Mesothelin Expression As A Predictive Biomarker of Breast Cancer Outcomes

11119 Background: Mesothelin, previously-shown to be expressed in triple negative breast cancer (TNBC) tumors, is a potential therapeutic target and prognostic marker in breast cancer. Methods: We analyzed clinical data from two cohorts: a 141 patient-cohort treated between 2009 and 2011 at the UPHS (discovery) and the 844 patient-cohort from The Cancer Genome Atlas (TCGA) (validation). Mesothelin expression was quantified by immunohistochemistry (IHC) (discovery) or RNA transcript levels by whole-transcriptome sequencing (validation). Results: Median follow up for our discovery cohort was 3.54 years. Univariate analyses demonstrated that tumor size (HR=1.30, 95% CI 1.115-1.515, p < 4.58 x10-4), number of positive axillary lymph nodes (HR=1.131; 95% CI 1.06-1.21; p-value < 9.20 x10-5), tumor stage (HR (Grade III to I) = 21.294, 95% CI 2.69-168.69, p < 3.40 x10-5), at least one lymph node removed (HR=1.07, 95% CI 1.021-1.116, p< 2.45 x10-3), and most importantly, mesothelin expression (HR= 2.377; 95% CI 1.12-5.02; p < 3.01 x10-3) were associated with both overall and disease-specific survival. We used a Cox-proportional hazard (Cox-PH) model to adjust for the only other independent predictors of survival, namely axillary lymph nodes involved and tumor size, and stratifying by African American race, we found a significant association between mesothelin expression and overall and disease-specific survival in the discovery cohort (HR = 3.138, 85% CI 1.38-7.10, p < 6.14 x10-3). Using the TCGA dataset, we confirmed that, over a median follow-up of 16.0months, patients with mesothelin-expressing tumors had poorer overall survival (HR=1.463; 95% CI 1.053-2.033; p<0.021). On Cox-PH analysis, mesothelin-positivity was independently predictive of poorer survival, after adjusting for the number of involved axillary lymph nodes and tumor size (HR = 1.688; 95% CI 1.174-2.425; p<4.67x10-3). Conclusions: Our results suggest that mesothelin is a prognostic breast tumor marker and that its expression in a large proportion in TNBC holds promise that existing targeted therapy directed against mesothelin may be effective for the treatment of TNBC. Further work is needed to elucidate the mechanistic role of mesothelin in breast cancer.