Prognostic effect of specific RAS/BRAF mutations in patients (pts) with metastatic colorectal cancer (mCRC).

Abstract

4050 Background: Somatic mutations in KRAS, HRAS, NRAS (extended RAS) and BRAF have prognostic and predictive impact in pts with mCRC. We analyzed the prognostic impact of specific somatic mutations in extended RAS and BRAF. Methods: We retrospectively reviewed the electronic medical records of pts with mCRC at our institution who underwent comprehensive genomic profiling (CGP) utilizing the Foundation One assay. DNA was extracted from clinical specimens and CGP was performed on hybrid-capture, adaptor ligation-based libraries for up to 315 genes plus 47 introns from 19 genes frequently rearranged in cancer. BRAF mutations were classified as class I, II and III according to accepted nomenclature. Fisher’s exact test and Kaplan Meier estimates were used for statistical analyses. This project was approved by the Medical College of Wisconsin Institutional Review Board. Results: 273 pts were identified - median age at diagnosis was 57, 48% were male. Somatic mutations in extended RAS were found in 138 (50%) pts, majority being mutations in KRAS (46%). Among pts with KRAS mutations, codon 12, 13, 61 and 146 mutations accounted for 73%, 11%, 4% and 6% respectively while KRAS G12C mutations accounted for 9%. BRAF mutations were detected in 22 (8%) pts - BRAF V600E and non–V600E mutations accounting for 4.4% and 3.6% respectively. Among pts with BRAF mutations, 17 (77%) were kinase domain mutations, 16 of which could be further classified as class I (12/16), II (1/16) and III (3/16). Median overall survival (mOS) for the entire cohort was 26.4 months (mo). KRAS mutated pts had a mOS of 25.8 mo; pts with KRAS G12C mutation had a mOS of 23 mo compared to 27.1 mo for pts with other KRAS mutations (p < 0.001).Pts with BRAF mutation had a mOS of 26.2 mo; pts with BRAF V600E mutation had a mOS of 14.1 mo compared to 30.6 mo for pts with BRAF non-V600E mutations (p = 0.1). Conclusions: The poor prognosis of pts with KRAS G12C and BRAF V600E mutations compared to pts with other KRAS and BRAF mutations merit further biologic characterization with functional assays. Individualized therapeutic strategies must be conceptualized for mCRC pts with specific RAS/BRAF mutations, considering their widely disparate prognosis and putative downstream signaling mechanisms. Dynamic molecular simulation to understand conformational changes in proteins associated with specific mutations will be pivotal to optimizing precision therapeutic strategies.

Retrospective Comparative Analysis of KRAS G12C vs. Other KRAS Mutations in mCRC Patients Treated With First-Line Chemotherapy Doublet + Bevacizumab

“…Indeed, looking at other prognostic factors that might have lessened the impact of KRAS G12C mutation both on PFS and OS, it can be observed that the cohort of our study is well balanced for all stratification factors that are usually considered when assessing survival outcomes. Other studies have not performed the same: George et al (20), for example, have reported that KRAS G12C mutations might be associated with statistically significant differences in OS. Differently from our study, those authors did not report any kind of matching for other relevant prognostic factors (ECOG PS, tumor sidedness, surgery of metastatic sites with radical intent, etc.…”

“…Other studies have not performed the same: George et al. ( 20 ), for example, have reported that KRAS G12C mutations might be associated with statistically significant differences in OS. Differently from our study, those authors did not report any kind of matching for other relevant prognostic factors (ECOG PS, tumor sidedness, surgery of metastatic sites with radical intent, etc.…”

Progress in companion diagnosis of colorectal cancer

“…More than two MSI were identified as MSI-H, one MSI locus was identified as low-grade microsatellite instability (MSI-L), and no MSI was identified as MSS. Although most microsatellites are located in non-coding regions, misplaced mutations can lead to frameshift mutations, causing tumor-related gene abnormalities, which in turn induce the development of cancer [25][26][27].…”