Breast cancer multigene germline panel testing in mainstream oncology based on clinical-public health utility (cancer mortality benefit): ESMO Precision Oncology Working Group recommendations
Authors: Turnbull C. , Achatz M.I. , Balmaña J. , Castro E. , Curigliano G. , Cybulski C. , Domchek S.M. , Evans D.G. , Hanson H. , Hoogerbrugge N. , James P.A. , Krause A. , Nathanson K. L. , Yie J. Ngeow Yuen , Robson M. , Tischkowitz M. , Westphalen B. , Foulkes W.D. 
Published: February 2025

Background

With 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.

Methods

ESMO’s 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).

Results

The 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, RAD51DandTP53(for BC diagnosed <40 years), withBRIP1later added. Whilst potentially informative for BC risk estimation,CHEK2andATMwere judged to offer insufficient evidence for improving cancer-specific mortality. The expert group recommended strongly against inclusion of ‘syndromic’ genes such asSTK11, PTEN, NF1andCDH1.

Conclusion

With 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).

Highlights

ESMO expert panel settled a list of genes for inclusion on a BC-MGPT based on potential cancer-specific mortality benefit

This BC-MGPT should include 7 genes:BRCA1, BRCA2, PALB2, RAD51C, RAD51D, BRIP1andTP53(for BC diagnosed <40 years)

This BC-MGPT would service urgent diagnostic mainstreaming germline testing requirements for all eligible BC cases

‘Syndromic’ genes such asSTK11, PTEN, NF1andCDH1should only be tested downstream post expert review in a minority of BC

The mortality benefit was deemed equivocal forATMandCHEK2, being primarily of intermediate penetrance for ER-positive BC