KRAS mutations in circulating tumour DNA (ctDNA) in MRI-defined, high-risk, locally-advanced rectal cancer (LARC) patients (pts) from the EXPERT-C trial

Abstract

Background: Although the potential of detecting ctDNA in solid tumours has been increasingly reported, there are limited data in LARC. We sought to investigate frequency and relevance of KRAS mutations in ctDNA in a randomised phase II trial of CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX ± cetuximab in high‐risk LARC. Methods: RAS (exon 2‐4) mutations were previously analysed in the biopsy and resection samples using standard sequencing techniques. ctDNA was isolated from 2 ml of plasma collected prior to treatment start and analysed by digital droplet PCR. Commercially available and validated assays were used to detect KRAS mutations (G12D, G12V and G13D in all pts plus any patient‐specific, additional mutation previously detected in the tissue). The sensitivity cut‐off for the assay of ctDNA was set at a lower limit of 0.02% mutant alleles. Results: 97/164 study pts (59%) were assessable for ctDNA. G12D, G12V or G13D tissue mutations were previously identified in 28 pts (7 not assessable). KRAS mutations in ctDNA in these codons were found in 13/28 (46%) and 22/62 (35%) of pts who were KRAS mutant and wild type in tissue, respectively. 5/10 pts with G12A, G12C, G12S or A146T tissue mutations had the same mutation in the blood. Among 38 pts with any KRAS tissue mutation, ctDNA was detected in 18 pts (47%) and associated with a higher baseline T stage (p = 0.01). However, no association was found with complete response (CR) (16.7% vs 10.0%, p = 0.65), PFS (HR 0.86, 95% CI: 0.31‐2.37), p = 0.77) or OS (HR 0.92, 95% CI: 0.32‐2.65, p = 0.88). When tissue and ctDNA mutation data were combined to redefine the mutation status of the assessable EXPERT‐C study population (n = 119; 32 RAS wild‐type and 87 RAS mutant), no interaction was found between RAS status and cetuximab treatment with regards to CR (p = 0.99), PFS (p = 0.57) or OS (p = 0.98). Conclusions: In this series of high‐risk LARC, KRAS mutations in ctDNA were found in up to half and one third of pts with KRAS mutant and KRAS wild‐type tumours, respectively, as defined by previous tissue mutation analyses. Larger studies are needed to better address the potential role of ctDNA as a prognostic or predictive tool in LARC.