Role of RAS mutation status as a prognostic factor for patients with advanced colorectal cancer treated with first-line chemotherapy based on fluoropyrimidines and oxaliplatin, with or without bevavizumab: A retrospective analysis

Abstract

Abstract. The role of Kirsten rat sarcoma viral oncogene homolog (KRAS) and neuroblastoma RAS viral oncogene homolog (NRAS) mutations as negative predictors for anti-epidermal growth factor receptor (EGFR) therapies in metastatic colorectal cancer (CRC) has been firmly established. However, whether the RAS mutation status plays a role as a biomarker for anti-vascular endothelial growth factor (VEGF) treatment remains controversial. Data from 93 CRC patients who received first-line cytotoxic chemotherapy with fluoropyrimidines and oxaliplatin, with or without bevacizumab, were analyzed. We investigated the association between the RAS mutation status and clinical outcomes in terms of response rate, progression-free survival (PFS) and overall survival (OS). Mutations in RAS genes were observed in 47 (52.6%) patients (45 KRAS and 2 NRAS mutations). Patients with tumours harbouring RAS mutations were less suitable for primary tumour resection, were more likely to develop lung metastases, and received bevacizumab treatment for a shorter time period compared with those with wild-type tumours. The response rate to chemotherapy did not differ according to the RAS mutation status, and there were no significant differences in PFS [RAS mutation: 12 months, 95% confidence interval (CI): 8.7-15.2 vs. RAS wild-type: 12 months, 95% CI: 9.67-14.32; P=0.857] or OS (RAS mutation: 20 months, 95% CI: 14.3-25.6 vs. RAS wild-type: 24 months, 95% CI: 18.7-29.2; P=0.631). Patients with RAS mutation vs. those with RAS wild-type exhibited a favourable trend in PFS when treated with bevacizumab (13 months, 95% CI: 6.5-19.4 vs. 10 months, 95% CI: 4.2-15.7, respectively; P=0.07) and OS (27 months, 95% CI: 18.5-35.4 vs. 15 months, 95% CI: 12.4-17.5, respectively; P=0.22). In conclusion, RAS mutations are not a prognostic marker for PFS and OS in CRC patients receiving fluoropyrimidine-oxaliplatine treatment, with or without bevacizumab. RAS mutations are not predictive of the lack of efficacy of bevacizumab, and these patients appear to benefit from anti-angiogenic treatment.

Mutation status and prognostic value of KRAS and NRAS mutations in Moroccan colon cancer patients: A first report

“…This study demonstrates that RAS and KRAS mutant status underline special clinicopathological and molecular features. As reported in some studies [15,28,29], in our context, RAS mutated CC was associated with female gender, distal colon, classical adenocarcinoma subtype, moderately differentiated tumors, and presence of vascular invasion. Interestingly, our study demonstrated that CC with RAS and epically KRAS mutations show a lower rate of the total lymph node.…”

“…Interestingly, our study demonstrated that CC with RAS and epically KRAS mutations show a lower rate of the total lymph node. Recently, NOGUERA et al [29] found the same observation, but the difference was not statistically significant. Besides, patients with KRAS mutations showed a significantly higher rate of positive lymph nodes.…”

Pharmacogenomics of Targeted Agents for Personalization of Colorectal Cancer Treatment

“…Even if these differences did not reach the statistically significant level, probably due to the relatively small effect of RAS mutations and the rarity of BRAF mutations, RAS/PIK3CA/BRAF status appeared to be a promising candidate to help in identifying tumors that will respond to the anti-VEGF drug [ 13 ]. Another work was not able to found an association between RAS mutational status and BV efficacy; however, this investigation was performed on small study population and only a subgroup of patients ( n = 35) was treated with BV-containing regimes [ 14 ]. Interestingly, a recent pioneering study on 167 patients who underwent lung metastasectomy for mCRC, has reported for the first-time that for patients with KRAS codon 12 mutations, perioperative bevacizumab was associated with a significant improvement in both loco-regional recurrence free survival and OS [ 15 ].…”

Cross-platform comparison for the detection of RAS mutations in cfDNA (ddPCR Biorad detection assay, BEAMing assay, and NGS strategy)

“…Epidermal growth factor receptor (EGFR) - targeted monoclonal antibodies (MAb), such as cetuximab and panitumumab, have been used in the treatment of metastatic colorectal cancer (mCRC) since 2004. Numerous studies have demonstrated that RAS mutations are associated with resistance to anti-EGFR antibodies and that approximately 45–50% of CRCs harbor a RAS mutation [ 4 , 5 ]. Based on these findings, anti-EGFR MAbs have been recommended for use in first-line therapy of metastatic CRC (mCRC) for those patients whose tumors are wild-type (WT) for RAS.…”