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Comparison of ESR1 Mutations in Tumor Tissue and Matched Plasma Samples from Metastatic Breast Cancer Patients.

ABSTRACT: ESR1 mutation in circulating cell-free DNA (cfDNA) is emerging as a noninvasive biomarker of acquired resistance to endocrine therapy, but there is a paucity of data comparing the status of ESR1 gene in cfDNA with that in its corresponding tumor tissue. The objective of this study is to validate the degree of concordance of ESR1 mutations between plasma and tumor tissue.ESR1 ligand-binding domain mutations Y537S, Y537N, Y537C, and D538G were analyzed using droplet digital PCR in 35 patients with metastatic breast cancer (MBC) (35 tumor tissue samples and 67 plasma samples).Of the 35 paired samples, 26 (74.3%) were concordant: one patient had detectable ESR1 mutations both plasma (ESR1 Y537S/Y537N) and tumor tissue (ESR1 Y537S/Y537C), and 25 had WT ESR1 alleles in both. Nine (25.7%) had discordance between the plasma and tissue results: five had mutations detected only in their tumor tissue (two Y537S, one Y537C, one D538G, and one Y537S/Y537N/D538G), and four had mutations detected only in their plasma (one Y537S, one Y537N, and two Y537S/Y537N/D538G). Furthermore, longitudinal plasma samples from 19 patients were used to assess changes in the presence of ESR1 mutations during treatment. Eleven patients had cfDNA ESR1 mutations over the course of treatment. A total of eight of 11 patients with MBC with cfDNA ESR1 mutations (72.7%) had the polyclonal mutations.We have shown the independent distribution of ESR1 mutations between plasma and tumor tissue in 35 patients with MBC.

SUBMITTER: Takeshita T

PROVIDER: S-EPMC5538967 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Comparison of ESR1 Mutations in Tumor Tissue and Matched Plasma Samples from Metastatic Breast Cancer Patients.

Takeshita Takashi T Yamamoto Yutaka Y Yamamoto-Ibusuki Mutsuko M Tomiguchi Mai M Sueta Aiko A Murakami Keiichi K Omoto Yoko Y Iwase Hirotaka H

Translational oncology 20170801 5

<h4>Background</h4>ESR1 mutation in circulating cell-free DNA (cfDNA) is emerging as a noninvasive biomarker of acquired resistance to endocrine therapy, but there is a paucity of data comparing the status of ESR1 gene in cfDNA with that in its corresponding tumor tissue. The objective of this study is to validate the degree of concordance of ESR1 mutations between plasma and tumor tissue.<h4>Methods</h4>ESR1 ligand-binding domain mutations Y537S, Y537N, Y537C, and D538G were analyzed using drop ...[more]

PMID: 28778025

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Project description:BackgroundScreening for epidermal growth factor receptor (EGFR) mutations is the key to select suitable patients with non-small cell lung cancer (NSCLC) for EGFR-TKI therapy in clinical practice. Nevertheless, tumor tissue that needed for mutation analysis is frequently unavailable, especially for patients with recurrence after operation. Therefore, detection of EGFR from circulating tumor DNA (ctDNA) in patients with NSCLC is a sensitive and convenient method to direct patient sequential treatment strategy.MethodsOne hundred and seventy-nine NSCLC patients with both tumor tissue samples and paired plasma samples were recruited. EGFR mutations were detected in 68 tumor tissue samples and 179 plasma samples using Anlongen Locked Nucleic Acid-Amplification Refractory Mutation System (LNA-ARMS) EGFR Mutation Detection Kit. The remaining 111 tumor tissue samples were detected with the use of multiplex PCR-Based NGS sequence. We calculated the sensitivity, specificity, positive prediction value (PPV) and negative prediction value (NPV) of LAN-ARMS PCR. The objective response rate (ORR) of patients received TKIs therapy was calculated.ResultsOf the 179 patients, EGFR mutations were detected in 77 of the 179 tumor tissue samples, with a positive rate of 43.01% (77/179). In addition, EGFR mutations were detected in 42 of the 179 plasma samples. The sensitivity and specificity of LAN-ARMS in detecting EGFR mutations were 57.18% and 98.04% respectively compared to tissue results. The PPV was 95.24%, and NPV was 72.99%. Of the 179 pair of samples, EGFR mutations were inconsistent in 39 pairs of tissue and plasma. The overall agreement of EGFR mutation detection was 78.21% (140/179). The ORR was higher in patients with both tissue and plasma EGFR mutations compared with that in patients with only tissue EGFR mutations (73.33% vs. 68.29%), but the difference was not significant. It was suggested that tissue detection combined with plasma detection could improve the mutation rate.ConclusionIn plasma samples, Anlongen LAN-ARMS EGFR Mutation Detection Kit had a high sensitivity and specificity for the detection of EGFR mutations. Anlongen LAN-ARMS EGFR Mutation Detection Kit had the advantages of easy-to-operate and high sensitivity in clinical application.

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

Comparison of ESR1 Mutations in Tumor Tissue and Matched Plasma Samples from Metastatic Breast Cancer Patients.

Publications

Comparison of ESR1 Mutations in Tumor Tissue and Matched Plasma Samples from Metastatic Breast Cancer Patients.

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