Esmeralda Celia Marginean1, Barbara Melosky1. 1. From the Department of Pathology, University of Ottawa, Ottawa, Ontario, Canada (Dr Marginean); the Gastrointestinal Pathology Section, Ottawa Hospital, Ottawa (Dr Marginean); the Department of Medical Oncology, University of British Columbia, Vancouver, Canada (Dr Melosky); and the Department of Oncology, British Columbia Cancer Agency, Vancouver (Dr Melosky).
Abstract
CONTEXT: - Colorectal cancer (CRC) represents the third most-common cancer in developed countries and is a leading cause of cancer deaths worldwide. Two recognized pathways contribute to CRC development: a more-common chromosomal instability pathway and, in 15% of cases, a deficient mismatch repair or microsatellite instability-high (MSI-H) pathway. The MSI-H CRC can be associated with somatic or germline mutations. Microsatellite status has been recognized as a prognostic and predictive biomarker. OBJECTIVES: - To summarize the molecular pathways of CRC, with an emphasis on the MSI (mismatch repair) pathway; the recommended MSI testing algorithms and interpretation; and the prognostic and predictive role of MSI-H status in personalized treatment, including adjuvant chemotherapy, targeted therapy, and immune checkpoint inhibitor therapy. DATA SOURCES: - A PubMed (US National Library of Medicine, Bethesda, Maryland) review was performed for articles pertaining to CRC, MSI and mismatch repair systems, molecular classification, immune response, programmed death receptor-1/programmed death ligand-1, and immunotherapy. CONCLUSIONS: - Although the TNM classification of malignant tumor stage remains the key determinant of CRC prognosis and treatment, there are considerable stage-independent, interindividual differences in clinical outcome and therapy response by patients. In addition, MSI-H status has an important role in CRC management and can be reliably detected by molecular and immunohistochemistry techniques and genetic testing. Efforts must be made to identify whether MSI-H CRC is germline or sporadic to ensure appropriate treatment, accurate prognosis, and risk assessment for relatives. Microsatellite status has been recognized as a good prognostic indicator and is predictive of a poor response to 5-fluorouracil-based chemotherapy and a good response to programmed death ligand-1 inhibitor pembrolizumab in metastatic/refractory MSI-H CRC.
CONTEXT: - Colorectal cancer (CRC) represents the third most-common cancer in developed countries and is a leading cause of cancer deaths worldwide. Two recognized pathways contribute to CRC development: a more-common chromosomal instability pathway and, in 15% of cases, a deficient mismatch repair or microsatellite instability-high (MSI-H) pathway. The MSI-H CRC can be associated with somatic or germline mutations. Microsatellite status has been recognized as a prognostic and predictive biomarker. OBJECTIVES: - To summarize the molecular pathways of CRC, with an emphasis on the MSI (mismatch repair) pathway; the recommended MSI testing algorithms and interpretation; and the prognostic and predictive role of MSI-H status in personalized treatment, including adjuvant chemotherapy, targeted therapy, and immune checkpoint inhibitor therapy. DATA SOURCES: - A PubMed (US National Library of Medicine, Bethesda, Maryland) review was performed for articles pertaining to CRC, MSI and mismatch repair systems, molecular classification, immune response, programmed death receptor-1/programmed death ligand-1, and immunotherapy. CONCLUSIONS: - Although the TNM classification of malignant tumor stage remains the key determinant of CRC prognosis and treatment, there are considerable stage-independent, interindividual differences in clinical outcome and therapy response by patients. In addition, MSI-H status has an important role in CRC management and can be reliably detected by molecular and immunohistochemistry techniques and genetic testing. Efforts must be made to identify whether MSI-H CRC is germline or sporadic to ensure appropriate treatment, accurate prognosis, and risk assessment for relatives. Microsatellite status has been recognized as a good prognostic indicator and is predictive of a poor response to 5-fluorouracil-based chemotherapy and a good response to programmed death ligand-1 inhibitor pembrolizumab in metastatic/refractory MSI-H CRC.