@article{6a8e4fef87db48ab9a1600e40c4b4ac7,
title = "Impact of her2 heterogeneity on treatment response of early-stage her2-positive breast cancer: Phase ii neoadjuvant clinical trial of t-dm1 combined with pertuzumab",
abstract = "Intratumor heterogeneity is postulated to cause therapeutic resistance. To prospectively assess the impact of HER2 (ERBB2) heterogeneity on response to HER2-targeted therapy, we treated 164 patients with centrally confirmed HER2-positive early-stage breast cancer with neoadjuvant trastuzumab emtansine plus pertuzumab. HER2 heterogeneity was assessed on pretreatment biopsies from two locations of each tumor. HER2 heterogeneity, defined as an area with ERBB2 amplification in >5% but <50% of tumor cells, or a HER2-negative area by FISH, was detected in 10% (16/157) of evaluable cases. The pathologic complete response rate was 55% in the nonheterogeneous subgroup and 0% in the heterogeneous group (P < 0.0001, adjusted for hormone receptor status). Single-cell ERBB2 FISH analysis of cellular heterogeneity identified the fraction of ERBB2 nonamplified cells as a driver of therapeutic resistance. These data suggest HER2 heterogeneity is associated with resistance to HER2-targeted therapy and should be considered in efforts to optimize treatment strategies. Significance: HER2-targeted therapies improve cure rates in HER2-positive breast cancer, suggesting chemotherapy can be avoided in a subset of patients. We show that HER2 heterogeneity, particularly the fraction of ERBB2 nonamplified cancer cells, is a strong predictor of resistance to HER2 therapies and could potentially be used to optimize treatment selection.",
author = "Filho, {Otto Metzger} and Giuseppe Viale and Shayna Stein and Lorenzo Trippa and Yardley, {Denise A.} and Mayer, {Ingrid A.} and Abramson, {Vandana G.} and Arteaga, {Carlos L.} and Spring, {Laura M.} and Waks, {Adrienne G.} and Eileen Wrabel and Demeo, {Michelle K.} and Aditya Bardia and Patrizia Dell{\textquoteright}Orto and Leila Russo and King, {Tari A.} and Kornelia Polyak and Franziska Michor and Winer, {Eric P.} and Krop, {Ian E.}",
note = "Funding Information: We thank Drs. Paul Catalano, Michalina Janiszewska, Simona Cristea, and Jamie Dean for their critical reading of our manuscript and useful suggestions. This work was supported by Roche, Susan G. Komen (to I.E. Krop), the Dana-Farber Cancer Institute?s Physical Sciences Oncology Center (NCI U54CA209988; to F. Michor and K. Polyak), and the National Cancer Institute grants F31CA239565 (to S. Stein) and R35CA197623 (to K. Polyak). Funding Information: We thank Drs. Paul Catalano, Michalina Janiszewska, Simona Cristea, and Jamie Dean for their critical reading of our manuscript and useful suggestions. This work was supported by Roche, Susan G. Komen (to I.E. Krop), the Dana-Farber Cancer Institute{\textquoteright}s Physical Sciences Oncology Center (NCI U54CA209988; to F. Michor and K. Polyak), and the National Cancer Institute grants F31CA239565 (to S. Stein) and R35CA197623 (to K. Polyak). Publisher Copyright: {\textcopyright} 2021 American Association for Cancer Research.",
year = "2021",
doi = "10.1158/2159-8290.CD-20-1557",
language = "English (US)",
volume = "11",
pages = "2474--2487",
journal = "Cancer discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "10",
}