Constitutively active ESR1 mutations in gynecologic malignancies and clinical response to estrogen-receptor directed therapies

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dc.contributorStéphanie L. Gaillard
dc.contributorKaitlyn J. Andreano
dc.contributorLaurie M. Gay
dc.contributorMeghan Steiner
dc.contributorMatthew S. Jorgensen
dc.contributorBrittany Anne Davidson
dc.contributorLaura J. Havrilesky
dc.contributorAngeles Alvarez Secord
dc.contributorFidel A. Valea
dc.contributorGerardo Colon-Otero
dc.contributorDeborah A. Zajchowski
dc.contributorChing-Yi Chang
dc.contributorDonald P. McDonnell
dc.contributorAndrew Berchuck
dc.contributorJulia A. Elvin
dc.date.accessioned2019-09-09T14:45:01Z
dc.date.available2019-09-09T14:45:01Z
dc.date.updated2019-09-09T14:45:00Z
dc.description.abstractOBJECTIVE: Endocrine therapy is often considered as a treatment for hormone-responsive gynecologic malignancies. In breast cancer, activating mutations in the estrogen receptor (mutESR1) contribute to therapeutic resistance to endocrine therapy, especially aromatase inhibitors (AIs). The purpose of this study was to evaluate the frequency and clinical relevance of ESR1 genomic alterations in gynecologic malignancies. METHODS: DNA from FFPE tumor tissue obtained during routine clinical care for 9645 gynecologic malignancies (ovary, fallopian tube, uterus, cervix, vagina, vulvar, and placenta) was analyzed for all classes of genomic alterations (base substitutions (muts), insertions, deletions, rearrangements, and amplifications) in ESR1 by hybrid capture next generation sequencing. A subset of alterations was characterized in laboratory-based transcription assays for response to endocrine therapies. RESULTS: A total of 295 ESR1 genomic alterations were identified in 285 (3.0%) cases. mutESR1 were present in 86 (0.9%) cases and were more common in uterine compared to other cancers (2.0% vs <1%, respectively p < 0.001). mutESR1 were enriched in carcinomas with endometrioid versus serous histology (4.4% vs 0.2% respectively, p < 0.0001 in uterine and 3.5% vs 0.3% respectively, p = 0.0004 in ovarian carcinomas). In three of four patients with serial sampling, mutESR1 emerged under the selective pressure of AI therapy. Despite decreased potency of estrogen receptor (ER) antagonists in transcriptional assays, clinical benefit was observed following treatment with selective ER-targeted therapy, in one case lasting >48 months. CONCLUSIONS: While the prevalence of ESR1 mutations in gynecologic malignancies is low, there are significant clinical implications useful in guiding therapeutic approaches for these cancers.
dc.identifier.citationStéphanie L. Gaillard, Kaitlyn J. Andreano, Laurie M. Gay, et al. (2019-7). "Constitutively active ESR1 mutations in gynecologic malignancies and clinical response to estrogen-receptor directed therapies." Gynecologic Oncology. 154 (1). 10.1016/j.ygyno.2019.04.010.
dc.identifier.urihttp://jhir.library.jhu.edu/handle/1774.2/61858
dc.languageen
dc.publisherElsevier BV
dc.titleConstitutively active ESR1 mutations in gynecologic malignancies and clinical response to estrogen-receptor directed therapies
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