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ESR1 Mutations in Circulating Plasma Tumor DNA from Metastatic Breast Cancer Patients.

ABSTRACT: Mutations in the estrogen receptor (ER)? gene, ESR1, have been identified in breast cancer metastases after progression on endocrine therapies. Because of limitations of metastatic biopsies, the reported frequency of ESR1 mutations may be underestimated. Here, we show a high frequency of ESR1 mutations using circulating plasma tumor DNA (ptDNA) from patients with metastatic breast cancer.We retrospectively obtained plasma samples from eight patients with known ESR1 mutations and three patients with wild-type ESR1 identified by next-generation sequencing (NGS) of biopsied metastatic tissues. Three common ESR1 mutations were queried for using droplet digital PCR (ddPCR). In a prospective cohort, metastatic tissue and plasma were collected contemporaneously from eight ER-positive and four ER-negative patients. Tissue biopsies were sequenced by NGS, and ptDNA ESR1 mutations were analyzed by ddPCR.In the retrospective cohort, all corresponding mutations were detected in ptDNA, with two patients harboring additional ESR1 mutations not present in their metastatic tissues. In the prospective cohort, three ER-positive patients did not have adequate tissue for NGS, and no ESR1 mutations were identified in tissue biopsies from the other nine patients. In contrast, ddPCR detected seven ptDNA ESR1 mutations in 6 of 12 patients (50%).We show that ESR1 mutations can occur at a high frequency and suggest that blood can be used to identify additional mutations not found by sequencing of a single metastatic lesion.

SUBMITTER: Chu D

PROVIDER: S-EPMC4993201 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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ESR1 Mutations in Circulating Plasma Tumor DNA from Metastatic Breast Cancer Patients.

Chu David D Paoletti Costanza C Gersch Christina C VanDenBerg Dustin A DA Zabransky Daniel J DJ Cochran Rory L RL Wong Hong Yuen HY Toro Patricia Valda PV Cidado Justin J Croessmann Sarah S Erlanger Bracha B Cravero Karen K Kyker-Snowman Kelly K Button Berry B Parsons Heather A HA Dalton W Brian WB Gillani Riaz R Medford Arielle A Aung Kimberly K Tokudome Nahomi N Chinnaiyan Arul M AM Schott Anne A Robinson Dan D Jacks Karen S KS Lauring Josh J Hurley Paula J PJ Hayes Daniel F DF Rae James M JM Park Ben Ho BH

Clinical cancer research : an official journal of the American Association for Cancer Research 20150810 4

<h4>Purpose</h4>Mutations in the estrogen receptor (ER)α gene, ESR1, have been identified in breast cancer metastases after progression on endocrine therapies. Because of limitations of metastatic biopsies, the reported frequency of ESR1 mutations may be underestimated. Here, we show a high frequency of ESR1 mutations using circulating plasma tumor DNA (ptDNA) from patients with metastatic breast cancer.<h4>Experimental design</h4>We retrospectively obtained plasma samples from eight patients wi ...[more]

PMID: 26261103

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Project description:BACKGROUND:ESR1 mutations are frequently detected in ER+ MBC, and have been reported to be associated with endocrine therapy resistance. However, there are little researches to validate whether dynamic monitoring of ESR1 mutations could serve as a predictive plasma biomarker of acquired resistance to endocrine therapy. Therefore, in this study, we performed longitudinal circulating tumor DNA (ctDNA) detection to evaluate the clinical implications of monitoring ESR1 mutations. METHODS:We performed longitudinal dynamic mutation analyses of plasma samples from 45 patients with metastatic breast cancer (MBC) and sequencing paired biopsy tissues, using a targeted NGS panel of 425 genes. These patients were treated at the Second Affiliated Hospital of Dalian Medical University between January 2017 and February 2019 with written informed consent. RESULTS:Mutations profiles were highly concordant between plasma and paired tissue samples from 45 MBC patients (r = 0.96, P < 0.0001). ESR1 mutations were enriched in ER+ MBC patients after AI therapy (17.8%, 8/45). The median time from AI endocrine therapies to the initial detection of ESR1 mutation was 39 months (95% CI 21.32-57.57). Some hotspot mutations (Y537S (n = 5), Y537N (n = 1), D538G (n = 2), E380Q (n = 2)) and several rare mutations (L345SfsX7, 24fs, G344delinsGC) were identified in our cohort. In addition, we observed that two patients obtained multiple ESR1 mutations over the course of treatment (Y537N/Y537S/D538G, L345SfsX7/24fs/E380Q). Through dynamically monitoring ESR1 mutations by ctDNA, we demonstrated that the change of allele frequency of ESR1 mutations was an important biomarker, which could predict endocrine resistance of ER+ MBC in our study. We also observed that the combination of everolimus in four cases with acquired ESR1 mutations showed longer PFS than other therapies without everolimus. CONCLUSION:The dynamic monitoring of ESR1 mutations by ctDNA is a promising tool to predict endocrine therapy resistance in ER+ MBC patients.

Dataset Information

ESR1 Mutations in Circulating Plasma Tumor DNA from Metastatic Breast Cancer Patients.

Publications

ESR1 Mutations in Circulating Plasma Tumor DNA from Metastatic Breast Cancer Patients.

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