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Nat Genet. 2019 Feb;51(2):207-216. doi: 10.1038/s41588-018-0287-5. Epub 2018 Dec 10.

Acquired HER2 mutations in ER+ metastatic breast cancer confer resistance to estrogen receptor-directed therapies.

Nayar U1,2,3,4, Cohen O1,2,3,4, Kapstad C1,2,4, Cuoco MS5, Waks AG1,2,3,4,6, Wander SA1,2,3,4,6, Painter C4, Freeman S2,3,4, Persky NS4, Marini L1,2, Helvie K1,2, Oliver N1,2, Rozenblatt-Rosen O5, Ma CX7, Regev A5,8, Winer EP2,3,6, Lin NU2,3,6, Wagle N9,10,11,12,13.

Author information

1
Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA, USA.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
3
Harvard Medical School, Boston, MA, USA.
4
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
5
Klarman Cell Observatory, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
6
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
7
Division of Oncology, Department of Medicine, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA.
8
Howard Hughes Medical Institute and Koch Institute of Integrative Cancer Research, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA.
9
Center for Cancer Precision Medicine, Dana-Farber Cancer Institute, Boston, MA, USA. nikhil_wagle@dfci.harvard.edu.
10
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. nikhil_wagle@dfci.harvard.edu.
11
Harvard Medical School, Boston, MA, USA. nikhil_wagle@dfci.harvard.edu.
12
Broad Institute of MIT and Harvard, Cambridge, MA, USA. nikhil_wagle@dfci.harvard.edu.
13
Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA. nikhil_wagle@dfci.harvard.edu.

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 inhibitors1-4, 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.

PMID:
30531871
DOI:
10.1038/s41588-018-0287-5
[Indexed for MEDLINE]

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