Characteristics of breast cancer in Slovenian patients with germline CHEK2 c.444+1G>A mutation.

Abstract

e13536 Background: Different CHEK2 germline pathogenic variants/likely pathogenic variants (PV/LPV) are associated with distinct immunophenotypic molecular subtypes of breast cancer (BC). The aim of our study was to explore the characteristics of Slovenian BC patients with CHEK2 c.444+1G > A variant. Methods: Germline CHEK2 pathogenic PV/LPV were identified in 76 individuals from 50 families who underwent genetic counseling and testing using a multigene panel at our institution from year 2014 to 2019. The data on 41 Slovenian BC patients with CHEK2 PV/LPV were retrospectively collected and analyzed, with an emphasis on c.444+1G > A variant carriers. Results: BC in our CHEK2 positive patients was diagnosed in 40 females and one male. Mean age at BC diagnosis was 42.8 years (range 21-63). Four recurrent CHEK2 PV/LPV were found in 80% (33/41) of our BC patients: c.444+1G > A (12/41; 29%; 11 females, one male), c.349A > G (9/41; 22%). deletion of exons 9-10 (7/41; 17%) and c.1100delC (5/41; 12%). There was a trend for c.444+1G > A carriers to develop BC at younger age in comparison to patients with other CHEK2 PV/LPV (mean age 39.3 vs. 44.2 years; p = 0.089). None of the patients with the c.444+1G > A variant had invasive lobular carcinoma. Median tumor size in patients with c.444+1G > A variant was 34 mm and median number of positive lymph nodes was 2.67 (range 1-8). Patients with c.444+1G > A variant had a luminal A subtype in 2 cases, luminal B in 7 cases, HER2+ subtype in 3 cases, while none of patients had a triple negative BC. Mastectomy, tumorectomy and axillary lymphadenectomy was performed in 8, 4 and 12 patients, respectively. All c.444+1G > A carriers had to be treated with chemotherapy and external beam irradiation. Patients with the c.444+1G > A variant were more often treated with chemotherapy (p = 0.038) and/or external beam irradiation (p = 0.014) in comparison to patients with other PV/LPV. Distant metastases were diagnosed in two patients at age 45 and 47. Conclusions: Mutation c.444+1G > A was detected in 29% of Slovenian patients with CHEK2 PV/LPV. Distant dissemination was diagnosed despite aggressive treatment at a young age in 16% of these patients.