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Tumor microenvironment-adjusted prognostic implications of the KRAS mutation subtype in patients with stage III colorectal cancer treated with adjuvant FOLFOX.

ABSTRACT: Several studies have reported that the prognostic effect of KRAS mutations on colorectal cancers (CRCs) varies depending on the type of mutation. Considering the effect of KRAS mutations on tumor microenvironment, we analyzed the prognostic significance of KRAS mutation types after adjusting for the tumor-infiltrating lymphocytes (TIL) and tumor-stromal percentage (TSP) statuses. In two independent cohorts, KRAS mutations were analyzed by Sanger sequencing and/or next-generation sequencing. TIL density and the TSP were quantified from whole-slide immunohistochemical images. KRAS-mutant CRCs were divided into three subgroups (G12D/V, other codon 12 mutations and codon 13 mutations) to examine their differential effect on TIL density, the TSP and recurrence-free survival (RFS). Among the KRAS mutations, only the G12D/V subgroups showed significantly less TIL infiltration than the wild-type CRCs. According to survival analysis, G12D/V mutations were associated with short RFS; codon 13 mutations showed discordant trends in the two cohorts, and other codon 12 mutations showed no significant association. Multivariate analysis further supported the prognostic value of G12D/V mutations. This result is not only consistent with a recent study suggesting the immunosuppressive effect of mutant KRAS but also provides insight into the type-specific prognostic effect of KRAS mutations.

SUBMITTER: Park HE

PROVIDER: S-EPMC8285533 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Importance:The prognostic impact of DNA mismatch repair (MMR) status in stage III colon cancer patients receiving FOLFOX (folinic acid, fluorouracil, and oxaliplatin) adjuvant chemotherapy remains controversial. Objective:To determine the association of MMR status with disease-free survival (DFS) in patients with stage III colon cancer treated with FOLFOX. Design, Setting, and Participants:The evaluated biomarkers for MMR status were determined from prospectively collected tumor blocks from patients treated with FOLFOX in 2 open-label, phase 3 randomized clinical trials: NCCTG N0147 and PETACC8. The studies were conducted in general community practices, private practices, and institutional practices in the United States and Europe. All participants had stage III colon adenocarcinoma. They were enrolled in NCCTG N0147 from February 2004 to November 2009 and in PETACC8 from December 2005 to November 2009. Interventions:Patients in the clinical trials were randomly assigned to receive 6 months of chemotherapy with FOLFOX or FOLFOX plus cetuximab. Only those patients treated with FOLFOX alone were included in the present study. Main Outcomes and Measures:Association of MMR status with DFS was analyzed using a stratified Cox proportional hazards model. Multivariable models were adjusted for age, sex, tumor grade, pT/pN stage, tumor location, ECOG (Eastern Cooperative Oncology Group) performance status, and BRAF V600E mutational status. Results:Among 2636 patients with stage III colon cancer treated with FOLFOX, MMR status was available for 2501. Of these, 252 (10.1%) showed deficient MMR status (dMMR; 134 women, 118 men; median age, 59 years), while 2249 (89.9%) showed proficient MMR status (pMMR; 1020 women, 1229 men; median age, 59 years). The 3-year DFS rates in the dMMR and pMMR groups were 75.6% and 74.4%, respectively. By multivariate analysis, patients with dMMR phenotype had significantly longer DFS than those with pMMR (adjusted hazard ratio, 0.73; 95% CI, 0.54-0.97; P?=?.03). Conclusions and Relevance:The deficient MMR phenotype remains a favorable prognostic factor in patients with stage III colon cancer receiving FOLFOX adjuvant chemotherapy. Trial Registration:clinicaltrials.gov Identifier: NCT00079274 for the NCCTG N0147 trial and EudraCT identifier: 2005-003463-23 for the PETACC8 trial.

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Tumor microenvironment-adjusted prognostic implications of the KRAS mutation subtype in patients with stage III colorectal cancer treated with adjuvant FOLFOX.

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