American Cancer Society. Cancer Statistics Center. Available at: https://cancerstatisticscenter.cancer.org/#/cancer-site/Colorectum. Accessed January 25, 2020. 2020.

Angell HK, Bruni D, Barrett JC, Herbst R, Galon J. The immunoscore: colon cancer and beyond. Clin Cancer Res. 2020;26(2):332–9. https://doi.org/10.1158/1078-0432.Ccr-18-1851.

Article  PubMed  Google Scholar 

Reimers MS, Zeestraten EC, Kuppen PJ, Liefers GJ, van de Velde CJ. Biomarkers in precision therapy in colorectal cancer. Gastroenterol Rep (Oxf). 2013;1(3):166–83. https://doi.org/10.1093/gastro/got022.

Article  Google Scholar 

American Cancer Society. Cancer facts & figures 2020. Atlanta: American Cancer Society; 2020.

Google Scholar 

Sokolenko AP, Imyanitov EN. Molecular diagnostics in clinical oncology. Front Mol Biosci. 2018;5:76. https://doi.org/10.3389/fmolb.2018.00076.

CAS  Article  PubMed  PubMed Central  Google Scholar 

• Okita A, Takahashi S, Ouchi K, Inoue M, Watanabe M, Endo M, et al. Consensus molecular subtypes classification of colorectal cancer as a predictive factor for chemotherapeutic efficacy against metastatic colorectal cancer. Oncotarget. 2018;9(27):18698–711. https://doi.org/10.18632/oncotarget.24617This study assessed CMS subtypes of CRC for disease prognosis and therapeutic efficacy against mCRC and has had important implication in designing immunotherapy trials.

Article  PubMed  PubMed Central  Google Scholar 

Guinney J, Dienstmann R, Wang X, de Reynies A, Schlicker A, Soneson C, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–6. https://doi.org/10.1038/nm.3967.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Becht E, de Reynies A, Giraldo NA, Pilati C, Buttard B, Lacroix L, et al. Immune and stromal classification of colorectal cancer is associated with molecular subtypes and relevant for precision immunotherapy. Clin Cancer Res. 2016;22(16):4057–66. https://doi.org/10.1158/1078-0432.Ccr-15-2879.

CAS  Article  PubMed  Google Scholar 

Rodriguez-Salas N, Dominguez G, Barderas R, Mendiola M, Garcia-Albeniz X, Maurel J, et al. Clinical relevance of colorectal cancer molecular subtypes. Crit Rev Oncol Hematol. 2017;109:9–19. https://doi.org/10.1016/j.critrevonc.2016.11.007.

Article  PubMed  Google Scholar 

Peltomaki P. Role of DNA mismatch repair defects in the pathogenesis of human cancer. J Clin Oncol. 2003;21(6):1174–9. https://doi.org/10.1200/jco.2003.04.060.

CAS  Article  PubMed  Google Scholar 

Burt R. Inheritance of colorectal cancer. Drug Discov Today Dis Mech. 2007;4(4):293–300. https://doi.org/10.1016/j.ddmec.2008.05.004.

Article  PubMed  PubMed Central  Google Scholar 

Grady WM, Pritchard CC. Molecular alterations and biomarkers in colorectal cancer. Toxicol Pathol. 2014;42(1):124–39. https://doi.org/10.1177/0192623313505155.

CAS  Article  PubMed  Google Scholar 

Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology. 2010;138(6):2059–72. https://doi.org/10.1053/j.gastro.2009.12.065.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Galon J, Costes A, Sanchez-Cabo F, Kirilovsky A, Mlecnik B, Lagorce-Pages C, et al. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 2006;313(5795):1960–4. https://doi.org/10.1126/science.1129139.

CAS  Article  PubMed  Google Scholar 

Angell H, Galon J. From the immune contexture to the Immunoscore: the role of prognostic and predictive immune markers in cancer. Curr Opin Immunol. 2013;25(2):261–7. https://doi.org/10.1016/j.coi.2013.03.004.

CAS  Article  PubMed  Google Scholar 

• Pages F, Mlecnik B, Marliot F, Bindea G, Ou FS, Bifulco C, et al. International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet. 2018;391(10135):2128–39. https://doi.org/10.1016/s0140-6736(18)30789-xThis study highlights the importance of consensus immunoscore to aid TNM-immune classification system of cancer.

