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Page 2 of 11 Tanasanvimon. J Cancer Metastasis Treat 2018;4:57 I http://dx.doi.org/10.20517/2394-4722.2018.38

still the mainstay treatment in mCRC, its efficacy could be significantly enhanced by the biologic therapies
including anti-angiogenesis and anti-epidermal growth factor receptor (anti-EGFR) agents. In a selected
[1]
subgroup, the median overall survival is now up to 40 months with current treatment paradigm .
Recently, the molecular targeted therapy and immunotherapy have been demonstrated as the emerging
effective therapeutic options for some patients with mCRC. The molecular biomarker plays a critical role as
a tool for personalized therapy in current and upcoming treatment paradigm in patients with mCRC. The
optimal utilization of molecular biomarker testing is required for best treatment outcomes in individual
patients. This article reviews clinical application and limitation of current and emerging biomarkers in
management of mCRC.

BIOMARKERS FOR ANTI- EGFR THERAPY
EGFR is a transmembrane receptor tyrosine kinase playing a major role in carcinogenesis of several
cancers including CRC. Although the EGFR expression was required for patients to be eligible in the initial
[2,3]
anti-EGFR trials in mCRC . The later reports demonstrated poor correlation between EGFR expression
[4,5]
and treatment response . Instead, KRAS mutation is a robust negative predictor for benefit of anti-EGFR
in patients with mCRC. However, not all patients with wild-type KRAS mCRC will have benefit from first-
line chemotherapy and anti-EGFR combination therapy, patient selection for anti-EGFR therapy has been
evolved through biomarker analysis in subsequent clinical trials.

RAS
RAS protein is a critical regulator of growth factor-induced cell proliferation and survival in both cancer and
normal cells. There are three RAS family genes including KRAS, NRAS and HRAS. KRAS mutation is found
in 30%-40% of CRC. NRAS mutation has been demonstrated in up to 3% of CRC while HRAS mutation
[6]
was very rare in CRC . In mCRC, KRAS exon 2 (codon 12 and 13) is the most frequent location for RAS
mutation, with prevalence of 40%. Other RAS mutations were found at KRAS exon 3 and 4, and NRAS exon
2, 3 and 4, with prevalence of 15%-20%. Totally, the prevalence of all RAS mutations was around 55%-60%
[7,8]
in patients with mCRC . The mutations promote constitutive activation of GTP-bound RAS, resulting in
activation of downstream signaling pathways especially the RAF/MEK/ERK pathway and PI3K pathway.

As a key downstream regulator of EGFR pathway, the activated mutation of KRAS might be able to
abrogate the anti-EGFR treatment effects. In 2008, a retrospective analysis of KRAS exon2 mutation of a
phase III trial, CO.17, demonstrated that cetuximab improved overall survival (OS) and progression free
[9]
survival (PFS) only in patients with wild-type KRAS tumors, not in patients with mutant KRAS tumors .
This finding was subsequently confirmed in several cohorts of phase II and III trials of both available
anti-EGFR agents including cetuximab and panitumumab [3,10,11] . In PRIME study, a prospective analysis
of KRAS exon 2 mutation revealed a detrimental effect of additional panitumumab to chemotherapy for
[12]
untreated patients with mutant KRAS mCRC . In this cohort, a subsequent report demonstrated the
extended analysis of RAS mutation, including KRAS and NRAS exon 2, 3 and 4, as the better predictive
[13]
factor for panitumumab in patients with mCRC . There was a detrimental effect of panitumumab in
patients with wild-type KRAS exon2 with mutant other RAS mCRC. Similarly, this predictive effect of
extended RAS mutation was subsequently confirmed in several phase II/III cetuximab and panitumumab
trials. Therefore, the extended analysis of RAS mutation is required in selection of patients with mCRC for
anti-EGFR therapy.

In contrast, KRAS mutation did not predict benefit of bevacizumab in patients with mCRC. In the
analysis of phase III trial cohorts, additional bevacizumab to chemotherapy provides clinical benefit in
both patients with wild-type and mutant KRAS mCRC [14,15] . Although patients with mutatnt KRAS mCRC
seemed to live shorter than patients with wild-type KRAS mCRC in several anti-EGFR trials, prognostic