Figure 1.

Gastroesophageal and colorectal cancers main clinical challenges (inner circle), current clinical approaches (outer circle) and opportunities provided by neoantigen discovery. Current clinical challenges include: i) Lack of robust early diagnosis tools, requiring population screening and timely medical check-ups, especially for population subsets presenting known risk factors (poor diet; H. pylori infection; family history, age, gender, pre-neoplastic lesions; etc). The absence of molecular biomarkers with the necessary specificity and sensitivity to assist in this matter remains a tremendous obstacle for early cancer detection; ii) Need for patient stratification, mostly achieved based on the clinicopathological classification of the lesions and, most recently, moving towards the incorporation of molecular biomarkers; iii) Therapy selection and efficacy, currently based on clinicopathological features but rapidly evolving towards molecular-assisted settings capable of aiding therapy personalization and early definition of responders. Therapeutic management has been based on surgery, chemo and/or radiotherapy, encompassing severe toxicity and limited efficacy, particularly for advanced disease stages. However, this paradigm has started to change with the introduction of antibody-based targeted therapeutics against key oncogenic cell surface receptors and immune-check point proteins such as PD-1, PD-L1 and CTLA4. CAR-T immunotherapy is also amongst future promising approaches; iv) Non-invasive detection, necessary for real-time monitoring of disease status and evolution throughout the course of disease. The field of liquid biopsies has tremendously evolved with the evaluation of circulating tumor DNA/miRNAs, proteins, micro and nanovesicles (exosomes and others) and, more recently, the study of circulating tumor cells (CTCs). The evaluation of these biomarkers in bodily fluids has improved prognostications and helped refining therapeutic selection, evaluating responses, establishing the risk of metastasis development and the detection of radiologically occult micrometastasis; v) Molecular heterogeneity is also a critical clinical challenge. This aspect has been a major obstacle towards effective molecular-assisted oncology and the introduction of targeted therapeutics. Nevertheless, the field has experienced significant advances with next generation sequencing, which generated a significant amount of genomics and transcriptomics data that has been used to propose gastric and colorectal cancer molecular subtypes. Cancer proteomics characterization has also contributed to the identification of relevant biomarkers; however, with yet limited clinical translation; vi) Cancer neoantigens discovery also represents a critical objective and a daunting challenge. It will be crucial for the identification of cancer-specific fingerprints capable of guiding therapeutic decision and designing effective targeted therapies and immunotherapy with very limited off-targeted effects. The comprehensive integration of genomics, transcriptomics and proteomics as well as information on post-translational modifications, with emphasis on glycosylation, will be of key importance for the identification of relevant protein functional nodes and targetable biomarkers at the cell-surface.