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Prognostic and predictive value of extended RAS mutation and mismatch repair status in stage III colorectal cancer.

ABSTRACT: The prognostic and predictive value of KRAS gene mutations in stage III colorectal cancer is controversial because many recent clinical trials have not involved a surgery-alone arm. Additionally, data on the significance of extended RAS (KRAS/NRAS) mutations in stage III cancer are not available. Hence, we undertook a combined analysis of two phase III randomized trials, in which the usefulness of adjuvant chemotherapy with tegafur-uracil (UFT) was evaluated, as compared with surgery alone. We determined the association of extended RAS and mismatch repair (MMR) status with the effectiveness of adjuvant chemotherapy. Mutations in KRAS exons 2, 3, and 4 and NRAS exons 2 and 3 were detected by direct DNA sequencing. Tumor MMR status was determined by immunohistochemistry. Total RAS mutations were detected in 134/304 (44%) patients. In patients with RAS mutations, a significant benefit was associated with adjuvant UFT in relapse-free survival (RFS) (hazard ratio = 0.49; P = 0.02) and overall survival (hazard ratio = 0.51; P = 0.03). In contrast, among patients without RAS mutations, there was no difference in RFS or overall survival between the adjuvant UFT group and surgery-alone group. We detected deficient DNA MMR in 23/304 (8%) patients. The MMR status was neither prognostic nor predictive for adjuvant chemotherapy. An interaction analysis showed that there was better RFS among patients treated with UFT with RAS mutations, but not for those without RAS mutations. Extended RAS (KRAS/NRAS) mutations are proposed as predictive indicators with respect to the efficacy of adjuvant UFT chemotherapy in patients with resected stage III colorectal cancer.

SUBMITTER: Sasaki Y

PROVIDER: S-EPMC4946717 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Prognostic and predictive value of extended RAS mutation and mismatch repair status in stage III colorectal cancer.

Sasaki Yusuke Y Akasu Takayuki T Saito Norio N Kojima Hiroshi H Matsuda Keiji K Nakamori Shoji S Komori Koji K Amagai Kenji K Yamaguchi Tatsuro T Ohue Masayuki M Nagashima Kengo K Yamada Yasuhide Y

Cancer science 20160628 7

The prognostic and predictive value of KRAS gene mutations in stage III colorectal cancer is controversial because many recent clinical trials have not involved a surgery-alone arm. Additionally, data on the significance of extended RAS (KRAS/NRAS) mutations in stage III cancer are not available. Hence, we undertook a combined analysis of two phase III randomized trials, in which the usefulness of adjuvant chemotherapy with tegafur-uracil (UFT) was evaluated, as compared with surgery alone. We d ...[more]

PMID: 27089049

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Project description:BackgroundWe examined the predictive value of mismatch repair (MMR) status in relation to responses to neoadjuvant therapy and the prognosis of locally advanced rectal cancer patients.MethodsA total of 854 consecutive patients with locally advanced rectal cancer with MMR status who underwent neoadjuvant therapy followed by curative surgery between January 2013 and December 2018 were included this retrospective study. MMR status was determined by an analysis of MMR protein expression by immunohistochemistry (IHC). Propensity score matching was performed to reduce imbalances in baseline characteristics. The categorical variables were compared using the Chi-square test or Fisher's exact test. Local recurrence-free survival (LRFS) and disease-free survival (DFS) curves were estimated using the Kaplan-Meier method.ResultsDeficient MMR (dMMR) was detected in 63 of the 854 (7.4%) patients. Patients with dMMR had a lower proportion of tumor regression grade (TRG) of 0-1 compared with proficient MMR (pMMR) (28.6% vs. 43.7%; P=0.027). After propensity score matching at 1:4 for patients who received chemotherapy alone, proportion of TRG of 0-1 was observed to be significantly lower in dMMR than pMMR patients (9.1 vs. 30.3%%; P=0.013). For patients who received chemoradiation, after matching, no significant difference in the proportion of TRG 0-1 and the pathological complete response (pCR) rate was observed. The multivariable analysis revealed that patients whose tumors had dMMR had significantly longer DFS than those whose tumors had pMMR [hazards ratio (HR) =0.38, 95% confidence interval (CI): 0.18-0.81, P=0.013]. In the subgroup analysis, dMMR was only a statistically significant prognostic factor for DFS in patients with ypStage II/III (HR =0.38, 95% CI: 0.17-0.86; P=0.020).ConclusionsWe found that patients with dMMR responded worse to chemotherapy alone than patients with pMMR, in terms of TRG. Also, dMMR is a good prognostic marker for DFS in patients with ypStage II/III after neoadjuvant therapy.

Project description:ImportanceWe know of no data on the prognostic value of primary tumor location (PTL) according to BRAF, RAS, and microsatellite instability (MSI) status in patients who have undergone resection for colon cancer (CC) and have been treated with current standard adjuvant chemotherapy.ObjectiveTo determine the prognostic and predictive value of PTL according to BRAF, RAS, and MSI status in patients with stage III CC receiving adjuvant treatment with FOLFOX (folinic acid [leucovorin calcium], fluorouracil, and oxaliplatin) with or without cetuximab.Design, setting, and participantsThis post hoc analysis included patients with available tumor blocks of resected stage III colon adenocarcinoma who participated in the Pan-European Trials in Alimentary Tract Cancer (PETACC)-8 phase 3 randomized trial. Among the 2559 patients who underwent randomization, 1900 were screened by next-generation sequencing, which showed that 1869 had full information concerning PTL. We categorized primary tumor site as located proximal (right) or distal (left) to the splenic flexure.Main outcomes and measuresThe associations between PTL (right- vs left-sided) and disease-free survival (DFS), survival after relapse (SAR), and overall survival (OS) were assessed by Cox models and adjusted for clinical and pathological features, treatment, and MSI, BRAF, and RAS status.ResultsAmong the 1869 patients (1056 [57%] male; mean [SD] age, 59.4 [9.5] years) with full molecular data analyzed, 755 (40%) had a right-sided tumor, 164 (10%) had MSI, 942 (50%) had RAS mutations, and 212 (11%) had BRAF mutations. Right-sided tumor location was not prognostic for DFS in the whole population but was associated with a shorter SAR (hazard ratio [HR], 1.54; 95% CI, 1.23-1.93; P = .001) and OS (HR, 1.25; 95% CI, 1.02-1.54; P = .03). When looking at DFS in the different molecular subgroups, we found similar results for microsatellite-stable tumors and tumors with MSI; a better DFS in right-sided vs left-sided tumors in patients with RAS mutations (HR, 0.80; 95% CI, 0.64-1.00; P = .046); and a worse DFS in right-sided vs left-sided tumors in patients with RAS and BRAF double wild type (HR, 1.39; 95% CI, 1.01-1.92; P = .04). These results were found independently of the treatment received, and no beneficial effect of cetuximab on DFS or OS was observed in left-sided tumors.Conclusions and relevanceAlthough right-sided tumor location is associated with poor survival in patients with metastatic CC as previously reported, the association with disease recurrence appears to vary for patients with stage III CC and RAS or BRAF mutations vs those with double wild type.

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Prognostic and predictive value of extended RAS mutation and mismatch repair status in stage III colorectal cancer.

Publications

Prognostic and predictive value of extended RAS mutation and mismatch repair status in stage III colorectal cancer.

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