Genetic mediators of tumor-infiltrating lymphocytes associated with survival among African American women with triple-negative breast cancer

Abstract

Introduction: Tumor-infiltrating lymphocytes (TILs) are favorably associated with patient prognosis, particularly in the aggressive triple-negative breast cancer (TNBC) subtype. Among patients diagnosed with TNBC, racial/ethnic disparities persist, where black women suffer from higher incidence and poorer survival outcomes compared to their white or Hispanic counterparts. We profiled the pathological characteristics of tumor-infiltrating lymphocytes (TILs) and molecular characteristics of tumors among black women diagnosed with TNBC. Patients and Methods: Using the Metropolitan Detroit Cancer Surveillance System, we identified black women diagnosed with invasive primary TNBC who were treated with surgery between 2004 and 2015. Gene expression profiling of TNBC tissue and mediation analysis were used to evaluate genetic mediators of the association between TILs and survival. Results: Among sixty black patients with invasive primary TNBC, TILs were found to be significantly associated with mean age of diagnosis and favorable survival outcomes, where moderate and high TILs were associated with a 70-85% reduction in the hazard of death compared to no TILs [1-10%TILs Hazard Ratio (HR)=0.28, 95% Confidence Interval (CI) 0.09-0.84, p=0.023; >10% TILs HR=0.17, 95% CI 0.05-0.62, 7.1x10-3]. Mediation analysis for 524 transcript probes identified twenty probes that significantly mediated this association (p<0.05), of which sixteen probes also demonstrated a significant direct effect on TILs and survival (SRGAP2, GOLGA8S, PRSS50, YME1L1, PHC1, IGKV4-1, IL15RA, PAX6, IGK, IGKC, FAM90A1, TRIM64C, LOC100130502, TAP2, IGHV1-3, IGLV3-27) in TNBC. Conclusions: TILs are significantly associated with favorable survival outcomes among black women diagnosed with TNBC. Interleukin receptors and immunoglobulins are among the genes with significant mediation and direct effects on TILs and survival in TNBC for black women, and further studies to establish a gene signature that mediates the TIL-survival association can contribute to development of novel TNBC prognostic markers in the black population.