Breast cancer multigene germline panel testing in mainstream oncology based on clinical-public health utility (cancer mortality benefit): ESMO Precision Oncology Working Group recommendations

BackgroundWith widening therapeutic indications, germline genetic testing is offered to an increasing proportion of patients with breast cancer (BC) via mainstream oncology services. However, the gene set tested varies widely from just BRCA1/BRCA2 through to pan-cancer panels of near 100 genes. If a germline pathogenic variant (GPV) is detected, the BC proband and other family GPV-carriers may be offered interventions such as risk-reducing surgery and decades of intensive surveillance for the various cancers linked to that gene. MethodsESMOs Precision Oncology Working Group established an international expert group in breast cancer germline genetics. This group firstly established a framework of criteria by which to evaluate each breast cancer susceptibility gene (BCSG) for inclusion on a breast cancer multigene panel test (BC-MGPT) for universal mainstream testing for BC cases. Next the panel scored BCSGs for gene utility regarding (i) BC risk estimation, (ii) clinical actionability (iii) evidence of impact on cancer-specific mortality (and/or morbidity). ResultsThe group agreed genes should be included on the BC-MGPT based on potential cancer-specific mortality (and/or morbidity) benefit. Judged as of high or moderate utility on this basis were 7 genes: BRCA1, BRCA2, PALB2, RAD51C, RAD51D and TP53 (for BC diagnosed <40 years), with BRIP1 later added. Whilst potentially informative for BC risk estimation, CHEK2 and ATM were judged to offer insufficient evidence for improving cancer-specific mortality. The expert group recommended strongly against inclusion of syndromic genes such as STK11, PTEN, NF1 and CDH1. ConclusionWith expanded germline testing in patients with BC (and cascade testing into families), the number and nature of resultant GPV carriers identified will be dictated by the genes included on the upfront BC-MGPT. The potential harms, opportunity and economic costs of decades of surveillance of multiple organs and risk-reducing surgeries should be outweighed by strong evidence of meaningful benefit, improved cancer-specific mortality (and/or morbidity). HighlightsO_LIESMO expert panel settled a list of genes for inclusion on a BC-MGPT based on potential cancer-specific mortality benefit C_LIO_LIThis BC-MGPT should include 7 genes: BRCA1, BRCA2, PALB2, RAD51C, RAD51D, BRIP1 and TP53 (for BC diagnosed <40 years) C_LIO_LIThis BC-MGPT would service urgent diagnostic mainstreaming germline testing requirements for all eligible BC cases C_LIO_LI Syndromic genes such as STK11, PTEN, NF1 and CDH1 should only be tested downstream post expert review in a minority of BC C_LIO_LIThe mortality benefit was deemed equivocal for ATM and CHEK2, being primarily of intermediate penetrance for ER-positive BC C_LI