Abstract LB-A07: Clinical utility of genomic assessment of blood-derived circulating tumor (ctDNA) in patients with colorectal cancers

Abstract

Abstract Background: Genomic alterations in blood-derived circulating tumor DNA (ctDNA) from patients with colorectal cancers (CRC) were correlated with clinical characteristics and therapeutic outcomes. Methods: Plasma ctDNA testing (54-73 genes; all non-synonymous alterations are analyzed herein) was performed in 94 patients with CRC (PREDICT-UCSD; NCT02478931). Results: Ninety-six percent of patients had metastatic or recurrent disease at the time of blood draw. The median number of alterations/patient was 3 (range, 0-30). The most frequent alterations involved TP53 (52.1%), KRAS (34%), and APC (28.7%) genes; no two patients had identical molecular portfolios. Altogether, 74 patients (79%) had ≥ 1 alteration; 69 patients (93% of patients with ≥ 1 detectable ctDNA alteration) had ≥ 1 actionable alteration; 61 patients had an alteration actionable by an FDA-approved drug (on or off-label). Concordance between ctDNA and tissue genomics for the most frequent genes altered in ctDNA ranged from 63% to 86%, depending on the gene (median ~6 months between samples). Improved survival (multivariate) correlated with lung metastasis and with all ctDNA alteration fractions < 5%. To date, 35 patients (median of one prior therapy in the metastatic setting) were treated with matched (N = 18) or unmatched (N = 17) therapy after ctDNA testing. Overall, 67% versus 27% of patients (matched vs unmatched) achieved SD ≥ 6 months/PR/CR (P=0.02); PFS of 6.1 vs 2.3 months (P = 0.08); OS (13.2 vs 5.1 months; not significant) (all multivariable). In serial samples from patients on anti-EGFR therapy, multiple emerging alterations in genes known to be involved in therapeutic resistance, including KRAS, NRAS, BRAF, EGFR, ERBB2, and MET were detected. Conclusion: Most patients demonstrated potentially actionable ctDNA alterations. Improved outcomes were associated with lung metastases and low ctDNA percentage. Treatment with matched therapy correlated with significantly higher rates of SD ≥ 6 months/PR/CR (67% vs 27%). Dynamic changes in ctDNA were evident after anti-EGFR treatment, with emergence of resistance mutations, some of which may be druggable. Larger studies in CRC and other malignancies are ongoing. Citation Format: Maria C. Schwaederle, Shumei Kato, In Sil Choi, Paul T. Fanta, Lawrence Leichman, Scott Lippman, Razelle Kurzrock. Clinical utility of genomic assessment of blood-derived circulating tumor (ctDNA) in patients with colorectal cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-A07.