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Therefore, the clinical application of TMB is quite limited in patients with mCRC. Although, early report
of TMB assessment by comprehensive genomic profiling (CGP) demonstrated 20% high TMB in MSS CRC,
there was only 1% high TMB in MSS CRC in the subsequent study [56,57] . However, there were different cut
off levels for high TMB among these studies, clinical validation of these cut points in association with
benefit of anti-PD1 needed to be defined.

BIOMARKERS FOR EMERGING TARGETED THERAPY
Over the past decade, there have been several emerging molecular targeted therapies playing key role in
cancer personalized therapy. In CRC, the most common genomic alterations including APC, RAS and
TP53 are still undruggable. However, the current genomic profiling landscape leads to the discovery of
uncommon targetable genomic alterations such as BRAF mutation, human epidermal growth factor
receptor 2 (HER2) amplification and receptor tyrosine kinase (RTK) rearrangements in CRC.

BRAF
RAF protein is a key protein kinase transducing signal from RAS to MEK in MAPK pathway. BRAF
mutation was found in 10% of mCRC [16,58,59] . BRAF V600E is the most common mutation resulting in an
[60]
increased activity of BRAF . In patients with mutant BRAF CRC, there are distinct clinicopathological
[61]
features including proximal tumor location, T4 tumor, poor differentiation and older age . However,
recently, there was a report of patients with mutant BRAF 594 or 596 with different features including
rectal location, non-mucinous and no peritoneal metastasis. BRAF mutation is mutually exclusive with
[59]
KRAS mutation but associated with MSI .
BRAF mutation is a poor prognostic factor. The analysis of phase III first-line chemotherapy studies in
patients with mCRC demonstrated significantly shorter PFS and OS in patients with mutant BRAF tumors
compared to wild-type BRAF tumors [16,41] . However, this prognostic effect was demonstrated only in
[41]
patients with proficient MMR tumors .

In contrast to melanoma, BRAF targeted therapy did not have meaningful activity in patients with mutant
BRAF mCRC [62-65] . The preclinical study showed feedback activation of EGFR as a resistance mechanism
[66]
to BRAF inhibitor in mutant BRAF mCRC . Recently, a phase II trial showed significant improvement of
PFS from 2.0 to 4.4 months and a response rate from 4% to 16% by additional vemurafenib to cetuximab
[67]
and irinotecan in patients with mutant BRAF V600 mCRC .The addition of MEK inhibitor or PI3K
inhibitor to the dual therapy seemed to show better response rates and PFS [68,69] . Therefore, BRAF mutation
is now an emerging target for combined BRAF inhibitor therapy in patients with mCRC.

HER2
HER2 is an EGFR family member activating MAPK and PI3K pathways. HER2 amplification/ overexpres-
sion is a prognostic and predictive marker for breast and gastric cancers. In CRC, it accounts for 2%-3%
[70]
of mCRC, but up to 5% in wild-type KRAS tumors . It is very rare in patients with mutant RAS/BRAF
[70]
mCRC . HER2 amplification/overexpression could be conventionally detected by in situ hybridization or
immunohistochemical staining in tumor samples. The HER2 testing recommendation has been a consen-
sus in breast and gastric cancers, but not in CRC. In a matched sample analysis, Lee and colleagues showed
[71]
high discordance in positive results of FISH test between primary and metastatic sites . There was also
the possibility of changes in HER2 status after anti-EGFR therapy in patients with mCRC as shown in
[72]
an analysis of plasma samples . Moreover, there has been no consensus in diagnostic criteria for HER2
overexpression in CRC. The more stringent criteria including an intensely positive > 50% of cancer cells re-
quired for positivity by immunohistochemical staining was validated in HERACLES study, an anti-HER2
[73]
targeted study . In this study, there was 30% response rate to lapatinib and trastuzumab in patients with
HER2 overexpressed mCRC. Another trial evaluating efficacy of combination of pertuzumab and trastu-