In this study, which included only colon cancer patients, we evaluated the relationship between early-stage and late-stage mutation discordance, early-stage mutation status, and OS, PFS, and relapse pattern. PFS and OS were significantly lower in patients with early-stage RAS mutations compared to wild-type patients. We found no significant difference between the mutational status and the relapse pattern. However, we found that lung metastases were seen more frequently at the time of recurrence in patients with RAS mutants in the early stage.
Similar to our study, Yoon et al.'s randomized phase 3 study (N0147 Alliance) with a large patient population published in 2014, one of the studies examining the effect of mutational status on prognosis in early stage colon cancer, examined the effect of KRAS mutation on prognosis in patients with stage 3 colon cancer. The PFS values of the KRAS positive patients were found to be significantly lower than the other group [10]. The effect of KRAS and BRAF mutation status on prognosis independent of MSI was examined in the study by Kadowaki et al., which was conducted in Japan and published in 2015. Patients with stage 1, 2 and 3 colon cancer were included in the study. KRAS and BRAF mutations were associated with lower survival independent of MSI status [11]. In a study by Smeby et al., published in 2018, with the Norwegian patient population, it was shown that BRAF mutation has significantly worse OS compared to KRAS/BRAF wild type and BRAF mutation has a stronger prognostic effect than KRAS mutation [12]. In the subgroup analysis of the QUASAR 2 study, which included patients with stage 2 and 3 colorectal cancer, published in the same year, it was shown that the KRAS/BRAF positive group was associated with a worse prognosis than the wild type group [13].
In the multicenter PETACC-8 study published in 2016, similar to our study, the effect of KRAS and BRAF mutations on the prognosis of patients with stage 3 colon cancer was examined, and the poor prognostic effect of mutation positivity was shown [14]. Also, in the joint analysis of the PETACC-8 and N0147 Alliance phase 3 studies published in 2017, it was shown that KRAS and BRAF mutations were associated with shorter PFS and OS in patients with stage 3 colon cancer [15]. One of the limitations of our study is that the patient population with BRAF positive in the early stage was not included. Early stage preparations of the only BRAF positive case in our study could not be reached.
Birgisson et al.'s clinical study published in 2015 examined the association of KRAS mutational status with widespread disease. In this study, patients were divided into two groups as those who were diagnosed at stages 2 and 3 and did not relapse, those who were diagnosed and relapsed at stages 2 and 3, and those who were diagnosed with stage 4 patients. The KRAS mutation was more common in patients with extensive disease (recurrence in stages 2 and 3 and stage 4 patients). Also, a higher frequency of KRAS mutations was observed in tumors from patients with higher disease stages: 28% in stage 2; 38% in stage 3 and 62% in stage 4. Widespread disease was more common in KRAS-positive patients than in KRAS wild-type patients [16]. In this study, specific metastasis sites were not examined, and metastasis was considered as a common disease. In our study, the number of patients with KRAS mutant at stage 3 was higher than those with mutant at stage 2 (69%, 31%, respectively). In addition, we did not detect early stage mutations in 11% of stage-4 mutant patients.
In the subgroup analysis of the PETACC-8 study published in 2019, the relationship between RAS (KRAS and NRAS) and BRAF mutational status and relapse pattern in stage 3 patients was examined. Recurrence rate was higher in RAS/BRAF positive patients compared to wild type patients, but the RAS/BRAF mutational status was not associated with a specific relapse site. In addition, no significant difference was found regarding the site of recurrence between KRAS and NRAS mutant cases [17]. Since there was only one NRAS negative patient in the early stage in our study, its effect on the relapse pattern could not be clearly evaluated.
In a cohort study by Tie et al., in which oncogene mutation profiles among colorectal cancer metastases in different regions were investigated, the relationship of KRAS/NRAS/BRAF mutational states with lung, brain and liver metastases was examined. Patients from all stages of colorectal cancer were included in the study. KRAS positive cases had more lung and brain metastases and less liver metastases than NRAS and BRAF positive cases [18]. Again, in a different study conducted for a similar purpose, the distant metastasis sites of 56 patients with only BRAF mutants were examined, and higher peritoneal and distant lymph node metastases, but lower lung metastases were observed [19]. In our study, the only BRAF positive case was found to have relapsed with peritoneal and lymph node metastasis.
A large patient population study by Prasanna et al., published in 2018, showed that BRAF mutation was positively correlated with the incidence of peritoneal metastases and these cases were associated with lower OS. Similarly, in this study, similar to other studies, cases with KRAS mutation were shown to present with lung metastases more frequently than BRAF positive or KRAS/BRAF wild-type cases [20]. In a similar study published in 2020, lung metastases were more common in the KRAS mutant patient group and liver metastases were more common in the KRAS wild type group [21]. Similarly, in our study, patients who were positive for KRAS at an early stage relapsed with more lung metastases.
In this study, we performed a re-mutation analysis from the early stage preparations at the time of first diagnosis of patients known to have mutation positivity in stage 4, which makes our study different from other studies in the literature. The most important limitation of our study is its retrospective design and the small number of patients.