Abstract P4-07-01: DNA repair deficiency enhances immune response and correlates with excellent clinical outcome in triple negative breast cancer
Authors: Jiang T , Safonov A , Bianchini G , Shi W , Wali VB , Pusztai L , Hatzis C 
Published: May 2016

Abstract
Background: Mutations or epigenetic silencing of BRCA1/2 genes result in DNA repair deficiency in a large proportion of TNBC cases. Yet it is unclear whether this deficiency is associated with increased chemosensitivity and improved benefit from standard-of-care chemotherapy. We systematically evaluated BRCA deficiency in TNBC using integrated DNA and RNA sequencing data and its association clinical outcome, exploring the potential role of tumor immune response.
Patients and Methods: Whole-exome, DNA methylation, copy number variation, and RNA sequencing data from 102 stage I-III TNBCs were retrieved from The Cancer Genome Atlas (TCGA). Almost all patients received adjuvant taxane-anthracycline-cyclophosphamide (T-AC) chemotherapy and had &gt;30 days of follow-up. The number of predicted neoantigens and an estimate of the level of immune cell activity for 77 of these tumors were previously published. Deleterious germline or somatic BRCA1/2 mutations were identified by majority voting on predictions of 5 variant scoring algorithms. Definition of BRCA1/2 deficiency (BRCA-D) included carrier of deleterious BRCA1/2 mutations or BRACA1/2 normal (BRCA-N) with wild type BRCA1/2 expression less than the maximum observed in mutation carriers. Normalized genomic mutation rate and mutant allele tumor heterogeneity (MATH) were computed as broad measures of genomic instability. Characteristics of BRCA-D vs N tumors were compared using the Wilcoxon rank test.
Results: Twenty tumors (19.6%) had mutations in BRCA1, 6 (5.8%) in BRCA2, and 2 (1.9%) in both. Based on the expanded definition, 39 cases (38%) were characterized as BRCA1 deficient, 5 (4.9%) as BRCA2 deficient and 4 (3.9%) as deficient in both. BRCA-D tumors (47%) were associated with a significantly higher mutation rate (P=8x10-4) but had similar clonal heterogeneity (P=0.55) as BRCA-N tumors. BRCA-D tumors had excellent 4-year overall survival (100%) compared to 79.5% (95%CI: 66.6- 94.9) for BRCA-N tumors (log-rank P=0.02). BRCA-D tumors also presented a significantly higher number of predicted neoantigents (P=0.003), which resulted in increased level of immune cell activity. In contrast, low immunogenic TNBC tumors were underrepresented in BRCA-D (p=0.05) and showed potential signs of immunoediting (observed/expected number of predicted neoantigens &lt; 1; p=0.07).
Conclusions: Deleterious mutations in BRCA1/2 genes occur in 25% of TNBC tumors, but parallel quantification of wild-type BRCA1/2 expression identifies 47% of TNBC samples with double strand break DNA repair deficiency. These BRCA-D TNBC tumors are characterized by a significantly higher mutation rate and present a significantly greater number of neoantigens that result in increased immune cell activity. Our analysis suggested that enhanced immune activation could explain to a large extent the excellent clinical outcome in patients with BRCA-D tumors treated with standard-of-care T-AC chemotherapy.
Citation Format: Jiang T, Safonov A, Bianchini G, Shi W, Wali VB, Pusztai L, Hatzis C. DNA repair deficiency enhances immune response and correlates with excellent clinical outcome in triple negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-07-01.