Abstract 709: The utility of plasma ctDNA for detection of KRAS G12C and other mutations in lung cancers
Authors: Murciano-Goroff Yonina R. , Arbour Kathryn C. , Offin Michael D. , Tu Hai-Yan Y. , Lebow Emily S. , Shaffer Tristan S. , Bertucci Caterina , Hosseini Syed A. , Garg Kavita , Lim Lee P. , Li Mark , Chang Jason C. , Reis-Filho Jorge S. , Razavi Pedram , Isbell James M. , Riely Gregory J. , Hyman David M. , Lito Piro , Li Bob T. 
Published: September 2020

Abstract
Background: KRAS is the most common oncogene in lung cancer, but has historically been considered undruggable. The recent development of mutant-selective KRAS G12C inhibitors has for the first time created potential therapeutic opportunities for this unmet need. Simultaneously, circulating tumor DNA (ctDNA) is increasingly being used to detect targetable oncogenes in patients with metastatic lung cancers. There is limited data regarding the utility of plasma ctDNA in specifically identifying KRAS G12C mutations.
Methods: Plasma was collected from 599 patients with lung cancer seen at Memorial Sloan Kettering Cancer Center between 10/2016 and 1/2019. ctDNA sequencing was performed using the ctDX-Lung Assay (Resolution Bioscience; Kirkland, WA). Tissue DNA sequencing was carried out using the MSK-IMPACT assay.
Results: Mutations in KRAS (KRAS+) were detected in 129 patients (21.5%). Of patients with KRAS+ lung cancers, 116 had metastatic disease at the time of plasma testing. Plasma testing was carried out within 90 days of metastatic diagnosis in 92 of the 116 metastatic KRAS+ patients (79.3%), of whom 66 patients had both plasma and tissue sequencing available for comparison. 59 of the 66 patients (89.4%) had not had systemic treatment at the time of plasma testing. Average turn-around-time (TAT) for ctDNA testing in this cohort of 66 patients was 10 days, while average TAT for tissue sequencing was 22 days. ctDNA detected a KRAS mutation in 48 of the 66 patients (72.7%). A G12C mutation was found in the tissue and/or blood from 29 patients (43.9%), while 37 patients (56.1%) had other KRAS mutations. In one patient with a G12C mutation detected on plasma testing, no KRAS mutation or other known oncogenic drivers were found on tissue testing, though with limited tumor cells in the tissue sample. 75.6% of the patients with G12C mutations had KRAS detectable in the plasma, as compared to 70.3% of patients with other KRAS mutations (p=0.6). Within the cohort of patients with paired tissue and plasma testing, at a median follow-up of 202 days post-metastatic diagnosis, survival was longer in those patients without detectable KRAS in the plasma as compared to those patients with detectable plasma KRAS (log rank (Mantel-Cox), p&lt;0.001, log rank HR 7.9, 95% CI: 3.7-16.8).
Conclusion: Plasma testing was able to rapidly detect KRAS G12C mutations in the majority of patients with this alteration, which may guide G12C inhibitor therapy. In our cohort, patients that shed KRAS mutant DNA into the plasma had shorter survival.
Citation Format: Yonina R. Murciano-Goroff, Kathryn C. Arbour, Michael D. Offin, Hai-Yan Y. Tu, Emily S. Lebow, Tristan S. Shaffer, Caterina Bertucci, Syed A. Hosseini, Kavita Garg, Lee P. Lim, Mark Li, Jason C. Chang, Jorge S. Reis-Filho, Pedram Razavi, James M. Isbell, Gregory J. Riely, David M. Hyman, Piro Lito, Bob T. Li. The utility of plasma ctDNA for detection of KRAS G12C and other mutations in lung cancers [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 709.