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

Abstract

While the likelihood of identifying constitutional breast cancer-associated <i>BRCA1</i>, <i>BRCA2</i> and <i>TP53</i> pathogenic variants (PVs) increases with earlier diagnosis age, little is known about the correlation with age at diagnosis in other predisposition genes. Here, we assessed the contribution of known breast cancer-associated genes to very early onset disease. Sequencing of <i>BRCA1</i>, <i>BRCA2, TP53</i> and <i>CHEK2</i> c.1100delC was undertaken in women with breast cancer diagnosed ≤30 years. Those testing negative were screened for PVs in a minimum of eight additional breast cancer-associated genes. Rates of PVs were compared with cases ≤30 years from the Prospective study of Outcomes in Sporadic vs Hereditary breast cancer (POSH) study. Testing 379 women with breast cancer aged ≤30 years identified 75 PVs (19.7%) in <i>BRCA1</i>, 35 (9.2%) in <i>BRCA2</i>, 22 (5.8%) in <i>TP53</i> and 2 (0.5%) <i>CHEK2</i> c.1100delC. Extended screening of 184 PV negative women only identified eight additional actionable PVs. <i>BRCA1/2</i> PVs were more common in women aged 26-30 years than in younger women (p=0.0083) although the younger age group had rates more similar to those in the POSH cohort. Out of 26 women with ductal carcinoma <i>in situ</i> (DCIS) alone, most were high-grade and 11/26 (42.3%) had a PV (<i>TP53</i>=6, <i>BRCA2</i>=2, <i>BRCA1</i>=2, <i>PALB2</i>=1). This PV yield is similar to the 61 (48.8%) <i>BRCA1/2</i> PVs identified in 125 women with triple-negative breast cancer. The POSH cohort specifically excluded pure DCIS which may explain lower <i>TP53</i> PV rates in this group (1.7%). The rates of <i>BRCA1</i>, <i>BRCA2</i> and <i>TP53</i> PVs are high in very early onset breast cancer, with limited benefit from testing of additional breast cancer-associated genes.