Genetic counselling, testing and management of hereditary breast cancer in South Africa

Abstract

Breast cancer (BC) is common in South Africa (SA), with some cases due to a pathogenic or likely pathogenic (P/LP) variant in a BC susceptibility gene. Data on hereditary BC testing and management in SA remains limited. The aim of this study was to assess the prevalence of P/LP variants and variants of uncertain significance (VUS) in BC genes in SA populations with BC, and to investigate genetic counselling and testing (GCT) and the subsequent clinical management pathway in BC probands and their family members. The study was based on records and sequence data from 534 BC patients who attended GCT in the Western Cape and 115 of their relatives, and on 272 Black SA women with BC aged ≤50 recruited by the Johannesburg Cancer Study (JCS). P/LP prevalence was 18.1% in BC probands from the GCT group who had gene panel testing at Invitae Laboratory in the USA, and similar across ancestry groups. Broadening the gene test panel from 9 to 84 genes yielded few additional actionable variants but many more VUS which had a higher prevalence in the Black and Mixed ancestry participants. Of 611 VUS detected, 27% could be reclassified using frequency data from African genomes. P/LP variant prevalence in a population study of Black African women from the JCS aged ≤50 years with BC was 10.3%. The SA National Department of Health (NDOH) testing guidelines were evaluated in 376 participants who met criteria, with P/LP detection rates calculated and multivariate analysis used to identify criteria most strongly associated with P/LP detection. P/LP prevalence was 19.9%, with higher detection in those meeting ≥2 criteria. Family history and Black African ancestry were associated with P/LP variants in BRCA1/2. The uptake of genetic testing and risk-reducing measures, and factors influencing test uptake were examined in probands and family members from the GCT study. Test uptake was high in probands but much lower in family members, where it was associated with proband family history, being female, and being a first-degree relative. Risk-reducing mastectomy was the most accepted intervention. The outcomes from this study have implications for future testing strategy and clinical management in the SA population. Restricting testing to genes associated with BC will vii optimise the detection of clinically relevant variants and minimize uncertain results. African genomic data has the potential to resolve a significant proportion of VUS. The population study of Black women with BC indicates a substantial prevalence of P/LP variants in women diagnosed ≤ 50 years. The assessment of the NDOH guidelines demonstrated its usefulness in women of diverse ancestries. Limited uptake of cascade testing and variable uptake of risk- reducing options reduced the potential impact of the GCT program.