Germline testing of <i>BRCA1</i>, <i>BRCA2</i>, <i>PALB2</i> and <i>CHEK2</i> c.1100delC in 1514 triple negative familial and isolated breast cancers from a single centre, with extended testing of <i>ATM</i>, <i>RAD51C</i> and <i>RAD51D</i> in over 400.

Abstract

The 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. Outcomes of germline <i>BRCA1</i>, <i>BRCA2</i> and <i>CHEK2</i>_c.1100delC testing were recorded in 1514 women (743-isolated, 771-familial), and for <i>PALB2</i> in 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. <i>BRCA1</i>_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), <i>BRCA2</i>_PGVs in 21 (2.8%) isolated and 67 (8.7%) familial cases (isolated-OR=5.0, 95% CI: 2.3 to 11.2), <i>PALB2_</i>PGVs in 9 (1.7%) isolated and 12 (3.9%) familial cases (isolated-OR=8.8, 95% CI: 2.5 to 30.4) and <i>CHEK2_c</i>.1100delC in 0 isolated and 3 (0.45%) familial cases (isolated-OR=0.0, 95% CI: 0.00 to 2.11). <i>BRCA1</i>_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 a <i>BRCA1_</i>PGV as compared with a <i>BRCA2</i> or <i>PALB2</i>_PGV (p<0.0001). 0/743 isolated TNBC had the <i>CHEK2_</i>c.1100delC PGV and 0/305 any <i>ATM</i>_PGV, but 2/240 (0.83%) had a <i>RAD51D</i>_PGV. PGVs in <i>BRCA1</i> are associated with G3_TNBCs. Familial TNBCs and isolated TNBCs <30 years have a >10% likelihood of a PGV in <i>BRCA1. BRCA1</i>_PGVs are associated with younger age of familial TNBC. There was no evidence for any increased risk of TNBC with <i>CHEK2</i> or <i>ATM</i> PGVs.