TY - JOUR
T1 - Constitutively active ESR1 mutations in gynecologic malignancies and clinical response to estrogen-receptor directed therapies
AU - Gaillard, Stéphanie L.
AU - Andreano, Kaitlyn J.
AU - Gay, Laurie M.
AU - Steiner, Meghan
AU - Jorgensen, Matthew S.
AU - Davidson, Brittany Anne
AU - Havrilesky, Laura J.
AU - Alvarez Secord, Angeles
AU - Valea, Fidel A.
AU - Colon-Otero, Gerardo
AU - Zajchowski, Deborah A.
AU - Chang, Ching Yi
AU - McDonnell, Donald P.
AU - Berchuck, Andrew
AU - Elvin, Julia A.
N1 - Funding Information:
Dr. Gaillard reports the following disclosures outside of the submitted work: grants and personal fees from Merck, Tesaro, Pfizer, Genentech/Roche, PharmaMar; grants to institution from Abbvie, Bristol-Myers Squibb, Gradalis, Iovance Biotherapeutics, Tetralogic Pharmaceuticals; personal fees from AstraZeneca and Immunogen; In addition, Dr. Gaillard has a patent Application No. 62/774597 licensed to Sermonix Pharmaceuticals. Ms. Andreano has a patent Application No. 62/774597 licensed to Sermonix Pharmaceuticals. Dr. Gay reports personal fees from Foundation Medicine and Gilead Sciences outside the submitted work. Dr. Steiner has nothing to disclose. Mr. Jorgensen has nothing to disclose. Dr. Davidson reports personal fees from EMD Serono outside the submitted work. Dr. Havrilesky reports grants to institution from AstraZeneca outside the submitted work. Dr. Alvarez Secord reports the following disclosures outside the submitted work: grants to institution from Abbvie, Amgen, Astellas Pharma, Boehringer Ingelheim, Bristol-Myers Squibb, Incyte, Merck, Morphotek, Eisai, Endocyte, Exelixis, PharmaMar, and Prima BioMed; grants to institution and personal fees from Astex Pharmaceuticals, AstraZeneca, Genentech, and Tesaro; personal fees from Clovis Oncology, Janssen, Myriad, and Alexion Pharmaceuticals; and other (royalties) from UpToDate. Dr. Valea reports other (royalties) from Elsevier, Comprehensive Gynecology and UpToDate, outside the submitted work. Dr. Colon-Otero reports grants from Novartis outside the submitted work. Dr. Zajchowski has nothing to disclose. Dr. Chang reports grants from Sermonix Pharmaceuticals, outside the submitted work; In addition, Dr. Chang has a patent Application No. 62/774597 licensed to Sermonix Pharmaceuticals. Dr. McDonnell reports the following outside the submitted work: grants, personal fees and other from G1 Therapeutics, other from X-RAD Therapeutics, personal fees and other from Zeno Pharmaceuticals, grants and personal fees from Celgene, personal fees from Novartis, personal fees from Pfizer, personal fees from Arvinas, grants and personal fees from Cell Design Labs, personal fees from Viba Therapeutics, grants from Innocrin Pharma; In addition, Dr. McDonnell has a patent Application No. 62/774597 licensed to Sermonix Pharmaceuticals. Dr. Berchuck reports the following disclosures outside the submitted work: personal fees from Clovis Oncology, Merck, and Tesaro, grants from Novadaq Technologies, and non-financial support from Merck. Dr. Elvin reports personal fees from Foundation Medicine outside the submitted work.
