The relationship between tumor antigenicity and anti-tumor immune responses in breast cancer are poorly understood. Metrics that can accurately predict tumor immunogenic potential could guide therapeutic decisions for breast cancer patients. We examined the relationship between tumor immune subclasses and patient overall survival in the context of the rate of nonsynonymous mutations in breast cancers. These analyses were conducted using RNAseq and exome sequencing data from the Cancer Genome Atlas (TCGA) breast cancer cohort (n=1,098 patients). A previously described tumor-immune classification system, based on the relative abundance of infiltrating effector immune cells, was employed for assigning patients to favorable, weak or poor immunogenic dispositions (FID, WID or PID, respectively). In breast tumors exhibiting low mutation rates (LMR), no significant survival differences were observed among patients comprising the immune subclasses. By contrast, in the context of tumors with high mutation rates (HMR), the immune subclasses exhibited highly significant survival differences (p<0.001). Patients with FID tumors achieved 100% survival at 10 years as compared to those with PID tumors who displayed a 10-year survival rate of 44%. These survival differences were independent of molecular subtype composition, with the majority of the excellent-outcome FID subclass comprising predominantly of Basal-like, HER2-enriched and Luminal B breast tumors. In the smaller subset of HMR Luminal A breast tumors, the immune subclasses also exhibited significantly different survival outcomes (p=0.01), with patients of the poor-outcome Luminal A PID subclass experiencing a 10-year survival rate of 22%. By Cox proportional hazards regression analysis, the immune subclasses contributed significant additive prognostic information in the presence of AJCC stage (p=0.003). A mutation rate of 1.63 mutations per megabase of sequenced DNA was found to be an optimal threshold for distinguishing immune-relevant low and high mutational load. These findings fit a model where mutational burden, reflective of tumor antigenicity, is a major determinant of clinically-relevant breast tumor immunogenicity. This relationship between immunogenic tumor subclasses, overall survival and mutational burden may offer opportunities for therapeutic stratification of breast cancer patients.

Citation Format: Lance D. Miller, Eric D. Routh, Jeff W. Chou, Alexandra Thomas. Protective anti-tumor immune responses in breast cancer depend on tumor mutation rate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4715. doi:10.1158/1538-7445.AM2017-4715