Cardiac outcomes of subjects on adjuvant trastuzumab emtansine vs paclitaxel in combination with trastuzumab for stage I HER2-positive breast cancer (ATEMPT) study (TBCRC033): a randomized controlled trial

Romualdo Barroso‐Sousa ,Audrey Merrill Garrett,Bryan Schneider,Vicente Valero,Eric P Winer,Steven J Isakoff,Denise A Yardley,Michael Constantine,Rachel C Jankowitz,Ann H Partridge ,Chau T Dang ,Blair Ardman,Vijayakrishna K Gadi,P Kelly Marcom ,Nabihah Tayob,Douglas Weckstein,Katherine E Reeder‐Hayes ,Yue Zheng,Dan Sayam Zuckerman ,Kathryn J Ruddy,Meredith Faggen,Paolo Tarantino,Ron Bose,Michelle K Demeo ,Richard D Gelber,Kathy S Albain ,Catherine Van Poznak,Bhuvaneswari Ramaswamy,Rita Nanda,Ian E Krop ,William T Barry ,Antonio C Wolff,Frederick Briccetti,Patricia Defusco,Vandana G Abramson ,Hope S Rugo,Harold J Burstein ,Jiani Hu,Minetta C Liu ,Mothaffar F Rimawi ,Therese M Mulvey ,Kit Cheng,Paula R Pohlmann,Lowell L Hart ,Andres Forero‐Torres ,Shoshana M Rosenberg,Lorenzo Trippa,Nadine Tung,Sara M Tolaney

doi:10.1038/s41523-022-00385-2

Abstract

The excellent outcomes seen in patients treated with adjuvant trastuzumab emtansine (T-DM1) in the ATEMPT trial and the favorable toxicity profile associated with this agent make T-DM1 a potential therapeutic option for select patients with stage I HER2-positive breast cancer. Moreover, T-DM1 is an established adjuvant treatment for patients with HER2-positive breast cancer with the residual invasive disease after neoadjuvant therapy. Given that cardiotoxicity is the most significant adverse event of trastuzumab, which is a main molecular component of T-DM1, we conducted a sub-analysis of the ATEMPT trial to determine the cardiac safety of adjuvant T-DM1. In this analysis, the incidence of grade 3–4 left ventricular systolic dysfunction (LVSD) in T-DM1 or trastuzumab plus paclitaxel arms were respectively 0.8 and 1.8%. In addition, three (0.8%) patients in the T-DM1 arm and six (5.3%) patients in the adjuvant paclitaxel with trastuzumab (TH) arm experienced a significant asymptomatic left ventricular ejection fraction (LVEF) decline that per-protocol required holding T-DM1 or trastuzumab. All patients with available follow-up data experienced full resolution of cardiac symptoms and LVEF normalization. Furthermore, we performed an exploratory analysis to assess the relationship between age, baseline LVEF, and body mass index with cardiac outcomes. No significant association between these baseline characteristics and the incidence of significant asymptomatic LVEF decline or symptomatic LVSD was identified. The low incidence of significant cardiac adverse events in this population during therapy with adjuvant T-DM1 suggests that studies on the cost-effectiveness of cardiac monitoring during adjuvant therapy using anthracycline-free regimens are needed.Clinical Trial Registration: ClinicalTrials.gov, NCT01853748

Highlights

Amplification or overexpression of the human epidermal growth factor receptor 2 (HER2/neu) oncogene is present in ~15–20% of early-stage breast cancers[1,2], identifying an aggressive disease subtype with a relatively high risk of recurrence in the absence of HER2/neu-directed systemic therapy[3]
Because the outcomes seen in patients treated with adjuvant T-DM1 in the ATEMPT trial and the manageable toxicity profile associated with this agent, it has emerged as a potential alternative therapy to regimens such as TH for select patients with stage I HER2-positive breast cancer[14]
In view of this emerging utilization, as well as its established role as adjuvant treatment for patients with stage II-III breast cancer with residual disease after neoadjuvant therapy, it is of compelling interest to characterize the cardiotoxic profile of T-DM1

Summary

Introduction

Amplification or overexpression of the human epidermal growth factor receptor 2 (HER2/neu) oncogene is present in ~15–20% of early-stage breast cancers[1,2], identifying an aggressive disease subtype with a relatively high risk of recurrence in the absence of HER2/neu-directed systemic therapy[3]. While patients with stage I HER2-positive breast cancer were either excluded from or underrepresented in pivotal trials that established the survival benefits of trastuzumab in combination with poly-chemotherapy, retrospective data of untreated patients showed that even these small HER2-positive breast cancers have recurrence rates between 10–30%, justifying the need of adjuvant treatment in this context[5,6,7,8]. Efforts to evaluate less toxic adjuvant regimens for small HER2positive breast cancer have been conducted[9], and based on the excellent efficacy outcomes in the adjuvant paclitaxel and trastuzumab (APT) study[10,11], adjuvant paclitaxel with trastuzumab (TH) is currently considered a standard option for patients with stage I HER2-positive breast cancer[12,13]. There has been substantially more use of T-DM1 as adjuvant treatment, and subsequently more risk of T-DM1-related adverse events

Methods

Results

Conclusion