@article{5253402881da4ed99cf886123da5a18d,
title = " Acquired HER2 mutations in ER + metastatic breast cancer confer resistance to estrogen receptor–directed therapies ",
abstract = " Seventy percent of breast cancers express the estrogen receptor (ER), and agents that target the ER are the mainstay of treatment. However, virtually all people with ER + breast cancer develop resistance to ER-directed agents in the metastatic setting. Beyond mutations in the ER itself, which occur in 25–30% of people treated with aromatase inhibitors 1 –4 , knowledge about clinical resistance mechanisms remains incomplete. We identified activating HER2 mutations in metastatic biopsies from eight patients with ER + metastatic breast cancer who had developed resistance to aromatase inhibitors, tamoxifen or fulvestrant. Examination of treatment-naive primary tumors in five patients showed no evidence of pre-existing mutations in four of five patients, suggesting that these mutations were acquired under the selective pressure of ER-directed therapy. The HER2 mutations and ER mutations were mutually exclusive, suggesting a distinct mechanism of acquired resistance to ER-directed therapies. In vitro analysis confirmed that the HER2 mutations conferred estrogen independence as well as—in contrast to ER mutations—resistance to tamoxifen, fulvestrant and the CDK4 and CDK6 inhibitor palbociclib. Resistance was overcome by combining ER-directed therapy with the irreversible HER2 kinase inhibitor neratinib.",
author = "Utthara Nayar and Ofir Cohen and Christian Kapstad and Cuoco, {Michael S.} and Waks, {Adrienne G.} and Wander, {Seth A.} and Corrie Painter and Samuel Freeman and Persky, {Nicole S.} and Lori Marini and Karla Helvie and Nelly Oliver and Orit Rozenblatt-Rosen and Ma, {Cynthia X.} and Aviv Regev and Winer, {Eric P.} and Lin, {Nancy U.} and Nikhil Wagle",
note = "Funding Information: We thank Q. Quartey and P. Ram for technical assistance, F. Luo, R. Jeselsohn, C. Strathdee, I. Leshchiner, D. Rosebrock, D. Livitz and G. Getz for technical advice, and B. Kaplan, H. Greulich, C. Strathdee, F. Luo, E. Goetz and L. Garraway for providing reagents. We thank C. Johannessen, M. Brown, M. Meyerson and R. Bose for helpful discussions and comments on the manuscript. We are grateful to all the patients who volunteered for our tumor biopsy protocol and generously provided the tissue analyzed in this study. This work was supported by the Department of Defense W81XWH-13-1-0032 (N.W.), AACR Landon Foundation 13-60-27-WAGL (N.W.), National Cancer Institute Breast Cancer SPORE at DF/HCC P50CA168504 (N.W.), Susan G. Komen CCR15333343 (N.W.), the V Foundation (N.W.), the Breast Cancer Alliance (N.W.), the Cancer Couch Foundation (N.W.), the MBC Collective (N.W.), Breast Cancer Research Foundation (N.U.L. and E.P.W.), ACT NOW (to Dana-Farber Cancer Institute Breast Oncology Program), Fashion Footwear Association of New York (to Dana-Farber Cancer Institute Breast Oncology Program), Friends of Dana-Farber Cancer Institute (to N.U.L.), the Klarman Family Foundation and HHMI (to A.R.) and Dana-Farber/Harvard Cancer Center SPORE grant P50CA168504. Publisher Copyright: {\textcopyright} 2018, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2019",
month = feb,
day = "1",
doi = "10.1038/s41588-018-0287-5",
language = "English",
volume = "51",
pages = "207--216",
journal = "Nature Genetics",
issn = "1061-4036",
number = "2",
}