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TRAIN-2 Update Supports Anthracycline Omission For Selected HER2-Positive Breast Cancer Patients

Event-free and overall survival are comparable for HER2-positive stage II–III breast cancer patients given dual HER2 blockade and chemotherapy with or without anthracyclines
27 May 2021
Anticancer Agents;  Breast Cancer;  Personalised/Precision Medicine

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: Three-year results for the TRAIN-2 trial indicate that omitting anthracyclines from neoadjuvant chemotherapy does not adversely impact survival for patients with stage II–III HER2-positive breast cancer undergoing dual HER2 blockade. 

“These results add to the literature on omitting anthracyclines in patients with early-stage [HER2]-positive breast cancer”, say Gabe Sonke, from the Netherlands Cancer Institute in Amsterdam, and co-workers in JAMA Oncology

The event-free survival (EFS) and overall survival (OS) findings follow the initial report showing that use of three cycles of neoadjuvant 5-fluorouracil, epirubicin and cyclophosphamide before six or nine cycles of paclitaxel plus carboplatin does not improve the primary endpoint of pathological complete response (pCR). 

All of the phase III trial participants also received trastuzumab and pertuzumab every 3 weeks during chemotherapy and were followed up for a median of 48.8 months, say the researchers. 

The 3-year estimated EFS rates were a comparable 92.7% for the 219 women given anthracycline-based chemotherapy and 93.6% for the 219 women given the non-anthracycline regimen, with estimated 3-year OS of 97.7% and 98.2%, respectively.  

And exploratory subgroup analysis did not indicate that receipt or omission of anthracycline-based chemotherapy affected EFS when assessing patients by hormone receptor status, age, tumour stage or grade, disease stage or nodal status. 

However, patients who did not achieve pCR of the breast and axillary lymph nodes had significantly poorer disease-free survival than those who did, with a hazard ratio (HR) for progression or death of 0.42.  

Gabe Sonke and co-authors say this effect was “more pronounced” among hormone receptor-negative versus positive patients (HR=0.25 vs 0.56), but there was no difference by study regimen received, leading the researchers to find “no indication that patients with a higher risk of breast cancer recurrence derive benefit from anthracyclines.” 

Safety analysis showed that anthracycline-treated patients were significantly more likely to develop grade 3 or more severe febrile neutropenia (10.5 vs 1.4%) and hypokalaemia (8.6 vs 3.7%) than the non-anthracycline group, as well as experience a left ventricular ejection fraction (LVEF) decline of at least 10% with an LVEF of less than 50% after treatment (7.7 vs 3.2%). 

In addition, two patients developed acute leukaemia attributed to anthracycline therapy, and patients given anthracyclines were less likely to complete a full year of adjuvant trastuzumab than those who were not (89.0 vs 97.3%), with 6.9% discontinuing the agent because of cardiotoxicity.  

Writing in an accompanying editorial, Sara Hurvitz, from the University of California, Los Angeles, in the USA, acknowledges the lack of large randomised trials to demonstrate either noninferiority of omitting anthracyclines or superior efficacy with anthracyclines in the trastuzumab era. 

Highlighting the “expanding armamentarium of biologically targeted therapies for those patients at highest risk of relapse”, she observes that these agents’ “risk of life-threatening toxic effects is smaller than that seen with anthracyclines.” 

Sara Hurvitz concludes: “Data from studies like TRAIN-2 have played a critical role in redefining how we approach the use of anthracyclines in this setting, challenging us to carefully consider whether we have enough evidence to justify their inclusion in treatment for the patient sitting before us.” 


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 trialJAMA Oncol; Advance online publication 20 May 2021. DOI:10.1001/jamaoncol.2021.1371

Hurvitz SA. Anthracycline use in ERBB2-positive breast cancer. It is time to re-TRAINJAMA Oncol; Advance online publication 20 May 2021. DOI:10.1001/jamaoncol.2021.1314

medwireNews (www.medwireNews.com) is an independent medical news service provided by Springer Healthcare. © 2021 Springer Healthcare part of the Springer Nature group

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