New Therapeutic Approaches in Microsatellite Stable Colorectal Cancer Patients.

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Background

Colorectal cancer is the third most commonly diagnosed cancer and the second leading cause of cancer-related deaths worldwide. Despite significant advances in the treatment of CRC, the prognosis of metastatic colorectal cancer remains poor. Consequently, there is an unmet need to improve therapeutic options and outcomes in this patient population. In colorectal cancer, immunotherapy has had a significant impact in patients who have microsatellite instability-high (MSI-H) or DNA mismatch repair deficiency (dMMR). Based on the impressive results from clinical trials among patients with dMMR/MSI-H, the Food and Drug Administration (FDA) granted approval to two anti-PD-1 antibodies, representing a paradigm shift in this setting with a dramatic impact on patients prognosis. However, the vast majority of patients (about 95%) who are microsatellite stable (MSS) do not benefit from immunotherapy and are still treated with chemotherapy in combination with anti-VEGF and/or anti-EGFR agents. In the last decade, few advances have been made for these patients.

Colorectal cancer is a highly heterogenous disease at both genetic and molecular levels, which contributes to patients’ subgroups that differ in their prognosis and response to treatment. To date, median overall survival in patients with metastatic and previously untreated colorectal cancer ranges from 24 to 36 months, when combining molecular targeted therapies and chemotherapy. Currently, only DNA mismatch-repair status (dMMR/MSI-H), RAS-mutation and BRAF-mutation status influence clinical decision-making, although emerging biomarkers such as HER2 amplification or NTRK fusions may guide personalized therapeutic strategies in the future. Immune checkpoints inhibitors drastically improved the prognosis of dMMR/MSI-H patients, which is observed in only 5% of metastatic colorectal cancer patients. However, immunotherapy have rather limited benefit, if any, in microsatellite stable (MSS) colorectal cancer patients, that comprise the vast majority of patients. Several approaches have been proposed and are currently under evaluation in the attempt to overcome the mechanisms of resistance to immune checkpoint inhibitors, such as the combination with an anti-lymphocyte activation gene 3 (anti-LAG-3), with promising results. In addition, novel prognostic and predictive biomarkers are needed for a more personalized approach in this setting.

The scope of this collection is to explore all the new potential therapeutic approaches - in different phases of research - that may become new standard of care in microsatellite stable colorectal cancer patients in the near future. These may include new pathways, mutations or emerging biomarkers (e.g., DNA damage response pathway, POLE and KRAS mutations,) that could become targets for new compounds, as well as novel combination of drugs (e.g. immunotherapy +/- chemotherapy or targeted agents) which may overcome primary and/or acquired resistance to treatment. Moreover, new technologies (e.g. ctDNA) may become standard of care as a prognostic and predictive tool in these patients and may guide clinicians to personalized therapeutic strategies. We are interested in both original and review articles that may add some novel perspectives in this unmet clinical need.

Please note: manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent cohort or biological validation in vitro or in vivo) will not be accepted in any of the sections of Frontiers in Oncology.

Keywords: Microsatellite, Colorectal Cancer, Cancer Therapy

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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