Funding Information:
The authors would like to acknowledge patients who contributed their samples/or data to the public databases and to the Clearity Foundation Data Repository, as well as the Cancer Genome Atlas Research Network (http://cancergenome.nih.gov), the American Association for Cancer Research and its financial and material support in the development of the AACR Project GENIE registry, and members of the consortium for their commitment to data sharing. Interpretations are the responsibility of study authors. The authors would like to thank Jessica Kreb for assistance with Fig. 2. Conception and design: Stéphanie L. Gaillard, Kaitlyn J. Andreano, Laurie M. Gay, Ching-Yi Chang, and Julia A. Elvin. Collection and assembly of data: Stéphanie L. Gaillard, Kaitlyn J. Andreano, Laurie M. Gay, Meghan Steiner, Matthew S. Jorgensen, Brittany Anne Davidson, Laura J. Havrilesky, Angeles Alvarez Secord, Fidel A. Valea, Gerardo Colon-Otero, Deborah A. Zajchowski, Ching-Yi Chang, and Julia A. Elvin. Data analysis and interpretation: All authors. Manuscript writing: All authors. Final approval of manuscript: All authors. Dr. Gaillard reports the following disclosures outside of the submitted work: grants and personal fees from Merck, Tesaro, Pfizer, Genentech/Roche, PharmaMar; grants to institution from Abbvie, Bristol-Myers Squibb, Gradalis, Iovance Biotherapeutics, Tetralogic Pharmaceuticals; personal fees from AstraZeneca and Immunogen; In addition, Dr. Gaillard has a patent Application No. 62/774597 licensed to Sermonix Pharmaceuticals. Ms. Andreano has a patent Application No. 62/774597 licensed to Sermonix Pharmaceuticals. Dr. Gay reports personal fees from Foundation Medicine and Gilead Sciences outside the submitted work. Dr. Steiner has nothing to disclose. Mr. Jorgensen has nothing to disclose. Dr. Davidson reports personal fees from EMD Serono outside the submitted work. Dr. Havrilesky reports grants to institution from AstraZeneca outside the submitted work. Dr. Alvarez Secord reports the following disclosures outside the submitted work: grants to institution from Abbvie, Amgen, Astellas Pharma, Boehringer Ingelheim, Bristol-Myers Squibb, Incyte, Merck, Morphotek, Eisai, Endocyte, Exelixis, PharmaMar, and Prima BioMed; grants to institution and personal fees from Astex Pharmaceuticals, AstraZeneca, Genentech, and Tesaro; personal fees from Clovis Oncology, Janssen, Myriad, and Alexion Pharmaceuticals; and other (royalties) from UpToDate. Dr. Valea reports other (royalties) from Elsevier, Comprehensive Gynecology and UpToDate, outside the submitted work. Dr. Colon-Otero reports grants from Novartis outside the submitted work. Dr. Zajchowski has nothing to disclose. Dr. Chang reports grants from Sermonix Pharmaceuticals, outside the submitted work; In addition, Dr. Chang has a patent Application No. 62/774597 licensed to Sermonix Pharmaceuticals. Dr. McDonnell reports the following outside the submitted work: grants, personal fees and other from G1 Therapeutics, other from X-RAD Therapeutics, personal fees and other from Zeno Pharmaceuticals, grants and personal fees from Celgene, personal fees from Novartis, personal fees from Pfizer, personal fees from Arvinas, grants and personal fees from Cell Design Labs, personal fees from Viba Therapeutics, grants from Innocrin Pharma; In addition, Dr. McDonnell has a patent Application No. 62/774597 licensed to Sermonix Pharmaceuticals. Dr. Berchuck reports the following disclosures outside the submitted work: personal fees from Clovis Oncology, Merck, and Tesaro, grants from Novadaq Technologies, and non-financial support from Merck. Dr. Elvin reports personal fees from Foundation Medicine outside the submitted work.
Publisher Copyright:
© 2019 Elsevier Inc.
PY - 2019/7
Y1 - 2019/7
N2 - Objective: 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.
AB - Objective: 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.
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U2 - 10.1016/j.ygyno.2019.04.010
DO - 10.1016/j.ygyno.2019.04.010
M3 - Article
C2 - 30987772
AN - SCOPUS:85064207575
VL - 154
SP - 199
EP - 206
JO - Gynecologic Oncology
JF - Gynecologic Oncology
SN - 0090-8258
IS - 1
ER -