Differential involvement of germline pathogenic variants in breast cancer genes between DCIS and low-grade invasive cancers.

Abstract

To investigate frequency of germline pathogenic variants (PVs) in women with ductal carcinoma in situ (DCIS) and grade 1 invasive breast cancer (G1BC). We undertook <i>BRCA1/2</i> analysis in 311 women with DCIS and 392 with G1BC and extended panel testing (non-<i>BRCA1</i>/<i>2</i>) in 176/311 with DCIS and 156/392 with G1BC. We investigated PV detection by age at diagnosis, Manchester Score (MS), DCIS grade and receptor status. 30/311 (9.6%) with DCIS and 16/392 with G1BC (4.1%) had a <i>BRCA1</i>/<i>2</i> PV (p=0.003), and 24/176-(13.6%) and 7/156-(4.5%), respectively, a non-<i>BRCA1</i>/<i>2</i> PV (p=0.004). Increasing MS was associated with increased likelihood of <i>BRCA1/2</i> PV in both DCIS and G1BC, although the 10% threshold was not predictive for G1GB. 13/32 (40.6%) DCIS and 0/17 with G1BC <40 years had a non-BRCA1/2 PV (p<0.001). 0/16 DCIS G1 had a PV. For G2 and G3 DCIS, PV rates were 10/98 (<i>BRCA1</i>/<i>2</i>) and 9/90 (non-<i>BRCA1</i>/<i>2</i>), and 8/47 (<i>BRCA1</i>/<i>2</i>) and 8/45 (non-<i>BRCA1</i>/<i>2</i>), respectively. 6/9 <i>BRCA1</i> and 3/26 <i>BRCA2</i>-associated DCIS were oestrogen receptor negative-(p=0.003). G1BC population testing showed no increased PV rate (OR=1.16, 95% CI 0.28 to 4.80). DCIS is more likely to be associated with both <i>BRCA1/2</i> and non-<i>BRCA1</i>/<i>2</i> PVs than G1BC. Extended panel testing ought to be offered in young-onset DCIS where PV detection rates are highest.