Impact of circulating tumor DNA mutant allele fraction on prognosis in RAS‐mutant metastatic colorectal cancer

Abstract

Despite major advances in the treatment of metastatic colorectal cancer (mCRC), the survival rate remains very poor. This study aims at exploring the prognostic value of RAS ‐mutant allele fraction (MAF) in plasma in mCRC. Forty‐seven plasma samples from 37 RAS ‐mutated patients with nonresectable metastases were tested for RAS in circulating tumor DNA using BEAMing before first‐ and/or second‐line treatment. RAS MAF was correlated with several clinical parameters (number of metastatic sites, hepatic volume, carcinoembryonic antigen, CA19‐9 levels, primary site location, and treatment line) and clinical outcome [progression‐free survival (PFS) and overall survival (OS)]. An independent cohort of 32 patients from the CAPRI‐GOIM trial was assessed for clinical outcome based on plasma baseline MAF. RAS MAF analysis at baseline revealed a significant correlation with longer OS [Hazard ratios (HR) = 3.514; P = 0.00066]. Patients with lower MAF also showed a tendency to longer PFS, although not statistically significant. Multivariate analysis showed RAS MAFs as an independent prognostic factor in both OS (HR = 2.73; P = 0.006) and first‐line PFS (HR = 3.74; P = 0.049). Tumor response to treatment in patients with higher MAF was progression disease ( P = 0.007). Patients with low MAFs at baseline in the CAPRI‐GOIM group also showed better OS [HR = 3.84; 95% confidence intervals (CI) 1.5–9.6; P = 0.004] and better PFS (HR = 2.5; 95% CI: 1.07–5.62; P = 0.033). This minimally invasive test may help in adding an independent factor to better estimate outcomes before initiating treatment. Further prospective studies using MAF as a stratification factor could further validate its utility in clinical practice.

Evolution of Mutational Landscape and Tumor Immune-Microenvironment in Liver Oligo-Metastatic Colorectal Cancer

“…TMB was measured by exome sequencing [ 38 ], counting all coding, somatic base substitutions and indels in the targeted regions, including synonymous alterations. The size of the targeted (coding) genomic region was 1.9 Mb.…”

Cross-sectional analysis of circulating tumor DNA in primary colorectal cancer at surgery and during post-surgery follow-up by liquid biopsy

“…Whereas a large number of studies have addressed mCRC [15][16][17][18][19][20][21][22][23] only a few have investigated the role of liquid biopsy in early, non-metastatic CRC patients at surgery, e.g. in conditions of extremely low tumor burden [24][25][26][27][28].…”

Resistance to anti-epidermal growth factor receptor in metastatic colorectal cancer: What does still need to be addressed?

“…Many other issues have to be addressed, among them the concordance of data between formalin-fixed, paraffin-embedded (FFPE) tumor tissue determined by PCR standard of care (SoC) analysis and ctDNA. Different studies demonstrated that ctDNA analysis by BEAMing technology or qPCR-based platforms reaches about 90% of concordance when compared with tumor tissue analysis to detect molecular alterations in KRAS, NRAS and BRAF genes (Table 3), [71,75,76]. Concordance between tissue and plasma does not meet 100% due to dynamic changes that occur in CRC disease.…”

“…This dynamic spatial and temporal heterogeneity of CRC could be resolved by repeating genomic profiles at different time points during the course of treatment. Due to the small amount of tumor ctDNA in the blood of patients with mCRC, high sensitive liquid biopsy analysis is always required to avoid false negative results, even if a negative result, in some cases, could be attributed to biological processes that impede the ctDNA release in the blood, the tumor histology (mucinous tumors) and the presence of peritoneal and lung metastases [76]. Of note, analyses of the CRYSTAL phase III study showed that patients with RAS mutant allele fraction (MAF) mutations lower than 5% achieved better outcomes when cetuximab was added to a FOLFIRI based first line treatment [27].…”