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

               BIOMARKERS FOR IMMUNOTHERAPY
               Recently, immune checkpoint inhibitors including anti-programmed cell death-1 (PD-1)/PD-ligand 1
               (PD-L1) and anti-cytotoxic T lymphocyte associate protein-4 (anti-CTLA-4), have emerged as a new
               treatment paradigm in several cancers especially non-small cell lung cancer and melanoma. Given the
               low tumor mutational burden, colorectal cancer was considered as a “cold” tumor for immune response.
               Correspondingly, the early anti-PD-1 trial revealed almost no response in mCRC. However, subsequent
               studies demonstrated high response rate in patients with mCRC with high microsatellite instability (MSI-H).


               MSI
               MSI-H or DNA mismatch repair (MMR) deficiency is found in 12%-15% of CRC. It is a hallmark
               phenotype of Lynch syndrome caused by germline mutation of MMR genes including MLH1, MSH2, MSH6
               and PMS2. However, 80% of MSI-H/ deficient MMR (dMMR) CRC are sporadic and caused by epigenetic
               inactivation of MLH1. The prevalences of MSI-H/MMR deficiency are 20%, 12% and 5% in CRC stage II,
               III and IV, respectively [41,42] . MSI-H/dMMR CRCs have distinct clinicopathologic features including right-
               sided location, poor differentiation, mucinous type and lymphocyte infiltration. To detect dMMR tumor,
               there are two diagnostic methods including MSI test and MMR protein immunohistochemical staining.
               MSI-H/dMMR is a good prognostic factor in early stage CRC, but patients with MSI-H/dMMR mCRC had
               poorer prognosis than patients with microsatellite stable (MSS) or proficient MMR (pMMR) mCRC [41,43,44] .
               Although MSI-H/dMMR may negatively predict the benefit of adjuvant fluouracil in stage II CRC, the
               metanalysis showed no significant difference in chemotherapy response rates between MSI-H/dMMR and
                                [45]
               MSS/pMMR mCRC .
               Currently, MSI-H/dMMR is the only predictive biomarker for immunotherapy in patients with mCRC.
               In early reports of anti-PD1 in human tumors, it seemed to be inactive in mCRC. However, 1 out of 33
               patients with mCRC obtained complete response [46,47] . Given the hypermutated state and lymphocytic
               infiltration features of MSI-H/dMMR tumors, this particular subgroup has been explored for anti-PD-1 in
               mCRC. In a phase II trial, the response rates were 40% and 0% in patients with dMMR and pMMR mCRC,
                         [48]
               respectively . Recently, the combination of anti-PD-1 and anti-CTLA-4, nivolumab and ipilimumab, had
               shown more robust treatment outcomes including response rate of 55% and 1-yr PFS of 71% in previously
                                               [49]
               treated patients with dMMR mCRC . Anti-PD-1 is now a standard treatment option in patients with
               MSI-H/dMMR mCRC.

               PD-L1
               PD-1 is expressed in activated mature T cells, while PD-L1 is constitutively expressed in tissue including
               tumor cells. Ligation of PD-1 and PD-L1 results in co-inhibitory signal repressing the T cell response. PD-L1
               expression is currently the predictive and companion biomarker for anti-PD1 especially pembrolizumab in
               several cancers. In CRC, PD-L1 expression rate varied among several reports [50-52] . Although some reports
               showed higher PD-L1 expression in MSI-H CRC than MSS CRC [50-52] . This correlation was not consistent
                                                                                       [53]
               as reported by Droeser and colleagues in the largest study with 1,491 tumor samples . These inconsistent
               findings in CRC might be largely caused by the variation of PD-L1 expression assessment including
               staining techniques, antibodies and scoring systems. Also there are some evidenced of temporal and spatial
               heterogeneity of PD-L1 expression in mCRC [54,55] . With these limitations and no evidence of its predictive
               effect for anti-PD1 therapy, there is still no clinical application of PD-L1 expression in patient with mCRC.


               Tumor mutational burden
               Recently, tumor mutational burden has become the potential predictive factor for anti-PD1 therapy in
               several cancers. Generally, CRC is considered low tumor mutational burden (TMB) cancer, but MSI-H/
               dMMR CRC is constitutively high TMB tumor. As mentioned, MSI is very robust in predictive effect for
               anti-PD1 in mCRC. Moreover, MSI and MMR test is simple and less expensive than TMB assessment.
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