Routine germline genetic testing in 3552 unselected NHS breast cancer patients: Evidence informing testing criteria and implementation of a 'BRCA-DIRECT' mainstreaming pathway

BackgroundBreast cancer susceptibility gene testing (BCSG-testing) is expanding in relation to both eligibility for testing and number of genes included on testing panels. However, uncertainty remains regarding the most effective testing strategies for identifying clinically actionable germline pathogenic variants (gPVs) while balancing increased burden on breast and genetics clinical services. Patients and MethodsThe North Thames Mainstreaming of Breast Cancer Genetic Testing (NT-MBGT) programme piloted unselected breast cancer (BC) patient BCSG-testing via a clinician-light BRCA-DIRECT mainstreaming pathway. We present real-world evaluation of (i) gPV pick-up rates according to BC characteristics and (ii) operational feasibility, acceptability, and satisfaction with the BRCA-DIRECT expanded testing pathway. ResultsThe BRCA-DIRECT pathway successfully tested 3,517 newly-diagnosed BC patients within 14 National Health Service (NHS) breast oncology units, with high levels of patient and breast healthcare professional (HCP) satisfaction, and genetics HCPs reporting concomitant decrease in service referrals. The overall pick-up rate of gPVs was 4.7%. Current NHS eligibility criteria would have offered testing to 20.6% of patients and identified 49.2% of observed gPVs in high penetrance (HP)-BCSGs (BRCA1/BRCA2/PALB2) and 18.2% of gPVs in intermediate penetrance (IP)-BCSGs (CHEK2/ATM/RAD51C/RAD51D). Ultra-simple eligibility criteria could improve detection (sensitivity) to 74.6% and 61.4%, respectively, whilst increasing testing to 50.2% of BC cases. ConclusionsEvidence from the NT-MBGT programme demonstrates that expanding BCSG-testing via a clinician-light pathway is acceptable and feasible, without increasing the burden on limited breast and genetics workforce, and has high satisfaction. Simplified testing criteria could improve identification of gPVs in HP-BCSGs. The concomitant increased pick-up of gPVs in IP-BCSGs warrants further consideration. highlightsO_LIIn this real-world evaluation we observed the successful rollout of the BRCA-DIRECT streamlined, clinician-light mainstreaming pathway for a pilot of germline breast cancer susceptibility gene testing in 3517 unselected breast cancer patients from 14 regional breast oncology/surgical units. C_LIO_LIPatients undergoing testing via the pathway reported high levels of satisfaction and low decisional regret, with breast and genetics healthcare professionals highly recommending the pathway for mainstream testing. C_LIO_LIDifferences were observed between breast healthcare professionals preferring unselected breast cancer patient testing and genetics healthcare professionals preferring restriction to current national testing criteria due to broader concerns around equity of access to testing. C_LIO_LIWe identified that current national testing criteria would have missed identifying 50.8% of germline pathogenic variants in high-penetrance, clinically actionable genes, likely having implications for treatment and surgical decision-making in the breast cancer patients. C_LIO_LIWe evaluated the performance of two additional approaches for establishing testing eligibility criteria to understand how we could best balance maximising identification of germline pathogenic variants (sensitivity) whilst limiting (unnecessary) testing within the breast cancer patient population (specificity). C_LI