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PLoS Med. 2016 Dec 13;13(12):e1002193. doi: 10.1371/journal.pmed.1002193. eCollection 2016 Dec.

Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis.

Author information

1
Department of Medicine, Yale School of Medicine, Yale University, New Haven, Connecticut, United States of America.
2
MTA TTK Lendulet Cancer Biomarker Research Group, Research Center for Natural Sciences, Budapest, Hungary.
3
2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
4
Department of Genetics, Yale School of Medicine, Yale University, New Haven, Connecticut, United States of America.
5
Department of Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
6
Yale Cancer Center, New Haven, Connecticut, United States of America.

Abstract

BACKGROUND:

Triple negative breast cancer (TNBC) is a highly heterogeneous and aggressive disease, and although no effective targeted therapies are available to date, about one-third of patients with TNBC achieve pathologic complete response (pCR) from standard-of-care anthracycline/taxane (ACT) chemotherapy. The heterogeneity of these tumors, however, has hindered the discovery of effective biomarkers to identify such patients.

METHODS AND FINDINGS:

We performed whole exome sequencing on 29 TNBC cases from the MD Anderson Cancer Center (MDACC) selected because they had either pCR (n = 18) or extensive residual disease (n = 11) after neoadjuvant chemotherapy, with cases from The Cancer Genome Atlas (TCGA; n = 144) and METABRIC (n = 278) cohorts serving as validation cohorts. Our analysis revealed that mutations in the AR- and FOXA1-regulated networks, in which BRCA1 plays a key role, are associated with significantly higher sensitivity to ACT chemotherapy in the MDACC cohort (pCR rate of 94.1% compared to 16.6% in tumors without mutations in AR/FOXA1 pathway, adjusted p = 0.02) and significantly better survival outcome in the TCGA TNBC cohort (log-rank test, p = 0.05). Combined analysis of DNA sequencing, DNA methylation, and RNA sequencing identified tumors of a distinct BRCA-deficient (BRCA-D) TNBC subtype characterized by low levels of wild-type BRCA1/2 expression. Patients with functionally BRCA-D tumors had significantly better survival with standard-of-care chemotherapy than patients whose tumors were not BRCA-D (log-rank test, p = 0.021), and they had significantly higher mutation burden (p < 0.001) and presented clonal neoantigens that were associated with increased immune cell activity. A transcriptional signature of BRCA-D TNBC tumors was independently validated to be significantly associated with improved survival in the METABRIC dataset (log-rank test, p = 0.009). As a retrospective study, limitations include the small size and potential selection bias in the discovery cohort.

CONCLUSIONS:

The comprehensive molecular analysis presented in this study directly links BRCA deficiency with increased clonal mutation burden and significantly enhanced chemosensitivity in TNBC and suggests that functional RNA-based BRCA deficiency needs to be further examined in TNBC.

PMID:
27959926
PMCID:
PMC5154510
DOI:
10.1371/journal.pmed.1002193
[Indexed for MEDLINE]
Free PMC Article

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