer were enrolled in this randomized, clinical, open-label phase 3 trial across 37 hospitals in the Netherlands from December 9, 2013, until January 14, 2016. Follow-up analyses were performed after a median follow-up of 48.8 months (interquartile range, 44.1-55.2 months). Analysis was performed on an intention-to-treat basis. <h3>Interventions</h3> Participants were randomly assigned on a 1:1 basis, stratified by age, tumor stage, nodal stage, and estrogen receptor status, to receive 3 cycles of fluorouracil (500 mg/m<sup>2</sup>), epirubicin (90 mg/m<sup>2</sup>), and cyclophosphamide (500 mg/m<sup>2</sup>), followed by 6 cycles of paclitaxel and carboplatin or 9 cycles of paclitaxel (80 mg/m<sup>2</sup>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 intravenously; loading dose 840 mg) every 3 weeks. <h3>Main Outcomes and Measures</h3> Three-year EFS, OS, and safety. <h3>Results</h3> A total of 438 women were randomized, with 219 per group (anthracycline group, median age, 49 years [interquartile range, 43-55 years]; and nonanthracycline group, median age, 48 years [interquartile range, 43-56 years]). A total of 23 EFS events (10.5%) occurred in the anthracycline group and 21 EFS events (9.6%) occurred in the nonanthracycline group (hazard ratio, 0.90; 95% CI, 0.50-1.63; favoring nonanthracyclines). Three-year EFS estimates were 92.7% (95% CI, 89.3%-96.2%) in the anthracycline group and 93.6% (95% CI, 90.4%-96.9%) in the nonanthracycline group and 3-year OS estimates were 97.7% (95% CI, 95.7%-99.7%) in the anthracycline group and 98.2% (95% CI, 96.4%-100%) in the nonanthracycline group. The results were irrespective of hormone receptor and nodal status. A decline in left ventricular ejection fraction of 10% or more from baseline to less than 50% was more common in patients who received anthracyclines than those who did not (17 of 220 [7.7%] vs 7 of 218 [3.2%];<i>P</i> = .04). Two patients treated with anthracyclines developed acute leukemia. <h3>Conclusions and Relevance</h3> This follow-up analysis of the TRAIN-2 study shows similar 3-year EFS and OS estimates with or without anthracyclines in patients with stage II and III<i>ERBB2</i>-positive breast cancer. Anthracycline use is associated with increased risk of febrile neutropenia, cardiotoxic effects, and secondary malignant neoplasms. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT01996267