Martina Rotolo

The management of patients with multiple synchronous primary tumors remains challenging, particularly in individuals who are not candidates for surgery. While immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) tumors, evidence supporting their use as a non-operative strategy in patients with multiple malignancies is limited, as this population is excluded from clinical trials. We report three cases of patients with synchronous primary tumors, including gastrointestinal malignancies with dMMR status, treated with up-front ICIs. Treatment strategies were individualized based on the patient’s clinical condition, tumor burden, and molecular profile. All patients achieved meaningful and durable responses with long-term survival exceeding two to four years, supporting the feasibility of a non-operative strategy and organ preservation in carefully selected patients, including the frail subgroup population. Immunotherapy-based approaches were well tolerated, with a manageable safety profile. Notably, none of our patients underwent surgical resection. However, these observations are hypothesis-generating and cannot establish the efficacy or equivalence of immunotherapy to standard surgical management. Our findings extend current evidence to a largely underrepresented population and support a personalized, multidisciplinary, response-adapted approach. Prospective studies are warranted to better define patient selection, optimal treatment duration, and long-term outcomes of non-operative strategies in this setting.

Genetic alterations in CRC have shown a negative predictive and prognostic role in specific target therapies. The onset of immunotherapy has also undergone remarkable therapeutic innovation, although limited to a small subgroup of patients, the MSI-H/dMMR, which represents only 5% of CRC. Research is moving forward to identify whether other biomarkers can predict response to ICIs, despite various limitations regarding expression and identification methods. For this purpose, TMB, LAG3, and PD-L1 expression have been retrospectively evaluated in several solid tumors establishing the rationale to design clinical trials with concurrent inhibition of LAG3 and PD-1 results in a significant advantage in PFS and OS in advanced melanoma patients. Based on these data, there are clinical trials ongoing in the CRC as well. This review aims to highlight what is already known about genetic mutations and genomic alterations in CRC, their inhibition with targeted therapies and immune checkpoints inhibitors, and new findings useful to future treatment strategies.