Pharmacological prevention of second primary cancers: From chemoprevention to precision cancer interception

BACKGROUND: The growing population of cancer survivors is increasingly exposed to the long-term risk of second primary cancers (SPCs), which represents a major source of morbidity and mortality. While current prevention mainly relies on surveillance and screening, pharmacological and immunological strategies may offer opportunities to reduce SPC incidence in selected high-risk populations. METHODS: This narrative review synthesises current evidence on pharmacological prevention strategies for SPCs, including endocrine therapy, aspirin and non-steroidal anti-inflammatory drugs, PARP inhibitors, metformin, GLP-1 receptor agonists, statins, nicotinamide, immune checkpoint inhibitors, cancer vaccines, and microbiome modulation. Evidence from randomised trials, observational studies, translational research, and ongoing clinical trials was reviewed, with particular attention to SPC-specific endpoints, biological rationale, safety, and clinical applicability. RESULTS: The strongest evidence currently supports endocrine therapy for reducing contralateral breast cancer in patients with hormone receptor-positive breast cancer, and aspirin in selected populations such as Lynch syndrome carriers or patients with molecularly defined colorectal cancer. Other repurposed agents, including metformin, statins, GLP-1 receptor agonists, and nicotinamide, remain investigational, with most available data addressing incident cancer, recurrence, or surrogate endpoints rather than SPC prevention specifically. Immunological approaches are emerging as particularly promising strategies. Retrospective studies and exploratory analyses of randomised trials suggest that immune checkpoint inhibitors may reduce the occurrence of new malignancies, while neoantigen-based vaccines, especially in Lynch syndrome, provide an early proof of concept for cancer immunoprevention. CONCLUSIONS: Pharmacological prevention of SPCs is an expanding but remains a heterogeneous field. Current evidence supports a shift from broad chemoprevention toward biologically informed, risk-adapted prevention strategies. Future progress will depend on dedicated SPC-focused trials, biomarker-driven patient selection, long-term safety evaluation, and integration of pharmacological prevention into broader cancer interception programmes.