Dataset Information

A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer.

ABSTRACT: Immune checkpoint inhibitors produce modest responses in metastatic breast cancer, however, combination approaches may improve responses. A single arm pilot study was designed to determine the overall response rate (ORR) of durvalumab and tremelimumab, and evaluate immunogenomic dynamics in metastatic endocrine receptor (ER) positive or triple negative breast cancer (TNBC). Simon two-stage design indicated at least four responses from the first 18 patients were needed to proceed with the second stage. T-cell receptor (TCR) sequencing and immune-gene expression profiling were conducted at baseline and two months, whole exome sequencing was conducted at baseline. Eighteen evaluable patients were accrued (11 ER-positive; seven TNBC). Only three patients had a response (ORR = 17%), thus the study did not proceed to the second stage. Responses were only observed in patients with TNBC (ORR = 43%). Responders versus non-responders had upregulation of CD8, granzyme A, and perforin 1 gene expression, and higher mutational and neoantigen burden. Patients with TNBC had an oligoclonal shift of the most abundant TCR-beta clonotypes compared to those with ER-positive disease, p = 0.004. We conclude responses are low in unselected metastatic breast cancer, however, higher rates of clinical benefit were observed in TNBC. Immunogenomic dynamics may help identify phenotypes most likely to respond to immunotherapy.

SUBMITTER: Santa-Maria CA

PROVIDER: S-EPMC5922371 | biostudies-other | 2018 Apr

REPOSITORIES: biostudies-other

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A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer.

Santa-Maria Cesar August CA Kato Taigo T Park Jae-Hyun JH Kiyotani Kazuma K Rademaker Alfred A Shah Ami N AN Gross Leeaht L Blanco Luis Z LZ Jain Sarika S Flaum Lisa L Tellez Claudia C Stein Regina R Uthe Regina R Gradishar William J WJ Cristofanilli Massimo M Nakamura Yusuke Y Giles Francis J FJ

Oncotarget 20180410 27

Immune checkpoint inhibitors produce modest responses in metastatic breast cancer, however, combination approaches may improve responses. A single arm pilot study was designed to determine the overall response rate (ORR) of durvalumab and tremelimumab, and evaluate immunogenomic dynamics in metastatic endocrine receptor (ER) positive or triple negative breast cancer (TNBC). Simon two-stage design indicated at least four responses from the first 18 patients were needed to proceed with the second ...[more]

PMID: 29721177

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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

A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer.

Publications

A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer.

Similar Datasets

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