Defining the current role of immune checkpoint inhibitors in the treatment of mismatch repair-deficient/microsatellite stability-high colorectal cancer and shedding light on future approaches

References

• Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA Cancer J Clin. 2020;70(1):7–30.
   PubMed Web of Science ®Google Scholar
• Ahnen DJ, Wade SW, Jones WF, et al. The increasing incidence of young-onset colorectal cancer: a call to action. In: Mayo Clinic Proceedings. (Ed.^(Eds) (Elsevier, 2014) 216–224.
   Google Scholar
• You YN, Xing Y, Feig BW, et al. Young-onset colorectal cancer: is it time to pay attention? Arch Internal Med. 2012;172(3):287–289.
   PubMedGoogle Scholar
• Guler I, Askan G, Klostergaard J, et al. Precision medicine for metastatic colorectal cancer: an evolving era. Expert Rev Gastroenterol Hepatol. 2019;13(10):919–931.
   PubMed Web of Science ®Google Scholar
• Guinney J, Dienstmann R, Wang X, et al. The consensus molecular subtypes of colorectal cancer. Nat Med. 2015;21(11):1350–1356.
   PubMed Web of Science ®Google Scholar
• Jenkins MA, Hayashi S, O’shea A-M, et al. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology. 2007;133(1):48–56.
   PubMed Web of Science ®Google Scholar
• Overman MJ, McDermott R, Leach JL, 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):1182–1191.
   PubMed Web of Science ®Google Scholar
• Overman MJ, Lonardi S, Wong KYM, 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):773–779.
   PubMed Web of Science ®Google Scholar
• Andre T, Shiu -K-K, Kim TW, et al. Pembrolizumab versus chemotherapy for microsatellite instability-high/mismatch repair deficient metastatic colorectal cancer: the phase 3 KEYNOTE-177 Study. (Ed.^(Eds) (American Society of Clinical Oncology, 2020)
   Google Scholar
• André T, Shiu -K-K, Kim TW, et al. Pembrolizumab in microsatellite-instability–high advanced colorectal cancer. N Engl J Med. 2020;383(23):2207–2218.
   PubMed Web of Science ®Google Scholar
• Liu B, Nicolaides NC, Markowitz S, et al. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet. 1995;9(1):48.
   PubMed Web of Science ®Google Scholar
• Boyer JC, Umar A, Risinger JI, et al. Microsatellite instability, mismatch repair deficiency, and genetic defects in human cancer cell lines. Cancer Res. 1995;55(24):6063–6070.
   PubMed Web of Science ®Google Scholar
• Li Z, Pearlman AH, Hsieh P. DNA mismatch repair and the DNA damage response. DNA Repair (Amst). 2016;38:94–101.
   PubMed Web of Science ®Google Scholar
• Umar A, Kunkel TA DNA-replication fidelity, mismatch repair and genome instability in cancer cells. In: EJB Reviews 1996. (Springer, 1996) 163–173.
   Google Scholar
• Parsons R, Li G-M, Longley MJ, et al. Hypermutability and mismatch repair deficiency in RER+ tumor cells. Cell. 1993;75(6):1227–1236.
   PubMed Web of Science ®Google Scholar
• Strauss BS. Frameshift mutation, microsatellites and mismatch repair. Mutat Res. 1999;437(3):195–203.
   PubMed Web of Science ®Google Scholar
• Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–2520.
   PubMed Web of Science ®Google Scholar
• Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357(6349):409–413.
   PubMed Web of Science ®Google Scholar
• Ogino S, Nosho K, Kirkner GJ, et al. CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer. Gut. 2009;58(1):90–96.
   PubMed Web of Science ®Google Scholar
• French AJ, Sargent DJ, Burgart LJ, et al. Prognostic significance of defective mismatch repair and BRAF V600E in patients with colon cancer. Clin Cancer Res. 2008;14(11):3408–3415.
   PubMed Web of Science ®Google Scholar
• Salipante SJ, Scroggins SM, Hampel HL, et al. Microsatellite instability detection by next generation sequencing. Clin Chem. 2014;60(9):1192–1199.
   PubMed Web of Science ®Google Scholar
• Sahin IH, Akce M, Alese O, et al. Immune checkpoint inhibitors for the treatment of MSI-H/MMR-D colorectal cancer and a perspective on resistance mechanisms. Br J Cancer. 2019;121(10):809–818.
   Web of Science ®Google Scholar
• Timmermann B, Kerick M, Roehr C, et al. Somatic mutation profiles of MSI and MSS colorectal cancer identified by whole exome next generation sequencing and bioinformatics analysis. PloS One. 2010;5(12):e15661.
   PubMed Web of Science ®Google Scholar
• Pawlik TM, Raut CP, Rodriguez-Bigas MA. Colorectal carcinogenesis: MSI-H versus MSI-L. Dis Markers. 2004;20(4, 5):199–206.
   PubMed Web of Science ®Google Scholar
• Le DT, Kim TW, Van Cutsem E, 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):11–19.
