Comprehensive genomic profiling of matched ctDNA and tissue from patients with less common cancers enrolled in but not eligible for a treatment arm of the NCI-MATCH trial.

Abstract

3006 Background: During NCI-MATCH (NCT02465060) clinical trial screening, 5961 advanced cancer patients underwent next-generation sequencing to assess eligibility. About 60% of these patients had less common tumors (i.e., cancers other than colon, rectal, breast, non-small cell lung, or prostate). Most patients lacked a study eligible mutation of interest (MOI) and thus didn’t receive a trial therapy. Analysis of plasma samples from these patients may illuminate circulating tumor DNA (ctDNA) profiles, potentially guiding ctDNA testing for clinically relevant mutations in less common cancer types. Here we report the molecular profiles of ctDNA and matched tumor from a subset of the NCI-MATCH screened patients. Methods: Comprehensive genomic profiling of ctDNA (from blood collected at enrollment) was performed using the TSO500 ctDNA v2 assay (523-genes) and sequenced on the Illumina NovaSeq 6000. Matched tumor was sequenced with the Oncomine Comprehensive Assay v2, a 143-gene panel. Positive percent agreement (PPA) between mutations of interest (MOI) identified in plasma ctDNA and tissue-based screening was calculated with tumor tissue as referent (PPA ref_tumor ). Results: We tested 2253 patients from the less common tumor cohort. 2194 samples were evaluable with 98.6% pass and 1.4% failure rates. A subset of five tumor histologies with larger representation (n > 35) in sample size were further analyzed: cholangiocarcinoma (CCA, n = 90), small cell lung cancer (SCLC, n = 59), adenocarcinoma of the esophagus (EAC, n = 37), adenocarcinoma of the pancreas (PDAC, n = 232), and salivary gland cancer (SGC, n = 47). Overall, PPA ref tumor was 83.4% (range: 76.5%-97.9%) in these five histologies. In patients with concordance < 75%, median tumor fraction (as determined by maximum somatic allele frequency) was much lower (0.37%) than for specimens with concordance > = 75% (6.49%). The most frequently mutated genes identified in CCA were TP53 , KRAS , and IDH1 ; in SCLC were TP53 and RB1 loss; in EAC were TP53 , KRAS, and ERRB2 amplification; in PDAC were TP53 and KRAS ; and in SGC was TP53 . Additionally, there were several clinically relevant mutations detected only in ctDNA such as IDH1 for CCA; and BRAF , TP53 , and PIK3CA in several histologies. Microsatellite instability, as measured only in ctDNA, was most prevalent in SCLC, followed by CCA. Conclusions: Concordance of rare tumors in the NCI-MATCH trial is 83.4% in the representative histologies analyzed, which is similar to concordance of clinically relevant MOIs in common cancer studies. Liquid biopsy may be a viable screening option for matching targeted therapies in clinical trials, especially when a tumor biopsy is not practical or evaluable. The detection of some mutations in ctDNA only may suggest the presence of tumor heterogeneity in multiple lesions in patients with less common cancers.