Date Published: December 13, 2016
Publisher: Public Library of Science
Author(s): 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, Marc Ladanyi
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.
Partial Text: Triple negative breast cancer (TNBC) disproportionately affects younger women and women of African ancestry, contributing to health disparities. In the era of personalized cancer therapy, patients with TNBC remain at considerably higher risk of relapse and death than patients with other breast cancer subtypes, due to the aggressive nature of TNBC and the lack of newer targeted therapies [1,2]. TNBC patients typically receive chemotherapy with anthracycline and cyclophosphamide followed by taxane (anthracycline/taxane [ACT]) as standard-of-care treatment. Approximately one-third of patients achieve pathologic complete response (pCR) and have excellent survival, but the remaining patients relapse and eventually die of the disease [3–5]. Identifying those TNBC patients who might benefit from ACT chemotherapy and directing the remaining patients to novel targeted therapies may be an effective strategy with near-term clinical impact for managing TNBC.
We report results from an integrated genomic analysis of a TNBC cohort deliberately selected to represent extremely chemosensitive tumors and tumors highly resistant to standard-of-care ACT chemotherapy. Although no significant associations were identified between recurrent functional somatic mutations in specific genes and chemotherapy response, aggregating at the pathway level revealed that mutations occurring in two pathways, “regulation of androgen receptor activity” and “FOXA1 transcription factor network,” were significantly associated with pCR in TNBC (94% pCR rate in tumors with mutated pathways versus 17% in tumors without such mutations). Furthermore, TNBC patients from the TCGA cohort whose tumors had at least one mutation in the above pathways had excellent survival, with no deaths observed in 4 y when treated with ACT-containing regimens.