BREAST CANCER PHENOTYPE IN TP53 P.R337H CARRIERS DOES NOT DIFFER FROM DNA-BINDING DOMAIN TP53 MUTATIONS

Introduction: Li-Fraumeni Syndrome (LFS) is an autosomal dominant pancancer predisposition syndrome caused byTP53 germline mutations. Breast cancer (BC) is the most prevalent malignancy among female carriers. Early-onset presentation and risk of multiple primary cancers are main features of the syndrome. Due to the presence of a founder mutation in Brazil (TP53 c.1010G>, p.R337H) it is prevalent in 0.3% of the South and Southeastern population. Carriers of the p.R337H variant are at a milder risk of developing most cancers in the LFS spectrum. Nevertheless it is estimated that the risk of BC in p.R337H female carriers remains similar to those with classical LFS. Objetives: We aimed to describe the BC phenotype among Brazilian LFS female carriers. Methods: A personal history of BC and previous identification of TP53 germline mutations were the inclusion criteria for the study. HER2 status was assessed by immunohistochemistry. HER2overexpression was represented by intense cytoplasmic membrane staining in at least 30% of tumour cells (score 3+). BC features were compared among TP53 p.R337H carriers, carriers of other TP53 germline mutations and published data. Results: The present cohort was represented by 72 female carriers of TP53 germline mutations from 65 families. A total of 55 patients (76.4%, 55/72) carried the TP53 p.R337H variant and 17 patients carried other TP53 mutations (23.6%, 17/72). Mutations in the TP53 DNA-binding domain represented 82.3% (14/17) of the non- p.R337H mutations. BC diagnosis occurred mainly between 3145 years in both groups (37/55 vs 11/17, median age 40 vs 34). HER2-enriched tumors represented 41.5% of p.R337H BCs (17/41) compared to 42.8% (6/14) in the other group. Fifty-two percent of patients (38/72) opted to undergo contralateral prophylatic mastectomy after 1stBC diagnosis. In the p.R337H cohort, bilateral BC was observed in 34.6% of the patients (9/26). Thirty-eight percent of p.R337H carriers (21/55 vs 9/17) developed more than one primary cancer. Chompret criteria was observed in52.7% of p.R337H carriers (29/55) versus 59% of other TP53 mutations carriers (10/17). Conclusion: One third of p.R337H female carriers develop a contralateral BC and there is a prevalence of HER2-enriched tumors. BC screening in p.R337H carriers should be similar to other non-p.R337H LFS carriers and prophylactic mastectomy should be discussed. BC phenotype in TP53 p.R337H carriers is similar to other TP53 germline mutations.