DISCUSSION
EFG, when bound to its receptor EFGR, activates two main signaling
pathways, RAS-BRAF-MEK-ERK and PIK3CA-AKT, which are responsible for
initiating processes of cell progression and differentiation, apoptosis
and DNA repair (2,11,17). Mutations in KRAS, BRAF, NRAS genes
(via MAPK/ERK) and PIK3CA (via PIK3CA/AKT) have been linked in
numerous studies to monoclonal antibodies (Cetuximab and Panitumumab)
response, progression and overall survival in CRC (3,8,10,13,14,18–27).
We analyzed the overall survival in 194 CRC patients according to the
status of different mutations in components of the EGFR pathway. Our
results showed association of the PIK3CA/AKT pathway, but not the
MAPK/ERK cascade on CRC overall survival. In particular, we observed an
association between risk of death and presence of H1047Y mutation in
exon 20 of PIK3CA (HR = 8.93, CI95%, 1.20-66.57, p = 0.03268).
We also observed a strong effect of ECOG 0 on greater overall survival
(HR = 0.17, CI95%, 0.10 -0.31, p = 1656.10-9). ECOG PS is a scale of 0
to 5 published in 1982 by the Eastern Cooperative Oncology Group that
measures how the disease affects the patient’s daily activities. It
seems logical to think that patients with ECOG 0 (full functionality)
have more chances to survive than those with ECOG 1-2. Given that the
effect of ECOG could be masking the effect of other variables on overall
survival, we performed a analysis stratifying the sample by ECOG status,
which confirmed that patients with PIK3CA20 H1047Y mutation had a
higher risk of death (HR = 8.93, CI95%, 1.20-66.57, p = 0.03268) and
showed a new association between the E545K mutation of exon 9 ofPIK3CA (HR = 5.49, CI95%, 1.28-23.51, p = 0.021720) and overall
survival in patients with ECOG 0.
Our findings are comparable to those obtained by Sartore-Bianchi (19)
and De Roock (8). Sartore-Bianchi and colleagues investigated the
influence of loss PTEN, PIK3CA exon 9 and 20 and KRAS exon
2 mutations on objective response and survival in 110 metastatic CRC
patients treated with anti-EFGR monoclonal antibodies (Panitumumab or
Cetuximab). Patients with at least one alteration in the PIK3CAand PTEN genes had a higher risk of progression (HR = 1.86,
CI95%, 1.16-2.96, p = 0.009). As observed in our patients, KRASmutations could not predict progression-free survival (HR = 1.50,
CI95%, 0.89-2.52, p = 0.128). They also failed to find association with
overall survival for any gene (PIK3CA , p = 0.2518; KRAS , p
= 0.1127), while in our patients, PIK3CA exon 20 (H1047Y)
mutation was associated with lower survival. De Roock explored the
possible effect of KRAS, NRAS, BRAF and PIK3CA mutations
on objective response, overall survival and progression-free survival of
773 CRC chemotherapy-refractory patients treated with Cetuximab plus
chemotherapy. As our results, they found that mutations of exon 20 were
capable to predict survival (progression-free and global), but only in
patients with KRAS wild-type tumors (HR = 2.27, CI95%,
1.10-4.66, p = 0.042 / HR = 3.30, CI95 %, 1.46-7.45, p = 0.012).
Wendy De Roock, in addition, suggests that PIK3CA exons 9 and 20
mutations should be studied separately, since the alterations they
produce are different and can lead to biased results (8). Exon 9
(helical domain) mutation produces the activation of the RAS protein,
while exon 20 (kinase domain) mutation induces a gain in function
independent of RAS (28). In our study, as De Roock suggests, and unlike
the Sartore-Bianchi study, we separately analyzed PIK3CA exons 9
and 20 mutations.
The limited size of our sample did not allow us to explore the effect of
the mutations on response to the treatment, since the patients were in
different stages of disease and lines of treatment at the time of our
study, and the follow-up period (two years) was also insufficient for
study progression-free survival in CRC. The statistical power proved to
be insufficient to investigate the influence on CCR survival of some of
the mutations in the EFGR pathway mutations KRAS (rs121913529,
rs121913530, rs121913535, rs112445441, rs17851045, rs121913238,
rs121913240), NRAS (rs121913237, rs121434596, rs11554290,
rs121913254) and BRAF (rs113488022)] and no mutations were
observed on those genes. Therefore, further studies with larger size
will be necessary to properly explore and elucidate those genes as
potential biomarkers in CRC survival. Despite the limited sample size,
we clearly demonstrated the influence of PIK3CA gene mutations on
CCR survival.