Abstract P6-09-03: 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, namely CASP8 -652 6N InsDel and CASP8 Asp302His, were shown to promote survival of T-lymphocytes and were repeatedly associated with reduced breast cancer susceptibility. However, besides some preliminary findings, clinical relevance of these polymorphisms in patients with already existing primary breast cancer has not yet been established. Considering an immunomodulatory and potentially 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: Primary breast cancer samples were collected at the Martin-Luther University, Halle-Wittenberg between 2009 and 2011 as part of the multicenter prospective PiA trial (NCT 01592825). The majority of patients had luminal-like tumors (75.9%), followed by triple negative (10.1%), luminal-Her2-like (9.6%) and Her2-enriched tumors (4.5%). 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 that both polymorphisms had an 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: In line with previous epidemiological findings, we propose a prognostically favorable role of the CASP8 -652 6N Del and the Asp302His variant in primary breast cancer patients. Moreover, we suggest for the first time a role of the Asp302His variant in immunosurveillance and lymphocyte infiltration of breast cancer. Our findings strongly encourage further analyze of these genetic variants as a biomarker for prognostic and immunotherapeutic considerations. Citation Format: Wimberger P, Bachmann HS, Kuhlmann JD, Link T, Krober E, Thomssen C, Malle B, Vetter M, Kantelhardt EJ. Association of Caspase 8 polymorphisms with TILs and disease-free survival in primary breast cancer patients [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-09-03.