No abstract

In the evolving molecular treatment landscape of metastatic colorectal cancer (mCRC), the identification of druggable alterations is pivotal to achieve the best therapeutic opportunity for each patient. Since the number of actionable targets is expanding, there is the need to timely detect their presence or emergence to guide the choice of different available treatment options. Liquid biopsy, through the analysis of circulating tumor DNA (ctDNA), has proven safe and effective as a complementary method to address cancer evolution while overcoming the limitations of tissue biopsy. Even though data are accumulating regarding the potential for ctDNA-guided treatments applied to targeted agents, still major gaps in knowledge exist as for their application to different areas of the continuum of care. In this review, we recapitulate how ctDNA information could be exploited to drive different targeted treatment strategies in mCRC patients, by refining molecular selection before treatment by addressing tumor heterogeneity beyond tumor tissue biopsy; longitudinally monitoring early-tumor response and resistance mechanisms to targeted agents, potentially leading to tailored, molecular-driven, therapeutic options; guiding the molecular triage towards rechallenge strategies with anti-EGFR agents suggesting the best time for retreatment; and providing opportunities for an “enhanced rechallenge” through additional treatments or combos aimed at overcoming acquired resistance. Besides, we discuss future perspectives concerning the potential role of ctDNA to fine-tune investigational strategies such as immuno-oncology.

Cancer immunotherapy, largely represented by immune checkpoint inhibitors (ICIs), has led to substantial changes in preclinical cancer research and clinical oncology practice over the past decade. However, the efficacy and toxicity profiles of ICIs remain highly variable among patients, with only a fraction achieving a significant benefit. New combination therapeutic strategies are being investigated, and the search for novel predictive biomarkers is ongoing, mainly focusing on tumor- and host-intrinsic components. Less attention has been directed to all the external, potentially modifiable factors that compose the exposome, including diet and lifestyle, infections, vaccinations, and concomitant medications, which could affect the immune system response and its activity against cancer cells. We hereby provide a review of the available clinical evidence elucidating the impact of host-extrinsic factors on ICI response and toxicity.