RESULTS

Clinical and sociodemographic characteristics of patients

Baseline characteristics of the 194 Caucasian patients are summarized in Table 1. Seventy-two of the 194 patients were women (37.1%). Median age at diagnosis was 62 years [57-69] and median tumor size was 4.6 cm [3.5-6.0]. Number of recorded deaths was 62 (31.9%), with a median overall survival of 41.4 months [30.8-55.9]. Approximately 85% of the patients presented ECOG 0 (157/185) at the time of diagnosis. One patient (0.5%) had a stage I tumor at the time of diagnosis; the rest of the patients were stages II (25.8%), III (49.0%) and IV (24.8%). The most frequent histopathology was adenocarcinoma (90.2%) and the most common location was in the sigmoid colon (38.1%). Regarding the first line of chemotherapy treatment, most of the schemes were based on pyrimidines in combination with oxaliplatin (85.57%) or monotherapy (11.34%).

Genetic characteristics of tumors

Table 2 details the frequency of mutations in KRAS, NRAS, BRAFand PIK3CA genes. The most frequent mutations were found in codon 12 of the KRAS gene (9.28% for SNP rs121913530 and 5.67% for SNP rs121913529). All patients analyzed for KRAS (rs112445441, rs121913238, rs121913240), NRAS (rs11554290, rs121913254) andPIK3CA (rs121913279) were found to be wild-type , so they were not included in the statistical analysis.

Influence of the clinical, histopathological and genetic characteristics on overall survival

Bivariate analysis

Patients with ECOG of 0 presented a greater overall survival (92.93 vs 28.76 months, p = 3.4 ยท 10-11) in bivariate analysis (Table 3) (Figure 1). There was no association between overall survival and the rest of clinical-pathological characteristics analyzed.
Patients with mutated BRAF gene (V600E; rs113488022) had lower overall survival (29.90 vs 77.43 months, p = 0.049). Same happened with the PIK3CA9 gene (E545K; rs104886003) (37.35 vs 77.43months, p = 0.0024). Patients with the PIK3CA20 H1047Y mutation (rs121913281) showed a trend towards an increased risk of death compared to wild type (30.40 vs 77.43 months, p = 0.055).

Multivariate analysis

Multivariate analysis confirmed that patients with ECOG of 0 presented lower risk of death (HR = 0.17, CI95%, 0.10 -0.31, p = 1656.10-9) compared to a higher ECOG (Table 4). The only independent genetic association was between PIK3CA20 mutation (H1047Y; rs121913281) and higher risk of death (HR = 8.93, CI95%, 1.20-66.57, p = 0.03268). No association was found between the rest of the mutations analyzed and overall survival.

Statistical analysis stratified by ECOG

To explore the effect of mutations in patients with different degrees of ECOG, a stratified analysis was performed.

Group of patients with ECOG 0

The bivariate analysis in patients with ECOG 0 group showed that overall survival was lower in those with mutated PIK3CA gene, both for E545K mutation (rs104886003) in exon 9 (37.35 vs 92.93 months; = 0.003) and H1047Y mutation (rs12191328) in exon 20 (30.40 vs 92.93 months, p = 0.0048) (Table 5) (Figure 2). Lower overall survival was also observed in patients whose tumor was located in colon (76.9 vs> 50 months, p = 0.012). Multivariate analysis confirmed the association between both mutations of PIK3CA and an increased risk of death: E545K (HR = 5.49, CI95%, 1.28-23.51, p = 0.021720) and H1047Y (HR = 53.49; %, 4.63-617.40, p = 0.001429) (Table 6). In addition, patients diagnosed with colon cancer had a higher risk of death than those diagnosed with rectal cancer (HR = 5.95, CI95%, 1.42-25.02, p = 0.014870).

Group of patients with ECOG 1-2

In the group of patients with ECOG greater than 0, those diagnosed with adenocarcinoma had greater overall survival (32.02 vs 22.95 months, HR = 0.27, CI95%, 0.08-0.93, p = 0.033) (Table 5), an association that was not confirmed in multivariate analysis (Table 6) (Figure 2).