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Page 6 of 11 Tanasanvimon. J Cancer Metastasis Treat 2018;4:57 I http://dx.doi.org/10.20517/2394-4722.2018.38
[74]
zumab demonstrated 37.5% response rate in patients with HER2 overexpressed mCRC . Though, HER2
is currently a predictive marker for the emerging anti-HER2 therapy in patients with mCRC. The optimal
HER2 testing still needs to be defined in patients with mCRC.

RTK rearrangement
RTK rearrangements play a critical role in carcinogenesis of several cancers. These uncommon alterations
are the emerging targets for novel effective therapies as demonstrated in ALK positive non-small lung can-
cer. Based on a few reports, RTK rearrangements are rare with prevalence of 0.2%-2.4% in CRC. Pietran-
[75]
tonio et al. had reported the clinicopathological analysis of 27 patients with ALK, ROS1 and NTRK gene
rearrangement mCRC. As compared with 319 patients with no rearrangements, ALK, ROS1 and NTRK
gene rearrangements were significantly more frequent in elderly patients with right sided, MSI-H and RAS/
RAF wild type tumor. The study also demonstrated significantly shorter survival and poorer response to
[75]
anti-EGFR in these patients with ALK, ROS1 and NTRK gene rearrangement . By detection of these al-
terations, the patients could have benefit from the corresponding targeted therapy such as entrectinib in
patients with CAD-ALK gene and LMNA-ETRK1 rearrangement [76-78] . However, given its rarity, the opti-
mal diagnostic approach for these subgroups should be defined.

CLINICAL SAMPLE FOR BIOMARKER ANALYSIS
With the advancement of genomic analysis techniques, tumor genomic profiling is currently feasible in
plasma samples. Although, tumor sample is still the gold standard for tumor genomic profiling, plasma
sample or “liquid biopsy” addresses some limitations of tumor biomarkers.

Tumor biomarkers
Genomic profiling on tumor sample is the mainstay strategy for biomarker analysis in mCRC. However,
there might be various available tumor sample sites, including primary tumor and metastatic sites. Primary
tumor sample is more likely available in most patients with mCRC. The high concordance rates of genomic
profiling of 90%-100% especially for RAS and BRAF mutations between primary and metastatic CRC samples
were demonstrated in many studies [79-81] . Though, these high concordance rates have not been shown for
uncommon genomic alteration, either primary or metastatic tumor was acceptable for genomic profiling in
mCRC. For MSI/MMR, Haraldsdottir and colleagues showed perfect concordance of MMR status between
primary tumor and metastasis, but a couple of reports showed up to 20% discordance rates [82-84] . Although,
the spatial heterogeneity seems to be small in mCRC, the temporal heterogeneity, especially after treatment
[85]
is potentially an issue for management in mCRC . Therefore, the appropriate tumor samples for biomarker
testing should be defined for the emerging genetic alterations and MSI/MMR tests, in order to maximize the
benefit of molecular targeted agents and immune checkpoint inhibitors in mCRC.

Liquid biopsy
Not only a non-invasive and reproducible technique, but also a “liquid biopsy” would be able to overcome
the limitation of tumor analysis including spatial and temporal heterogeneity. Currently, it is based on
detection of circulating tumor DNA (ctDNA) by advanced technologies such as BEAMing method, droplet
digital PCR or next generation sequencing (NGS). Several studies confirmed high concordance rate, 90%-
100%, in BRAF and KRAS mutations between tumor and liquid biopsy [86,87] . Two prospective studies
demonstrated that early reduction in ctDNA during chemotherapy treatment could predict good responder
in patients with mCRC [88,89] . Also, the emergence of KRAS mutation could be detected before radiographic
disease progression during anti-EGFR therapy in patients with wild-type KRAS mCRC [85,90] . So, the liquid
biopsy for disease monitoring during anti-EGFR therapy is potentially useful for clinical management
of mCRC. However, the comprehensive gene analysis of ctDNA in mCRC is still not ready for clinical
application, given the rarity of other than RAS targetable gene mutation and test sensitivity in mCRC.