Association of Caspase 8 polymorphisms with TILs and disease-free survival in primary breast cancer patients

Background:

The minor allele of two caspase-8 polymorphisms (CASP8 – 652 6N InsDel and CASP8 Asp302His) were shown to promote survival of T-lymphocytes and were associated with reduced breast cancer susceptibility. Clinical relevance of these polymorphisms in patients with already existing primary breast cancer has not been established. Considering an immunomodulatory and tumor-protective role of these caspase-8 variants, we genotyped 785 primary breast cancer patients and correlated caspase-8 variants with i) disease-free survival (DFS) and ii) the presence of tumor infiltrating lymphocytes (TILs).

Methods:

Genotyping was performed by pyrosequencing, TILs status was assessed by hematoxylin and eosin staining.

Results:

The CASP8 – 652 deletion was significantly associated with improved DFS in an allele-dose dependent manner (p = 0.027). Homozygosity for the -652 6N Del variant was an independent predictor for improved DFS (p = 0.005). In patients with a 302His/His genotype, there was no event of recurrence during the entire observation time. Combined analysis of diplotypes revealed an additive influence on DFS (p = 0.029). Interestingly, patients with the 302His/His variant among the unstratified patient cohort and among the luminal-like subtype alone had tumors with very low lymphocyte infiltration (0 – 10% TILs in 65% of cases compared to 31% of cases for other genotypes, p = 0.025).

Conclusion:

We propose a prognostically favorable role of the CASP8 – 652 6N Del and the Asp302His variant in primary breast cancer patients. Moreover, we suggest a role of the Asp302His variant in immunosurveillance and lymphocyte infiltration. Our findings strongly encourage further analyze of these genetic variants as a biomarker for prognostic and immunotherapeutic considerations.