Eva Mazzotti

Background: Metastatic colorectal cancer (mCRC) with TP53 gene mutations, which are commonly found in tumors that are microsatellite stable (MSS) and not prone to genetic errors seen in some cancers, is associated with aggressive cancer behavior and poor outcomes. While MSI-high (MSI-H, referring to high levels of gene instability) disease benefits markedly from PD-1–based immunotherapy (drugs that inhibit the PD-1 protein on immune cells), TP53-mutated MSS tumors rarely receive immune checkpoint inhibitors (ICIs, drugs that help immune cells attack cancer) outside of trials and often only in later lines of therapy. Objective: To synthesize translational and clinical evidence regarding the effects of early rationale-driven immunotherapy combinations on survival outcomes, in TP53-mutated metastatic colorectal cancer, with a focus on practical clinical implications. Methods: This narrative review was conducted in accordance with SANRA criteria. Literature searches were performed in PubMed/MEDLINE, Scopus, and Web of Science (2010–2025). Relevant ESMO and NCCN guidelines and key references were also reviewed. Results: In KEYNOTE-177 study (MSI-H/dMMR), pembrolizumab improved PFS (HR 0.60) and showed durable OS with >5-year follow-up. CheckMate-142 reported sustained activity with nivolumab ± ipilimumab. Preclinical/early clinical data in MSS/TP53 suggest that ICIs may become effective when combined with priming (chemo/DDR) and vascular normalization (anti-VEGF), particularly in subsets with elevated TMB. The randomized ROME trial supports the clinical utility of genomically matched, NGS-guided strategies. Conclusions: A precision approach integrating TP53 status, TMB, and TME modulation could extend the immunotherapy benefit beyond MSI-H to TP53-mutated MSS mCRC; prospective first-line trials are warranted.

Background: Female Sexual dysfunction (FSD) is a common but under-recognized outcome of rectal and anal cancer treatment. While survival has improved, sexual health remains insufficiently addressed in survivorship care, warranting a multidisciplinary perspective. Methods: A narrative review of studies published between 2000 and 2025 was conducted, including clinical trials, cohort studies, and guideline documents addressing female sexual dysfunction after anorectal cancer treatment. Articles that were not pertinent to the research topic, outdated, or methodologically inadequate were excluded from the analysis. Results: Over 60% of female survivors experience FSD, including decreased libido, vaginal dryness, dyspareunia, and arousal difficulties. Causes include hormonal deficiency, nerve injury, and radiation fibrosis, compounded by psychological distress, altered body image, stoma-related stigma, and communication issues. The FSFI is commonly applied but lacks specificity for this population. Geographic disparities persist, with greater stigma and limited care access in low- and middle-income countries. Emerging therapies, such as immunotherapy, may mitigate FSD risk, though evidence is scarce. Conclusions: FSD after anorectal cancer is highly prevalent and significantly impacts quality of life, yet remains under-assessed in follow-up care. Multidisciplinary, culturally sensitive strategies integrating screening, psychosexual support, and tailored rehabilitation are urgently needed. Future research should address sexual outcomes more systematically, particularly in novel treatment contexts.