Article  PubMed  Google Scholar 

Koopman M, Kortman GA, Mekenkamp L, Ligtenberg MJ, Hoogerbrugge N, Antonini NF, et al. Deficient mismatch repair system in patients with sporadic advanced colorectal cancer. Br J Cancer. 2009;100(2):266–73. https://doi.org/10.1038/sj.bjc.6604867.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Jo W-S, Carethers JM. Chemotherapeutic implications in microsatellite unstable colorectal cancer. Cancer Biomark. 2006;2(1–2):51–60. https://doi.org/10.3233/cbm-2006-21-206.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Papaioannou NE, Beniata OV, Vitsos P, Tsitsilonis O, Samara P. Harnessing the immune system to improve cancer therapy. Ann Transl Med. 2016;4(14):261. https://doi.org/10.21037/atm.2016.04.01.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Huyghe N, Baldin P, Van den Eynde M. Immunotherapy with immune checkpoint inhibitors in colorectal cancer: what is the future beyond deficient mismatch-repair tumours? Gastroenterol Rep. 2019;8:11–24. https://doi.org/10.1093/gastro/goz061.

Article  Google Scholar 

•• Overman MJ, McDermott R, Leach JL, Lonardi S, Lenz HJ, Morse MA, et al. Nivolumab in patients with metastatic DNA mismatch repair-deficient or microsatellite instability-high colorectal cancer (CheckMate 142): an open-label, multicentre, phase 2 study. Lancet Oncol. 2017;18(9):1182–91. https://doi.org/10.1016/s1470-2045(17)30422-9Study that first showed durable response and efficacy of Nivolumab in pre-treated patients with dMMR/MSI-H mCRC.

CAS  Article  PubMed  PubMed Central  Google Scholar 

•• Chalabi M, Fanchi LF, Van den Berg JG, Beets GL, Lopez-Yurda M, Aalbers AG, et al. Neoadjuvant ipilimumab plus nivolumab in early stage colon cancer. Ann Oncol. 2018;29(suppl_8). https://doi.org/10.1093/annonc/mdy424.047This study highlighted potential advantage of using neoadjuvant ipilumumab and nivolumab for early stage CRC.

Diaz LA, Marabelle A, Delord J-P, Shapira-Frommer R, Geva R, Peled N, et al. Pembrolizumab therapy for microsatellite instability high (MSI-H) colorectal cancer (CRC) and non-CRC. J Clin Oncol. 2017;35(15_suppl):3071. https://doi.org/10.1200/JCO.2017.35.15_suppl.3071.

Article  Google Scholar 

•• Pembrolizumab doubles time to disease progression in patients with advanced colorectal cancer with specific DNA mutations [press release]. Available at https://www.asco.org/about-asco/press-center/news-releases/pembrolizumab-doubles-time-disease-progression-patients Accessed on June 2, 2020 Phase III KEYNOTE-177 trial showing enhanced efficacy of Pembrolizumab compared to chemotherapy as first-line therapy for MSI-high/dMMR mCRC.

•• Overman MJ, Lonardi S, Wong KYM, Lenz HJ, Gelsomino F, Aglietta M, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36(8):773–9. https://doi.org/10.1200/jco.2017.76.9901Study showing enhanced efficacy of combination therapy with Nivolumab and Ipilimumab compared to mono therapy with Nivolumab for dMMR/MSI-H mCRC.

CAS  Article  PubMed  Google Scholar 

Lenz HJJ, Van Cutsem E, Limon ML, Wong KY, Hendlisz A, Aglietta M, et al. Durable clinical benefit with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line therapy in microsatellite instability-high/mismatch repair deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC). Ann Oncol. 2018;29:viii714. https://doi.org/10.1093/annonc/mdy424.019.

Article  Google Scholar 

• Fukuoka S, Hara H, Takahashi N, Kojima T, Kawazoe A, Asayama M, et al. Regorafenib plus nivolumab in patients with advanced gastric or colorectal cancer: an open-label, dose-escalation, and dose-expansion phase Ib trial (REGONIVO, EPOC1603). J Clin Oncol. 2020;38(18):2053–61. https://doi.org/10.1200/jco.19.03296This study reported first safety and efficacy profile of combination therapy with nivolumab and Regorafenib, a potent inhibitor of angiogenic and oncogenic kinsases for MSS CRC, which makes large proportion of CRC cases.

