High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer

Background: while the likelihood of identifyingconstitutional breast cancer-associated BRCA1, BRCA2and TP53 pathogenic variants (PVs) increases with earlierdiagnosis age, little is known about the correlation withage at diagnosis in other predisposition genes. Here,we assessed the contribution of known breast cancerassociated genes to very early onset disease.Methods: sequencing of BRCA1, BRCA2, TP53 andCHEK2 c.1100delC was undertaken in women withbreast cancer diagnosed ≤30 years. Those testingnegative were screened for PVs in a minimum of eightadditional breast cancer-associated genes. Rates ofPVs were compared with cases ≤30 years from theProspective study of Outcomes in Sporadic vs Hereditarybreast cancer (POSH) study.Results: testing 379 women with breast cancer aged≤30 years identified 75 PVs (19.7%) in BRCA1, 35(9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%)CHEK2 c.1100delC. Extended screening of 184 PVnegative women only identified eight additionalactionable PVs. BRCA1/2 PVs were more common inwomen aged 26–30 years than in younger women(p=0.0083) although the younger age group had ratesmore similar to those in the POSH cohort. Out of 26women with ductal carcinoma in situ (DCIS) alone,most were high-grade and 11/26 (42.3%) had a PV(TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yieldis similar to the 61 (48.8%) BRCA1/2 PVs identified in125 women with triple-negative breast cancer. The POSHcohort specifically excluded pure DCIS which may explainlower TP53 PV rates in this group (1.7%).Conclusion: the rates of BRCA1, BRCA2 and TP53PVs are high in very early onset breast cancer, withlimited benefit from testing of additional breast cancerassociated genes