Germline testing ofBRCA1,BRCA2,PALB2andCHEK2c.1100delC in 1514 triple negative familial and isolated breast cancers from a single centre, with extended testing ofATM,RAD51CandRAD51Din over 400

Abstract

BackgroundThe identification of germline pathogenic gene variants (PGVs) in triple negative breast cancer (TNBC) is important to inform further primary cancer risk reduction and TNBC treatment strategies. We therefore investigated the contribution of breast cancer associated PGVs to familial and isolated invasive TNBC.MethodsOutcomes of germlineBRCA1,BRCA2andCHEK2_c.1100delC testing were recorded in 1514 women (743—isolated, 771—familial), and forPALB2in 846 women (541—isolated, 305—familial), with TNBC and smaller numbers for additional genes. Breast cancer free controls were identified from Predicting Risk Of Cancer At Screening and BRIDGES (Breast cancer RIsk after Diagnostic GEne Sequencing) studies.ResultsBRCA1_PGVs were detected in 52 isolated (7.0%) and 195 (25.3%) familial cases (isolated—OR=58.9, 95% CI: 16.6 to 247.0),BRCA2_PGVs in 21 (2.8%) isolated and 67 (8.7%) familial cases (isolated—OR=5.0, 95% CI: 2.3 to 11.2),PALB2_PGVs in 9 (1.7%) isolated and 12 (3.9%) familial cases (isolated—OR=8.8, 95% CI: 2.5 to 30.4) andCHEK2_c.1100delC in 0 isolated and 3 (0.45%) familial cases (isolated—OR=0.0, 95% CI: 0.00 to 2.11).BRCA1_PGV detection rate was >10% for all familial TNBC age groups and significantly higher for younger diagnoses (familial: <50 years, n=165/538 (30.7%); ≥50 years, n=30/233 (12.9%); p<0.0001). Women with a G3_TNBC were more likely to have aBRCA1_PGV as compared with aBRCA2orPALB2_PGV (p<0.0001). 0/743 isolated TNBC had theCHEK2_c.1100delC PGV and 0/305 anyATM_PGV, but 2/240 (0.83%) had aRAD51D_PGV.ConclusionPGVs inBRCA1are associated with G3_TNBCs. Familial TNBCs and isolated TNBCs <30 years have a >10% likelihood of a PGV inBRCA1. BRCA1_PGVs are associated with younger age of familial TNBC. There was no evidence for any increased risk of TNBC withCHEK2orATMPGVs.