CLCA2 expression is associated with survival among African American women with triple negative breast cancer

Abstract

Purpose: Black/African American (AA) women are twice as likely to be diagnosed with triple negative breast cancer (TNBC) compared to whites, an aggressive breast cancer subtype associated with poor prognosis. There are no routinely used targeted clinical therapies for TNBC; thus there is a clear need to identify prognostic markers and potential therapeutic targets.

Methods: We evaluated expression of 27,016 genes in 155 treatment-naïve TN tumors from AA women in Detroit. Associations with survival were evaluated using Cox proportional hazards models adjusting for stage and age at diagnosis, and p-values were corrected using a false discovery rate. Our validation sample consisted of 494 TN tumors using four publically available data sets. Meta-analyses were performed using summary statistics from the four validation results.

Results: In the Detroit AA cohort, CLCA2 [Hazard ratio (HR) = 1.56, 95% confidence interval (CI) 1.31-1.86, nominal p = 5.1x10-7, FDR p = 0.014], SPIC [HR = 1.47, 95%CI 1.26-1.73, nominal p = 1.8x10-6, FDR p = 0.022], and MIR4311 [HR = 1.57, 95% CI 1.31-1.92, nominal p = 2.5x10-5, FDR p = 0.022] expression were associated with overall survival. Further adjustment for treatment and breast cancer specific survival analysis did not substantially alter effect estimates. CLCA2 was also associated with increased risk of death in the validation cohorts [HR = 1.14, 95% CI 1.05-1.24, p = 0.038, p-heterogeneity = 0.88].

Conclusions: We identified CLCA2 as a potential prognostic marker for TNBC in AA women.

Fig 1. Kaplan-Meier survival curves by CLCA2, SPIC, and MIR4311 quartile in the Detroit AA cohort.

Kaplan−Meier plots for overall survival by (a) CLCA2 quartile, (b) SPIC quartile, and (c) MIR4311 quartile among 155 treatment-naïve TN tumors (56 deaths) in the Detroit AA cohort. Solid lines represent curves for Q1, dashed lines represent curves for Q2, dotted lines represent curves for Q3, and dash-dotted lines represent curves for Q4 in each panel.

Fig 2. Forest plots for validation cohort analyses of CLCA2, SPIC, and overall survival.

Forest plots for analyses of GSE35629-GPL1390, GSE69031, TCGA, and METABRIC are shown for CLCA2 and SPIC. Only overall, rather than race-specific, analyses are shown because of small sample size (GPL1390, GSE69031) or lack of race data (METABRIC). All estimates are adjusted for age and stage at diagnosis. Study-specific hazard ratios (HR) are denoted by black boxes and 95% confidence intervals (CI) are denoted by corresponding black lines. Box heights are inversely proportional to precision of the HR estimate as influenced by sample size, such that a larger HR box indicates larger sample size and better precision. Summary estimates are denoted as diamonds, where the width of the diamond corresponds to the 95% CI. Estimates with confidence intervals that do not overlap the null line at 1.0 indicate significance at p<0.05.