Journal Article

Pathologic and molecular responses to neoadjuvant trastuzumab and/or lapatinib from a phase II randomized trial in HER2-positive breast cancer (TRIO-US B07)

Zoeller, Jason J., Dichmann, Robert, Allen, Heather, DiCarlo, Brian, Giuliano, Armando, Dering, Judy, Curtis, Christina, Perez, Alejandra, Slamon, Dennis J., Zehngebot, Lee, Calfa, Carmen, Molthrop, David, Adams, Brad, Chen, Hsiao-Wang, Brugge, Joan S., Mani, Aruna, Hurvitz, Sara A., Kotler, Eran, McNamara, Katherine L., Kennedy, April, Bean, Gregory R., Bosserman, Linda, Caswell-Jin, Jennifer L., Patel, Ravindranath, Press, Michael F.

2020

Overview

In this multicenter, open-label, randomized phase II investigator-sponsored neoadjuvant trial with funding provided by Sanofi and GlaxoSmithKline (TRIO-US B07, Clinical Trials NCT00769470), participants with early-stage HER2-positive breast cancer ( N  = 128) were recruited from 13 United States oncology centers throughout the Translational Research in Oncology network. Participants were randomized to receive trastuzumab (T; N  = 34), lapatinib (L; N  = 36), or both (TL; N  = 58) as HER2-targeted therapy, with each participant given one cycle of this designated anti-HER2 therapy alone followed by six cycles of standard combination chemotherapy with the same anti-HER2 therapy. The primary objective was to estimate the rate of pathologic complete response (pCR) at the time of surgery in each of the three arms. In the intent-to-treat population, we observed similar pCR rates between T (47%, 95% confidence interval [CI] 30–65%) and TL (52%, 95% CI 38–65%), and a lower pCR rate with L (25%, 95% CI 13–43%). In the T arm, 100% of participants completed all protocol-specified treatment prior to surgery, as compared to 69% in the L arm and 74% in the TL arm. Tumor or tumor bed tissue was collected whenever possible pre-treatment ( N  = 110), after one cycle of HER2-targeted therapy alone ( N  = 89), and at time of surgery ( N  = 59). Higher-level amplification of HER2 and hormone receptor (HR)-negative status were associated with a higher pCR rate. Large shifts in the tumor, immune, and stromal gene expression occurred after one cycle of HER2-targeted therapy. In contrast to pCR rates, the L-containing arms exhibited greater proliferation reduction than T at this timepoint. Immune expression signatures increased in all arms after one cycle of HER2-targeted therapy, decreasing again by the time of surgery. Our results inform approaches to early assessment of sensitivity to anti-HER2 therapy and shed light on the role of the immune microenvironment in response to HER2-targeted agents. HER2+ breast cancer patients can often develop resistance to trastuzumab and therefore potential combination therapies need to be explored. Here, the authors report the results of a multi-center randomized phase II clinical trial evaluating the pathological and molecular responses associated with trastuzumab and/or lapatinib in combination with chemotherapy in HER2+ breast cancer patients.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 38/1 / 38/39 / 38/61 / 631/67/1059/602 / 631/67/1347 / Aged / Antineoplastic Combined Chemotherapy Protocols - adverse effects / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Breast cancer / Breast Neoplasms - drug therapy / Breast Neoplasms - pathology / Breast Neoplasms - surgery / Cancer therapies / Chemotherapy / Clinical trials / Confidence intervals / ErbB-2 protein / Female / Gene expression / Gene Expression Regulation, Neoplastic / Humanities and Social Sciences / Humans / Immunotherapy / Inhibitor drugs / Lapatinib - administration & dosage / Lapatinib - therapeutic use / Middle Aged / Molecular Targeted Therapy - methods / Monoclonal antibodies / multidisciplinary / Neoadjuvant Therapy / Oncology / Patients / Pretreatment / Receptor, ErbB-2 - antagonists & inhibitors / Receptor, ErbB-2 - metabolism / Science / Science (multidisciplinary) / Surgery / Targeted cancer therapy / Trastuzumab / Trastuzumab - administration & dosage / Trastuzumab - therapeutic use / Treatment Outcome / Tumor Microenvironment - drug effects / Tumor Microenvironment - genetics / Tumors