Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis.
<h4>Background</h4>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 anthracycli...
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doaj-10e48ed9f47844dbabcb17db57e75d1b2021-04-21T18:30:30ZengPublic Library of Science (PLoS)PLoS Medicine1549-12771549-16762016-12-011312e100219310.1371/journal.pmed.1002193Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis.Tingting JiangWeiwei ShiVikram B WaliLőrinc S PongorCharles LiRosanna LauBalázs GyőrffyRichard P LiftonWilliam F SymmansLajos PusztaiChristos Hatzis<h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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.https://doi.org/10.1371/journal.pmed.1002193 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Tingting Jiang Weiwei Shi Vikram B Wali Lőrinc S Pongor Charles Li Rosanna Lau Balázs Győrffy Richard P Lifton William F Symmans Lajos Pusztai Christos Hatzis |
spellingShingle |
Tingting Jiang Weiwei Shi Vikram B Wali Lőrinc S Pongor Charles Li Rosanna Lau Balázs Győrffy Richard P Lifton William F Symmans Lajos Pusztai Christos Hatzis Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis. PLoS Medicine |
author_facet |
Tingting Jiang Weiwei Shi Vikram B Wali Lőrinc S Pongor Charles Li Rosanna Lau Balázs Győrffy Richard P Lifton William F Symmans Lajos Pusztai Christos Hatzis |
author_sort |
Tingting Jiang |
title |
Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis. |
title_short |
Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis. |
title_full |
Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis. |
title_fullStr |
Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis. |
title_full_unstemmed |
Predictors of Chemosensitivity in Triple Negative Breast Cancer: An Integrated Genomic Analysis. |
title_sort |
predictors of chemosensitivity in triple negative breast cancer: an integrated genomic analysis. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Medicine |
issn |
1549-1277 1549-1676 |
publishDate |
2016-12-01 |
description |
<h4>Background</h4>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.<h4>Methods and findings</h4>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.<h4>Conclusions</h4>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. |
url |
https://doi.org/10.1371/journal.pmed.1002193 |
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