Article  PubMed  Google Scholar 

•• Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–13. https://doi.org/10.1126/science.aan6733This study looked at 12 different tumor types and described MMR deficiency as a potential biomarker for predicting sucessfull treatment outcomes for these tumors including colorectal cancer.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Lee LH, Cavalcanti MS, Segal NH, Hechtman JF, Weiser MR, Smith JJ, et al. Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma. Mod Pathol. 2016;29(11):1433–42. https://doi.org/10.1038/modpathol.2016.139.

CAS  Article  PubMed  PubMed Central  Google Scholar 

•• Le DT, Kim TW, Van Cutsem E, Geva R, Jager D, Hara H, et al. Phase II open-label study of pembrolizumab in treatment-refractory, microsatellite instability-high/mismatch repair-deficient metastatic colorectal cancer: KEYNOTE-164. J Clin Oncol. 2020;38(1):11–9. https://doi.org/10.1200/jco.19.02107One of the promising clinical trials that showed efficacy and safety of Pembrolizumab against heavily pretreated patients with MSI-H CRC.

Article  PubMed  Google Scholar 

•• Marabelle A, Fakih MG, Lopez J, Shah M, Shapira-Frommer R, Nakagawa K, et al. 1192O - Association of tumour mutational burden with outcomes in patients with select advanced solid tumours treated with pembrolizumab in KEYNOTE-158. Ann Oncol. 2019;30:v477–v8 This study demonstrated that tumor-mutational burden high solid tumors can be targeted by immunotherapy, and suggest that immuntherapy can have a larger coverage. https://doi.org/10.1093/annonc/mdz253.018.

Article  Google Scholar 

Stenger M. Pembrolizumab in MSI-H or dMMR solid tumors: ‘first tissue/site-agnostic’ approval by FDA. 2018.

Google Scholar 

Yamamoto N, Nokihara H, Yamada Y, Shibata T, Tamura Y, Seki Y, et al. Phase I study of nivolumab, an anti-PD-1 antibody, in patients with malignant solid tumors. Investig New Drugs. 2017;35(2):207–16. https://doi.org/10.1007/s10637-016-0411-2.

CAS  Article  Google Scholar 

Andre T, Lonardi S, Wong M, Lenz H-J, Gelsomino F, Aglietta M, et al. Nivolumab + ipilimumab combination in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC): first report of the full cohort from CheckMate-142. J Clin Oncol. 2018;36(4_suppl):553. https://doi.org/10.1200/JCO.2018.36.4_suppl.553.

Article  Google Scholar 

Weisenberger DJ, Siegmund KD, Campan M, Young J, Long TI, Faasse MA, et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat Genet. 2006;38(7):787–93. https://doi.org/10.1038/ng1834.

CAS  Article  PubMed  Google Scholar 

Seppala TT, Bohm JP, Friman M, Lahtinen L, Vayrynen VM, Liipo TK, et al. Combination of microsatellite instability and BRAF mutation status for subtyping colorectal cancer. Br J Cancer. 2015;112(12):1966–75. https://doi.org/10.1038/bjc.2015.160.

CAS  Article  PubMed  PubMed Central  Google Scholar 

Pages F, Kirilovsky A, Mlecnik B, Asslaber M, Tosolini M, Bindea G, et al. In situ cytotoxic and memory T cells predict outcome in patients with early-stage colorectal cancer. J Clin Oncol. 2009;27(35):5944–51. https://doi.org/10.1200/jco.2008.19.6147.

CAS  Article  PubMed  Google Scholar 

Lee JJ, Chu E. Adjuvant chemotherapy for stage II colon cancer: the debate goes on. J Oncol Pract. 2017;13(4):245–6. https://doi.org/10.1200/JOP.2017.022178.

Article  PubMed  PubMed Central  Google Scholar 

Snook AE, Baybutt TR, Xiang B, Abraham TS, Flickinger JC, Hyslop T, et al. Split tolerance permits safe Ad5-GUCY2C-PADRE vaccine-induced T-cell responses in colon cancer patients. J Immuno Therapy Cancer. 2019;7(1):104. https://doi.org/10.1186/s40425-019-0576-2.