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

Abstract

BackgroundTriple 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 FindingsWe 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.ConclusionsThe 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.

Alterations in Immune-Related Genes as Potential Marker of Prognosis in Breast Cancer

“…The infiltration level of TILs could almost be a predictive factor for therapy response (32). Mechanistically, activated HER2 induces the production of CCL2 (C-C Motif Chemokine Ligand 2) through the PI3K-NF-κB axis, promoting recruitment and activation of infiltrated immune cells (35), and TNBC patients were found to have a higher tumor mutation burden (TMB) and to present neoantigens that are correlated with a more effective immunotherapy response (36), while estrogen and estrogen receptor (ER) signaling appears to have little impact on the immune environment (37). With regard to stromal signatures, cancer-associated fibroblasts (CAFs) are one of the most important stromal cell types in the breast cancer microenvironment.…”

Immune Gene Expression Is Associated with Genomic Aberrations in Breast Cancer

“…Overall deletion load was defined as the number of genes with GISTIC value of "À2," and amplification load was defined as the number of genes with GISTIC value of "þ2," indicating definite deletion or amplification of a given segment, respectively. Somatic mutations in TCGA whole exome sequencing samples were detected using MuTech, as previously described (24). Mutation load was calculated as the number of somatic mutations in a sample, normalized by the total length of sequences with adequate read coverage.…”

AR Signaling in Breast Cancer

“…Pathway databases were used to predict the impact of somatic mutations on certain pathways associated with cancer. Though no single mutation was found to be predictive of response to chemotherapy in TNBC, they did find tumors with mutations in the AR pathway and FOXA1 transcription factor networks had a significantly higher pCR (94.1% vs. 16.6%) compared to those that did not carry such mutations [122]. The FOXA1 transcription factor is thought to be activated by AR signaling [123].…”