Comparing <i>BRCA1/2</i> copy number loss assessment in circulating tumor DNA to tissue in advanced solid cancers.

Abstract

e14545 Background: Next generation sequencing (NGS) identifies genomic alterations in DNA obtained from tissue biopsies and/or blood [circulating tumor (ct)DNA]. We anticipate a lower rate of copy number loss (CNL) in ctDNA compared to tissue, as lower ctDNA tumor fraction may limit the ability to detect a deletion. However, we observed several instances of a CNL in ctDNA that was not identified in a tissue specimen, prompting this systematic evaluation of an institutional dataset. We focused on BRCA1/2 pathogenic variants (PVs) given their therapeutic implications and coverage across testing platforms. Methods: Using an IRB-approved protocol, we evaluated an institutional repository of NGS results performed across the Mayo Clinic Enterprise. We focused on patients (pts) who had both tissue and blood NGS testing performed. We further narrowed this cohort to those with a BRCA1/2 PVs, somatic and/or germline, as determined by testing performed at Guardant Health, Tempus, or Foundation Medicine. We abstracted information about each variant, including type of alteration classification and functional impact. Demographic information, cancer characteristics, and germline testing information was collected. Fisher’s exact test was used to compare alteration frequencies in ctDNA vs tissue using GraphPad Prism v 10.1. Results: From Dec 2015-Sept 2024, we identified 158 unique pts with BRCA1/2 PV who had NGS results for both tissue and ctDNA. The median age at first reporting BRCA1/2 variant was 67 years (range: 29-98 years). 48% of pts were female, and the most common cancer type sites were lung (23%), colorectal (20%), and pancreaticobiliary (20%). We identified 198 unique pathogenic genomic alterations; 71 in BRCA1 &amp; 127 in BRCA2 . Most common alteration was an SNV or indel (127/198), followed by CNL (n = 63), splice site variants (n = 5), fusions (n = 2), and rearrangements (n = 1). Of the 126 SNV or indels, 50 (39.7%) were identified in both ctDNA and tissue, 40 (31.7%) were detected in blood only, 36 (28.6%) identified only in tissue (p &lt; 0.0001). Amongst the 63 CNL, only 3 (4.8%) were identified in both ctDNA and tissue; 41(65.1%) were only identified in ctDNA, and 19 (30.2%) in tissue only (p &lt; 0.0001). In the 19 tissue-only CNL tests, 12/19 noted one or more additional pathogenic SNV/Indel in BRCA1/2. In the 41 ctDNA-only CNL tests, 1/41 noted one or more additional pathogenic SNV/Indel in BRCA 1/2 . Germline testing was available in 41/63 pts with copy number loss. 3/41 deletions were identified in germline (2 in ctDNA, 1 in tissue). Conclusions: We observed a low degree of concordance in CNL between tissue and ctDNA for BRCA1/2 . CNL detection in ctDNA that could not be confirmed in germline or with a second alteration warrants further attention. In particular, clinicians should be cautioned when interpreting ctDNA reports noting BRCA1/2 CNL without clarity if this represents biallelic loss or a synchronous loss of function.