Avaliação epidemiológica, de características e desfechos clínicos e modalidades terapêuticas em pacientes câncer de mama e ovário portadoras de variantes genéticas

Abstract

INTRODUCTION: Knowledge about the germline mutational spectrum among Brazilians patients with hereditary breast (BC) and/or ovarian (OC) cancer (HBOC) caused by high- and moderate penetrance genes is limited, as well as their epidemiological characteristics, therapeutic/preventive strategies access and clinical outcomes. OBJECTIVES: To describe pathogenic (PV), likely pathogenic (LPV) variants and variants of uncertain significance (VUS) pattern of HBOC syndrome related genes, and clinical-epidemiological characteristics and outcomes in a cohort of affected patients. MATERIAL AND METHODS: This is a retrospective observational cohort. Professionals from four oncology clinics and one philanthropic hospital located in Minas Gerais, a state southeast of Brazil, were invited to include patients diagnosed with BC or OC, previously identified with a PV/LPV/VUS in BRCA1, BRCA2, CHEK2, ATM, PALB2, BARD1, RAD51C, RAD51D, PTEN, NF1, TP53, MSH6, CDH1, RECQL or FANCC genes. Patients were invited to participate in the study, and those who accepted should sign an informed consent form (ICF). Pathology reports, medical record data were analyzed, and available patients were interviewed for clinical and epidemiological data. RESULTS: A total of 144 patients were evaluated, of whom 85 signed the ICF form. 19 patients had not been diagnosed with breast or ovarian cancer and were excluded. A total of 66 patients were included in this analysis, 61 who consented and 5 patients who had died, scenario were ICF was waived by the IRB. Forty-three patients with BC and an PV/LPV underwent primary breast surgery and 22 of them (51.1%) were aware of the genetic test result at the time of the surgery and 15 (68.2%) of them underwent bilateral surgery. In the group who wasn’t aware of the genetic test result, only one (4.7%) underwent bilateral mastectomy, (p<0.001). The median time from diagnosis to genetic testing was 0.4 years in patients diagnoses before 2015 and it was 7.9 years when diagnosis was after this date (p<0,001). A total of 85 variants were found, 51 PV/LPV and 34 VUS. Four (6%) patients were diagnosed with OC and 62 (94%) with BC. 19 PV/LPV were found in BRCA1, 13 in BRCA2, 6 in TP53, 4 in ATM, 4 in PALB2. Other PV/LPV were found in CHEK2(2), RAD51C and PTEN. One of the patients with a LPV in TP53 had a PV in MUTYH. The most commonly found variant was c.2T>G (p.Met1Arg) of BRCA2, present in 4 unrelated patients with BC A comparison between the classifications found in the patients’ test reports and the ClinVar and VarSome in May/2023 was made. Only 49.4% of the variant classifications (42 of 85 variants reported) showed complete agreement between the reports, ClinVar and VarSome Thirty-eight patients of this cohort (57.5%) had access to genetic counseling, compared to only 3 out of 18 (16%) from the philanthropic hospital. CONCLUSION: To our knowledge, this is the second largest study identifying patients with PV/LPV/VUS in the state of Minas Gerais and one of the largest in Brazil. The study also shows a significant delay in the test result and limited access to genetic counseling, which possibly has influenced on the high rate or conservative surgery. There is a great need to expand hereditary cancer testing and counseling in Brazil. Understanding Brazilian´s unique social and structural barriers is needed to attain a significant impact.