The introduction of novel oncologic therapies, including targeted agents, immunotherapies, and antibody–drug conjugates, has transformed the therapeutic landscape of cancer care. This evolution has resulted in a dual clinical scenario; while survival outcomes have markedly improved, leading to a growing population of long-term cancer survivors, an increasing incidence of previously unrecognized treatment-related toxicities has emerged. Among these, cardiovascular adverse events represent some of the most prevalent and clinically significant complications observed in both conventional chemotherapy and modern therapeutic regimens. Cardiotoxicity has become a major concern, with the potential to adversely affect not only cardiovascular health but also the continuity and efficacy of oncologic treatments, thereby impacting overall survival. This opinion paper synthesizes current evidence, identifies critical gaps in knowledge, and advocates for a multidisciplinary, evidence-based framework to guide the prevention, early detection, and optimal management of cardiotoxicity associated with anticancer therapies.

Colorectal cancer (CRC) remains a leading cause of cancer-related mortality, with metastatic disease posing significant therapeutic challenges. While anti-EGFR therapy has improved outcomes for patients with RAS and BRAF wild-type tumors, resistance remains a major hurdle, limiting treatment efficacy. The concept of negative hyperselection has emerged as a refinement of molecular profiling, identifying additional genomic alterations—such as HER2 and MET amplificationsand MAP2K1 mutations—that predict resistance to anti-EGFR agents. Studies incorporating these expanded assessments have demonstrated that nearly half of patients with RAS/BRAF wild-type tumors harbor alternative resistance biomarkers, underscoring the need for expanded selection criteria. Liquid biopsies, particularly circulating tumor DNA (ctDNA) analysis, have revolutionized precision oncology by providing a minimally invasive, real-time assessment of tumor dynamics. ctDNA-based hyperselection enables the detection of resistance-associated alterations, guiding treatment decisions with greater accuracy than conventional tissue biopsies. Recent trials support the predictive value of ctDNA-defined negative hyperselection, revealing superior outcomes for patients stratified through liquid biopsy. This narrative review explores the evolving role of molecular hyperselection in first-line anti-EGFR therapy, emphasizing the integration of ctDNA to refine patient selection, enhance therapeutic efficacy, and pave the way for personalized treatment strategies in metastatic CRC.

Background: Polyploid and chromosomal copy number gains (CNGs) cells may serve as key mediators of tumor plasticity, therapeutic resistance, and clonal evolution. Despite growing interest, their biological and clinical relevance in colorectal cancer, particularly in the metastatic setting, remains poorly defined. Methods: We performed an integrated morphological, cytogenetic, and genomic analysis of metastatic colon cancer. A tissue microarray comprising 100 tumors was evaluated, of which 47 cases were fully assessable for morphology and fluorescence in situ hybridization (FISH). Polyploid nuclei and chromosomal CNGs were assessed morphologically and cytogenetically. High-resolution targeted sequencing (TruSight Oncology 500) was conducted to characterize genomic alterations. Bioinformatic analyses included Gene Ontology enrichment and Phenolyzer network modeling. Associations with clinicopathological variables and survival outcomes were explored. Results: Polyploid nuclei and/or chromosomal CNGs were identified in approximately 25% of evaluable cases. These alterations were enriched in right-sided CRCs and in older patients, suggesting a link with age-related genomic instability. Polyploid/CNG tumors did not show significant enrichment for canonical CRC driver mutations (RAS, TP53, SMAD4), although trends toward co-occurrence with BRAF mutation and mutual exclusivity with HER2 amplification were observed. Integrative bioinformatic analyses highlighted dysregulation of pathways involved in mitotic control, centrosome organization, and DNA replication stress. Conclusions: In metastatic colon cancer, the presence of genome-wide copy number gain may delineate a tumor subset with distinctive clinicopathological and molecular characteristics. Further studies are warranted to elucidate the biological significance of these features and to explore their potential implications for tumor evolution, treatment response, and clinical stratification.

Real-world evidence on the influence of sex, age, and tumour type on pembroli-zumab-associated adverse reaction reporting remains limited. We retrospectively ana-lysed individual case safety reports (ICSRs) submitted to EudraVigilance between 1 January and 31 December 2025 involving pembrolizumab monotherapy. Adverse re-actions were classified according to MedDRA System Organ Class (SOC), and toxicity burden was defined as single- versus multiple-SOC involvement. Associations were assessed using Pearson’s chi-square test and Cramér’s V; sex comparisons across nine SOCs used a Bonferroni-adjusted threshold of p< 0.0056. Overall, 8,488 ICSRs were an-alysed; sex was available in 7,991 reports, age in 6,941, and 6,482 were evaluable across 14 tumour types. Overall toxicity burden did not differ by sex (p=0.110). Endocrine (18.4% vs 12.4%) and blood and lymphatic disorders (13.4% vs 9.5%) were more frequent in women, whereas respiratory (12.4% vs 7.0%) and cardiac disorders (13.9% vs 11.5%) were more frequent in men, all remaining significant after Bonferroni correction. However, none persisted after adjustment for tumour histotype and age (adjusted ORs: 1.06, 0.85, 1.22 and 1.02, respectively). Multiple-SOC reporting differed modestly by age, being lower in individuals >85 years (39.9% vs 47.7% and 48.1%; p=0.026), and by tumour type (p=0.016). Effect sizes were small. Observed sex-related reporting patterns may therefore largely reflect tumour-type composition rather than an independent sex effect. Findings are exploratory and require confirmation in denominator-based prospective studies.