   PubMed Web of Science ®Google Scholar
• Lenz H-J, Lonardi S, Zagonel V, et al. Subgroup analyses of patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) metastatic colorectal cancer (mCRC) treated with nivolumab (NIVO) plus low-dose ipilimumab (IPI) as first-line (1L) therapy: Two-year clinical update. (Ed.^(Eds) (American Society of Clinical Oncology, 2021)
   Google Scholar
• Sahin IH, Goyal S, Pumpalova YS, et al. Clinical and molecular markers of immune checkpoint inhibitor (ICI) response in dMMR colorectal cancer (CRC) patients (pts). (Ed.^(Eds) (American Society of Clinical Oncology, 2020)
   Google Scholar
• Lee JJ, Yothers G, Jacobs SA, et al. Colorectal Cancer Metastatic dMMR Immuno-Therapy (COMMIT) study (NRG-GI004/SWOG-S1610): a randomized phase III study of mFOLFOX6/bevacizumab combination chemotherapy with or without atezolizumab or atezolizumab monotherapy in the first-line treatment of patients (pts) with deficient DNA mismatch repair (dMMR) metastatic colorectal cancer (mCRC). (Ed.^(Eds) (American Society of Clinical Oncology, 2019)
   Google Scholar
• Khalili JS, Liu S, Rodríguez-Cruz TG, et al. Oncogenic BRAF (V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin Cancer Res. 2012;18(19):5329–5340.
   PubMed Web of Science ®Google Scholar
• Sumimoto H, Imabayashi F, Iwata T, et al. The BRAF–MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med. 2006;203(7):1651–1656.
   PubMed Web of Science ®Google Scholar
• Weisenberger DJ, Siegmund KD, Campan M, 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.
   PubMed Web of Science ®Google Scholar
• Frederick DT, Piris A, Cogdill AP, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013;19(5):1225–1231.
   PubMed Web of Science ®Google Scholar
• Stewart RA, Pilié PG, Yap TA. Development of PARP and immune-checkpoint inhibitor combinations. Cancer Res. 2018;78(24):6717–6725.
   PubMed Web of Science ®Google Scholar
• Huang J, Wang L, Cong Z, et al. The PARP1 inhibitor BMN 673 exhibits immunoregulatory effects in a Brca1−/− murine model of ovarian cancer. Biochem Biophys Res Commun. 2015;463(4):551–556.
   PubMed Web of Science ®Google Scholar
• Vinayak S, Tolaney SM, Schwartzberg LS, et al. TOPACIO/Keynote-162: niraparib+ pembrolizumab in patients (pts) with metastatic triple-negative breast cancer (TNBC), a phase 2 trial. (Ed.^(Eds) (American Society of Clinical Oncology, 2018)
   Google Scholar
• Friedlander M, Meniawy T, Markman B, et al. A phase 1b study of the anti-PD-1 monoclonal antibody BGB-A317 (A317) in combination with the PARP inhibitor BGB-290 (290) in advanced solid tumors. (Ed.^(Eds) (American Society of Clinical Oncology, 2017)
   Google Scholar
• Yu EY, Massard C, Retz M, et al. Keynote-365 cohort a: pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). (Ed.^(Eds) (American Society of Clinical Oncology, 2019)
   Google Scholar
• Cercek A, Fernandes GDS, Roxburgh CS, et al. Mismatch repair–deficient rectal cancer and resistance to neoadjuvant chemotherapy. Clin Cancer Res. 2020;26(13):3271–3279.
   PubMed Web of Science ®Google Scholar
• Parc YR, Halling KC, Wang L, et al. MSH6 alterations in patients with microsatellite instability-low colorectal cancer. Cancer Res. 2000;60(8):2225–2231.
   PubMed Web of Science ®Google Scholar
• Engel C, Ahadova A, Seppälä T, et al. Associations of pathogenic variants in MLH1, MSH2, and MSH6 with risk of colorectal adenomas and tumors and with somatic mutations in patients with lynch syndrome. Gastroenterology. 2020;158(5):1326–1333..
   PubMed Web of Science ®Google Scholar
• Toyota M, Ahuja N, Ohe-Toyota M, et al. CpG island methylator phenotype in colorectal cancer. Proc Nat Acad Sci. 1999;96(15):8681–8686.
   PubMed Web of Science ®Google Scholar
• Ahadova A, Von Knebel Doeberitz M, Bläker H, et al. CTNNB1-mutant colorectal carcinomas with immediate invasive growth: a model of interval cancers in Lynch syndrome. Fam Cancer. 2016;15(4):579–586.
   PubMed Web of Science ®Google Scholar
• Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature. 2015;523(7559):231.
   PubMed Web of Science ®Google Scholar
• Bicknell DC, Kaklamanis L, Hampson R, et al. Selection for β2-microglobulin mutation in mismatch repair-defective colorectal carcinomas. Curr Biol. 1996;6(12):1695–1697.
   PubMed Web of Science ®Google Scholar
• Zaretsky JM, Garcia-Diaz A, Shin DS, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375(9):819–829.
   PubMed Web of Science ®Google Scholar
• Kopetz S, Andre T, Overman MJ, et al. Exploratory analysis of Janus kinase 1 (JAK1) loss-of-function (LoF) mutations in patients with DNA mismatch repair-deficient/microsatellite instability-high (dMMR/MSI-H) metastatic colorectal cancer (mCRC) treated with nivolumab+ ipilimumab in CHECKMATE-142. (Ed.^(Eds) (AACR, 2018)
   Google Scholar
• Pansky A, Hildebrand P, Fasler‐Kan E, et al. Defective Jak‐STAT signal transduction pathway in melanoma cells resistant to growth inhibition by interferon‐α. Int J Cancer. 2000;85(5):720–725.
   PubMed Web of Science ®Google Scholar
• Chalabi M, Fanchi LF, Dijkstra KK, et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat Med. 2020;26(4):566–576.
   PubMed Web of Science ®Google Scholar