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).