Clinical practice-changing trials: the HERA study paradigm

Abstract

Trastuzumab, a humanized anti-HER2 monoclonal antibody targeting the extracellular domain of this oncoprotein, represents the archetype of HER2 blocking agents. Its unprecedented efficacy for HER2-positive metastatic breast cancer (BC) led to its clinical development in the adjuvant setting. The HERceptin Adjuvant (HERA) is one of the pivotal adjuvant trastuzumab trials which proved that this compound can change the natural course of early stage HER2-positive BC. The HERA study led to the registration of trastuzumab for the adjuvant treatment of early HER2-positive BC. This trial randomized more than 5000 patients between 1 and 2 years of trastuzumab and observation after the completion of locoregional therapy and (neo)-adjuvant chemotherapy. Additionally, an abundance of subsequent substudies were conducted, addressing important clinical issues for this patient population. The present review article presents a comprehensive overview of the HERA study and its major contributions to the adjuvant treatment of HER2-positive BC patients. Emphasis is given on the lessons learned from this international collaborative experience and how this can be used as a stepping stone for further improvements in the field.

Trial registration: ClinicalTrial.gov identifier: NCT00593697.

Trial registration: ClinicalTrial.gov identifier: NCT00712140.

Trial registration: ClinicalTrial.gov identifier: NCT00629278.

Trial registration: ClinicalTrial.gov identifier: NCT00615602.

Trial registration: ClinicalTrial.gov identifier: NCT00615602.

Trial registration: ClinicalTrial.gov identifier: NCT00490139.

Trial registration: ClinicalTrial.gov identifier: NCT01358877.

Keywords::

• adjuvant therapy
• breast cancer
• HER2-positive
• trastuzumab

Financial & competing interests disclosure

E de Azambuja has received honoraria and travel grant from Roche.The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• • Human EGF receptor 2 (HER2) is overexpressed in 15–25% of early-stage breast cancer (BC), conferring aggressive biologic behavior and thus poor clinical outcome.

• • Trastuzumab is a humanized monoclonal antibody targeting the extracellular domain of HER2 domain.

• • The HERceptin Adjuvant (HERA) trial assessed the efficacy of trastuzumab administered after the completion of (neo)-adjuvant chemotherapy in HER2-positive BC.

• • HERA is one of the seminal studies which led to the approval of trastuzumab in the adjuvant setting of HER2-positive BC.

• • HERA is the only study which assessed the efficacy of a longer duration of adjuvant trastuzumab, incorporating a 2-year arm, showing that no added benefit is derived by administration for 2 years.

• • Several substudies have been conducted utilizing the data-base of the HERA study, addressing clinically relevant issues about the HER2-positive BC population.

• • Further understanding of the molecular biology underlying HER2-positive BC promises improved clinical outcome for our patients, with the dual HER2-blockade strategies being the most advanced in terms of clinical development.

Notes