Abstract
Multiple studies showed the prognostic capacities of tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC), but not in other subtypes. We evaluated tumor expression of FAS, a key receptor in T-cell mediated apoptosis, as possible explanation for this differential prognostic value of TILs. Furthermore, we evaluated the prognostic relevance of FAS, both as an independent biomarker and in relation to CD8-positive T-cell presence. The study cohort consisted of 667 breast cancer patients treated in the LUMC between 1997 and 2009. FAS expression was determined using immunohistochemistry and the percentage of FAS-positive tumor cells was quantified. Furthermore, the number of CD8-positive infiltrating cells was determined, and its prognostic relevance was associated to FAS-expression using stratified survival analysis. In TNBC, FAS was averagely expressed in 49% of tumor cells, whereas ER-positive subtypes showed an average Fas expression of 16-20%. In the entire cohort, FAS was identified as significant prognostic marker for recurrence (adjusted HR 0.53, 95% CI 0.36-0.77) and borderline significant marker for overall survival (adjusted HR 0.72, 95% CI 0.52-1.01). Upon stratification for FAS-expression, CD8+ TILs were only prognostic at high levels (above median) of FAS expression in ER-negative disease. In summary, FAS was identified as an independent prognostic marker for recurrence free survival in breast cancer, with large variation in expression by receptor subtypes. Interestingly, the prognostic effect of CD8+ TILs in ER-negative disease was only valid for tumors with a high FAS expression.
Highlights
For decades the local immune response, among others represented by quantification of tumor-infiltrating lymphocytes (TILs), has been studied in breast cancer [1,2,3]
This study is the first study to determine the influence of the immune-editing protein FAS on the prognostic value of TILs
ER-negative status, a positive FAS-status is required for CD8+ TILs to be prognostic in breast cancer
Summary
For decades the local immune response, among others represented by quantification of tumor-infiltrating lymphocytes (TILs), has been studied in breast cancer [1,2,3]. Most studies observed a prognostic value of TILs, these studies have not resulted in any change in clinical practice. Studies have shown TILs to have strong prognostic impact in ER-negative, HER2-negative and triple negative breast cancer (TNBC), but not in ERpositive tumors [4,5,6,7,8,9,10,11,12,13,14]. In a recent meta-analysis by Ibrahim et al combining the results of 8 studies, a 30%. Reduction in disease recurrences and a 22% decrease in distant recurrences was shown for triple-negative patients www.impactjournals.com/oncotarget
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