January 2020: A combination of trastuzumab with tailored dose-dense adjuvant chemotherapy reduces risk of relapse in HER2-positive breast cancer

PANTHER is a prospective, randomized, open-label, multicenter phase 3 trial that was conducted between February 2007 and September 2011 at 86 centers in Sweden, Germany, and Austria. The trial investigated efficacy and safety of an adjuvant tailored dose-dense (tDD) sequence of epirubicin/cyclophosphamide and docetaxel in a cohort of lymph node-positive or high-risk lymph node-negative patients compared to a standard anthracycline/taxane containing regimen. Patients with HER2-positive disease (defined according to local guidelines) received one year of adjuvant trastuzumab that started either after the completion of adjuvant chemotherapy or concurrently with docetaxel (recommended after October 2007). The primary endpoint of the study was breast cancer relapse-free survival (BCRFS). Secondary endpoints included overall survival (OS), event-free survival (EFS), distant disease-free survival, and toxicity.

This study presented results of the predefined efficacy analysis of the HER2-positive population as well as substudy related to the cardiac safety of trastuzumab treatment from PANTHER trial. There were 342 HER2-positive patients; 335 received at least one dose of trastuzumab, and 29 patients discontinued trastuzumab prematurely. Median follow-up was 5.3 years (IQR 4.4-6.3 years). The 5-year BCRFS rates were not statistically significant in the tDD group compared to the standard treatment group (89.1 % vs 85.3%, respectively) with hazard ratio of 0.68 (95%CI 0.37-1.27; p=0.231); the absolute difference in 5-year BCRFS was 3.8% (95% CI –3.7% to 11.0%) in favor of tDD. Hence, a combination of tDD chemotherapy and trastuzumab decreased the relative risk of relapse by 32% for HER2-positive patients compared to standard treatment but did not reach a statistically significance. Data on cardiac outcomes at 4 years were available for 153 patients (77 were HER2 positive, and 76 were HER2 negative) with mean left ventricular ejection fraction (LVEF) values of 58.7% and 59.9%, respectively, (p=0.25). Similarly, data at 6 years were available for 151 patients (75 were HER2-positive and 76 were HER2-negative) with mean LVEF values of 58.8% and 59.0%, respectively (p=0.85). Cardiac outcomes after 4 and 6 years of follow-up did not differ significantly between HER2-positive and HER2-negative patients or between the two treatment groups.

In conclusion, combining tDD and trastuzumab as adjuvant therapy for early HER2-positive breast cancer could be a feasible strategy in terms of both efficacy and safety. Such a strategy needs further validation in a properly designed randomized trial before it can be considered as standard of care.

Papakonstantinou A, Matikas A, Bengtsson NO, Malmström P, Hedayati E, Steger G, Untch M, Hübbert L, Johansson H, Hellström M, Gnant M, Loibl S, Greil R, Moebus V, Foukakis T, Bergh J. Efficacy and Safety of Tailored and Dose-Dense Adjuvant Chemotherapy and Trastuzumab for Resected HER2-Positive Breast Cancer: Results From the Phase 3 PANTHER Trial. Cancer. 2019; doi:10.1002/cncr.32653.

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