Abstract
Colorectal cancer (CRC) is the third most common malignancy worldwide. Surgery remains the most important treatment for non-metastatic CRC, and the administration of adjuvant chemotherapy depends mainly on the disease stage, which is still the strongest prognostic factor. A refined understanding of the genomics of CRC has recently been achieved thanks to the widespread use of next generation sequencing with potential future therapeutic implications. Microsatellite instability (MSI) has been suggested as a predictive marker for response to anti-programmed-cell-death protein 1 (PD-1) therapy in solid tumors, including CRC. It should be noted that not all cancers with MSI phenotype respond to anti-PD-1 immunotherapy, highlighting the urgent need for even better predictive biomarkers. Mitogen-Activated Protein Kinase (MAPK) pathway genes KRAS, NRAS, and BRAF represent important molecular targets and could serve as independent prognostic biomarkers in CRC, and identify those who potentially benefit from anti-epidermal growth factor receptor (EGFR) treatment. Emerging evidence has attributed a significant role to inflammatory markers including blood cell ratios in the prognosis and survival of CRC patients; these biomarkers can be easily assessed in routine blood exams and be used to identify high-risk patients or those more likely to benefit from chemotherapy, targeted therapies and potentially immunotherapy. Analysis of cell-free DNA (cfDNA), circulating tumor cells (CTC) and/or micro RNAs (miRNAs) could provide useful information for the early diagnosis of CRC, the identification of minimal residual disease and, the evaluation of the risk of recurrence in early CRC patients. Even the selection of patients suitable for the new targeted therapy is becoming possible with the use of predictive miRNA biomarkers. Finally, the development of treatment resistance with the emergence of chemo-resistance clones after treatment remains the most important challenge in the clinical practice. In this context it is crucial to identify potential biomarkers and therapeutic targets which could lead to development of new and more effective treatments.
Highlights
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the fourth leading cause of cancer mortality worldwide [1]
This review focuses on KRAS, NRAS, BRAF, human epidermal growth factor receptor 2 (HER2)
The crucial role of epidermal growth factor receptor (EGFR) signaling in the survival of several tumors, including CRC, is supported by the approval of anti-EGFR targeted therapies; resistance to target therapy inevitably emerges; HER2 has recently been shown to represent one potential resistance mechanism leading to anti-EGFR antibody therapy resistance in KRAS wild type tumors [66]
Summary
Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the fourth leading cause of cancer mortality worldwide [1]. Risk factors associated with the incidence of CRC include older age, male sex, lifestyle, inflammatory bowel disease and a previous personal history of CRC It is mostly sporadic, though approximately 20–30% of patients carry inherited mutations [6,7]. Treatment of CRC usually involves surgical resection of the primary tumor followed by chemotherapy and/or targeted therapy for the advanced stage disease [9] Despite these advancements, as mentioned above, drug resistance still remains a widely unresolved issue [10]. MiRNAs have crucial regulatory functions, including regulation of important cellular functions like proliferation, apoptosis, angiogenesis, and immune response [21] They have been shown to have roles as tumor suppressor genes and oncogenes, and their diagnostic, prognostic, and predictive implications are being explored. Risk stratification by primary tumor site and assessment of tumor laterality in patient selection for EGFR antibody treatment are considered
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