Prognostic Value of Kras Mutations in Stage Iii Colon Cancer
Prognostic Value of Kras Mutations in Stage Iii Colon Cancer
We genotyped tumors from 1810 patients enrolled in a randomized phase III trial for KRAS exon 2 and BRAF mutations. The impact of KRAS mutations on TTR and DFS was studied excluding samples with BRAF mutations (8.45%), given that BRAF status itself affects the prognosis. The detection method used for genotyping was validated through various external quality control programs (European Society of Pathology KRAS EQA schemes). As expected in CRC (COSMIC database), KRAS exon 2 mutations were located at codons 12 and 13 in 79% and 21% of the samples, respectively.
Large population-based cohorts restricted to nonmetastatic CRC patients have yielded to different results concerning the prognostic value of KRAS mutations. For example, no association between KRAS mutations and relapse or survival was found in the PETACC-3 trial among 1404 CRC patients treated with 5-FU +/− irinotecan. In contrast, the Quasar study, which mainly included stage II patients, showed an increased risk of recurrence among KRAS-mutated patients, which was not affected by adjuvant chemotherapy. The RASCAL population-based studies showed that KRAS p.G12V only, was associated with poorer outcome and Imamura et al. found that codon 12 but not codon 13 (HR 1.25; 95% CI 0.85–1.84; NS) mutations negatively affected cancer specific mortality. In contrast, data from the NCCTG NO147 trial, which had a similar design to PETACC-08, showed that KRAS mutations at codons 12 (HR 1.52; 95% CI 1.28–1.8; P < 0.0001) and codon 13 (HR 1.36, 95% CI 1.04–1.72; P = 0.025) had a prognostic value. This may be due to the heterogeneity of the study populations, which included colon and rectal cancer, stage I–III tumors, patients receiving or not adjuvant treatments, patients with and without BRAF mutations and data from population-based cohorts or from clinical trials. In PETACC8 patients (n = 1657), KRAS codon 12 mutations were related to shorter TTR and DFS. Subsequently, we studied the impact of KRAS mutations on TTR and DFS according to tumor location. Proximal tumors were more frequently KRAS-mutated than were distal tumors. Previous studies also reported higher KRAS mutation rates in proximal when compared with distal colon cancer, but the relationship between cancer location, KRAS status and outcome remains unclear. Here, no effect of KRAS mutations was found for proximal tumors. In contrast, codon 12 alterations had a negative impact on TTR in patients with distal tumors and although the test did not reach statistical significance for p.G13D (P = 0.051), there was a clear trend for a similar effect. This borderline significance is possibly due to the poor number of events and patients in this subgroup. Larger series are needed to definitely state on the prognostic impact of p.G13D in colon tumors.
One limitation of our study is that MMR status was not available for patients enrolled in the PETACC8 trial. Deficient MMR phenotype tumors are mainly located in the proximal colon, associated with low recurrence rates, BRAF mutations and KRAS p.G13D. We estimated that more than 50% of MSI-H cancers (10–15% of CCR) were excluded through the exclusion of BRAF-mutated cancers that tends to limit the possible confounding role of MSI status in our series and suggests that our results, by approximation refer to an MSS population. Another limitation is the lack of data on rare KRAS and NRAS mutations. In a small cohort of patients, KRAS exon3/4- and NRAS-mutated tumors were associated to a better prognostic when compared with exon 2 alterations but large prospective series are still needed to validate the prognostic impact of rare KRAS an NRAS alterations in CCR.
In conclusion, we show in a series of stage III CCR patients included in a randomized, controlled phase III trial that codon 12 KRAS mutations have a significant impact on the TTR in distal CRC. The impact of the p.G13D mutation needs to be refined in a larger series according to tumor location and tumor phenotype (MSS/MSI) although this study suggests that p.G13D distal CRC might behave as p.G12X tumors. Future clinical trials in stage III colon cancer should consider both the tumor location and KRAS mutational status as important stratification factors.
Discussion
We genotyped tumors from 1810 patients enrolled in a randomized phase III trial for KRAS exon 2 and BRAF mutations. The impact of KRAS mutations on TTR and DFS was studied excluding samples with BRAF mutations (8.45%), given that BRAF status itself affects the prognosis. The detection method used for genotyping was validated through various external quality control programs (European Society of Pathology KRAS EQA schemes). As expected in CRC (COSMIC database), KRAS exon 2 mutations were located at codons 12 and 13 in 79% and 21% of the samples, respectively.
Large population-based cohorts restricted to nonmetastatic CRC patients have yielded to different results concerning the prognostic value of KRAS mutations. For example, no association between KRAS mutations and relapse or survival was found in the PETACC-3 trial among 1404 CRC patients treated with 5-FU +/− irinotecan. In contrast, the Quasar study, which mainly included stage II patients, showed an increased risk of recurrence among KRAS-mutated patients, which was not affected by adjuvant chemotherapy. The RASCAL population-based studies showed that KRAS p.G12V only, was associated with poorer outcome and Imamura et al. found that codon 12 but not codon 13 (HR 1.25; 95% CI 0.85–1.84; NS) mutations negatively affected cancer specific mortality. In contrast, data from the NCCTG NO147 trial, which had a similar design to PETACC-08, showed that KRAS mutations at codons 12 (HR 1.52; 95% CI 1.28–1.8; P < 0.0001) and codon 13 (HR 1.36, 95% CI 1.04–1.72; P = 0.025) had a prognostic value. This may be due to the heterogeneity of the study populations, which included colon and rectal cancer, stage I–III tumors, patients receiving or not adjuvant treatments, patients with and without BRAF mutations and data from population-based cohorts or from clinical trials. In PETACC8 patients (n = 1657), KRAS codon 12 mutations were related to shorter TTR and DFS. Subsequently, we studied the impact of KRAS mutations on TTR and DFS according to tumor location. Proximal tumors were more frequently KRAS-mutated than were distal tumors. Previous studies also reported higher KRAS mutation rates in proximal when compared with distal colon cancer, but the relationship between cancer location, KRAS status and outcome remains unclear. Here, no effect of KRAS mutations was found for proximal tumors. In contrast, codon 12 alterations had a negative impact on TTR in patients with distal tumors and although the test did not reach statistical significance for p.G13D (P = 0.051), there was a clear trend for a similar effect. This borderline significance is possibly due to the poor number of events and patients in this subgroup. Larger series are needed to definitely state on the prognostic impact of p.G13D in colon tumors.
One limitation of our study is that MMR status was not available for patients enrolled in the PETACC8 trial. Deficient MMR phenotype tumors are mainly located in the proximal colon, associated with low recurrence rates, BRAF mutations and KRAS p.G13D. We estimated that more than 50% of MSI-H cancers (10–15% of CCR) were excluded through the exclusion of BRAF-mutated cancers that tends to limit the possible confounding role of MSI status in our series and suggests that our results, by approximation refer to an MSS population. Another limitation is the lack of data on rare KRAS and NRAS mutations. In a small cohort of patients, KRAS exon3/4- and NRAS-mutated tumors were associated to a better prognostic when compared with exon 2 alterations but large prospective series are still needed to validate the prognostic impact of rare KRAS an NRAS alterations in CCR.
In conclusion, we show in a series of stage III CCR patients included in a randomized, controlled phase III trial that codon 12 KRAS mutations have a significant impact on the TTR in distal CRC. The impact of the p.G13D mutation needs to be refined in a larger series according to tumor location and tumor phenotype (MSS/MSI) although this study suggests that p.G13D distal CRC might behave as p.G12X tumors. Future clinical trials in stage III colon cancer should consider both the tumor location and KRAS mutational status as important stratification factors.
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