Abstract P2-04-19: Elucidating the tumor immune microenvironment phenotype in early stage untreated BRCA mutated breast cancer patients
Authors: Force J , Abbott S , Broadwater G , Kimmick G , Westbrook K , Hwang S , Kauff N , Stashko I , Weinhold K , Nair S , Hyslop T , Blackwell K , Castellar E , Marcom PK 
Published: March 2017

Background: Increased stromal tumor infiltrating lymphocytes (TILs) are predictive and prognostic for improved outcomes from neoadjuvant or adjuvant chemotherapy in triple negative breast cancer. Increased tumor mutational burden may promote neoantigens causing immune system upregulation. Microsatellite instability in gastrointestinal cancer predicts for response to checkpoint inhibition and is associated with inherited cancer predisposition. The immune system response in BRCA mutated breast cancer has not been described. The purpose of this study is to assess tumor infiltrating immune cells in early stage breast cancer patients with and without BRCA gene mutations.

Methods: We retrospectively investigated 124 early stage breast cancer patients with BRCA mutations (n=62, BRCA+) and without BRCA mutations (n=62, BRCA WT). The %TILs was measured manually by H&E. Our control group consisted of age, stage, and receptor status matched early stage untreated breast cancer patients who were deemed BRCA WT by extended gene panel testing or were negative for BRCA 1/2 and had a posttest probability of harboring an autosomal dominant mutated gene of ≤ 1% using the Bayes-Mendel algorithm. We used a two-sample binomial arcsin approximation to detect a 20% difference in TILs between cohorts to attain 80% power with a one-side alpha of 0.05. Wilcoxon Rank-Sums test was used to compare differences in the central tendencies for continuous variables. We used the Nanostring PanCancer immune profiling panel to immunophenotype a portion of the BRCA+ and BRCA WT cohorts and used nSolver for quality control, normalization, and bioinformatics analyses.

Results: Here we report TILs from the first 21 patients of our study. Thirteen patients harbored BRCA mutations and eight patients did not. All patients were HER2 negative. Eight (61%) and four (50%) patients were hormone receptor positive (HR+) in the BRCA+ and BRCA WT cohorts, respectively. Median %TILs were not significantly different between the BRCA+ (15, range 0-70) and BRCA WT (17.5, range 5-60; p=0.7) groups. Median %TILs in the HR+/BRCA+ (12.5, range 0-50) and HR-/BRCA+ (15, range 5-70) cohorts were not statistically different when compared to HR+/BRCA WT (10, range 5-15; p=0.4) and HR-/BRCA WT (30, range 20-60; p=0.2) cohorts, respectively. There were 2 patients with lymphocyte predominant breast cancer (n=1, HR-/BRCA+; n=1, HR-/BRCA WT).

Conclusions: This is the first study to characterize TILs and a tumor immune microenvironment phenotype in early stage breast cancer patients with BRCA mutations. These results suggest harboring a BRCA mutation is not associated with increased TILs in early stage untreated breast cancer patients. This conclusion stayed true regardless of hormone receptor status. However, a trend of decreased TILs was seen in HR-/BRCA+ patients when compared to those with HR-/BRCA WT disease. Moreover, the median and range of TILs were higher in the HR+/BRCA+ group compared to the HR+/BRCA WT group. This suggests increased TILs may exist in some HR+ patients with a BRCA mutation. Further investigation of TILs and immune profiling of early stage untreated breast cancer patients with and without BRCA mutations is warranted.

Citation Format: Force J, Abbott S, Broadwater G, Kimmick G, Westbrook K, Hwang S, Kauff N, Stashko I, Weinhold K, Nair S, Hyslop T, Blackwell K, Castellar E, Marcom PK. Elucidating the tumor immune microenvironment phenotype in early stage untreated BRCA mutated breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-04-19.