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Tanasanvimon. J Cancer Metastasis Treat 2018;4:57 I http://dx.doi.org/10.20517/2394-4722.2018.38 Page 3 of 11

value of KRAS mutation was confounded by the effectiveness of anti-EGFR therapy in patients with wild-
type KRAS [3,9-12] .There were conflicting results among the analysis in other RCT cohorts regarding the
prognostic value of RAS mutation in mCRC [14,16] .

BRAF
As BRAF is a key regulator in MAPK pathway, anti-EGFR therapy might not be effective in tumors with
activated BRAF mutation. However, given the small number of patients with mutant BRAF tumors, the
analysis of individual anti-EGFR randomized controlled trials did not consistently showed predictive effect
of BRAF mutation for anti-EGFR therapy in patients with mCRC [13,17-20] . Recently, there were two metanalyses
regarding predictive effect of BRAF mutation for anti-EGFR treatment in patients with mCRC, although they
[21]
showed no significant benefit of anti-EGFR therapy in patients with mutant BRAF mCRC. Pietrantonio et al.
[22]
suggested BRAF mutation as a negative predictive biomarker for anti-EGFR therapy, while Rowland et al.
concluded that there was insufficient evidence to exclude the benefit of anti-EGFR therapy in patients with
mutant BRAF mCRC [21,22] . Although, there has been no definitive conclusion, the patients with mutant BRAF
tumor are unlikely to derive treatment benefit from anti-EGFR therapy.

Other biomarkers
As one third of patients with wild-type RAS mCRC will not have objective response to first-line
chemotherapy and anti-EGFR combined therapy. The additional potential biomarkers would help
optimizing anti-EGFR therapy in mCRC.

PI3K-AKT-mTOR pathway is another key downstream signaling pathway of EGFR. Alterations of PIK3CA
and PTEN were explored for its predictive value for anti-EGFR therapy in mCRC. In contrast to other
RAS and BRAF, PIK3CA mutation and PTEN alterations are not mutually exclusive with KRAS exon 2
mutation. The prevalence of PIK3CA mutation was 4%-11% in patients with wild-type KRAS mCRC [19,23-27] .
The prevalence of PTEN loss and mutation was 19%-58% and 7%-9%, respectively, in patients with wild-
type KRAS mCRC [19,24-27] . For those patients with wild-type KRAS exon 2 mCRC, PIK3CA mutation and
PTEN alterations were associated with poorer objective response rate and OS for anti-EGFR therapy in two
metanalyses [28,29] . However, there might be different predictive effects between different PIK3CA mutations
and different techniques detecting PTEN alterations.

EGFR ligands, epiregulin (EREG) and amphiregulin (AREG) are overexpressed in CRC [30,31] . EREG and
AREG expressions in mRNA, tumor protein and plasma protein levels are associated with poor prognosis
in CRC [31-33] . In vitro studies demonstrated their autocrine activation and reduction of cetuximab effect
in AREG and EREG gene silencing CRC cells [34,35] . These preclinical studies led to several retrospective
analyses demonstrating the correlation of EREG and AREG with anti-EGFR benefit in mCRC [25,36,37] . Most
studies demonstrated association between high AREG and EREG mRNA expression and better survival
in patients with CRC receiving anti-EGFR. In a metanalysis, these associations were still statistically
[38]
significant only in patients with wild-type KRAS mCRC . In a tumor analysis of CO.17 trial, the benefit
of cetuximab was found only in high expression but not low expression of EREG mRNA in patients with
[39]
wild-type KRAS mCRC .This predictive effect was not shown in patients with mutant KRAS mCRC.
Recently, a retrospective analysis of PICCOLO trial demonstrated similar predictive effect of AREG/
EREG mRNA expression for benefits of the additional panitumumab to irinotecan in patients with wild-
[40]
type KRAS mCRC . However, there are limitations for utility of AREG/EREG expression as a predictive
biomarker for anti-EGFR including no standard cut off for these continuous variables and modest
concordance between their expression in primary and metastatic sites. Although, the plasma levels of
AREG and EREG might overcome these limitations, there have been limited data of their predictive value
in patients with mCRC.