Cancer cell-intrinsic and immunological phenotypes determine clinical outcomes in basal-like breast cancer

Purpose: Basal-like breast cancer (BLBC) is an aggressive molecular subtype of breast cancer that lacks targeted therapies and clinically useful tests to risk-stratify patients. We hypothesized that a transcriptome-based phenotypic characterization of BLBC tumors and their microenvironments may overcome this challenge. Experimental Design: We conducted a retrospective correlative genomic sequencing study using a matched-pairs design with validation in five independent cohorts. The study was conducted on a large population-based prospective cohort of the major molecular subtypes of breast cancer conducted in the greater Seattle-Puget Sound area identified through the population-based SEER program. Patients for this analysis (n=949) were identified from the 1408 patients with stage I-III triple-negative breast cancer. A matched set of 67 recurrent and non-recurrent BLBC tumors was subjected to transcriptome sequencing. Results: Through RNA-sequencing and statistical-learning techniques, we found that cancer-cell intrinsic and immunological phenotypes are independent predictors of recurrence in BLBC. By simultaneously interrogating the tumor and its microenvironment, we developed a compound risk model (BRAVO-DX) that stratified patients into low-, medium-, and high-risk groups. Non-recurrent tumors showed high lymphocyte infiltration with clonal expansion of T- and B-cells. We validated our model in five independent cohorts, including three large cohorts where it was informative in identifying patients with recurrence (HR 6.79 [95%CI 1.89-24.37], HR 3.45 [95%CI 2.41-4.93], HR 1.69 [95%CI 1.17-2.46]). Conclusions: These results indicate that phenotypic characteristics of BLBCs and their microenvironment are associated with recurrence-free survival and demonstrate the utility of intrinsic and extrinsic phenotypes as independent prognostic biomarkers in BLBC.