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An increasing number of people survive cancer. That is good news, but it has a hidden side: the long-term risk of developing a second primary cancer (SPC), distinct from the first, which has become an important cause of morbidity and mortality among survivors [PMID: 42556070].

Today, prevention of these second cancers relies almost entirely on surveillance and screening. The problem is that watching is not the same as preventing. A recent review by the Centre Léon Bérard (Lyon) examines pharmacological and immunological strategies that could reduce the incidence of SPCs in high-risk populations, honestly separating what we already know from what only promises [PMID: 42556070].

What evidence DOES support

Endocrine therapy and contralateral breast cancer. This is the strongest evidence of all. In women with hormone-sensitive breast cancer, endocrine therapy (e.g., tamoxifen or aromatase inhibitors) consistently reduces the risk of cancer in the opposite breast [PMID: 42556070]. It is not new data, but the review confirms it as the current cornerstone of pharmacological prevention of SPCs.

Aspirin in selected populations. Acetylsalicylic acid has support in very specific groups: carriers of Lynch syndrome and patients with molecularly defined colorectal cancer. In them, aspirin reduces the emergence of new malignancies [PMID: 42556070]. Outside those profiles (defined genetically or molecularly), evidence does not follow.

What for now only promises

The rest of the arsenal are “repurposed” drugs that shine in other scenarios but remain investigational for SPC prevention [PMID: 42556070]:

• Metformin, statins, GLP-1 agonists, nicotinamide: most available data address incident cancer, recurrence, or surrogate endpoints, not specific prevention of SPC [PMID: 42556070].
• PARP inhibitors: mentioned as a biologically plausible strategy in high-risk populations, but without dedicated SPC evidence yet [PMID: 42556070].

The immunological route: the interesting part

This is where the field moves fastest. Retrospective studies and exploratory analyses of randomized trials suggest that immune checkpoint inhibitors (ICI) could reduce the emergence of new malignancies [PMID: 42556070]. And neoantigen vaccines, especially in Lynch syndrome, already provide an “early proof-of-concept” for cancer immunoprevention [PMID: 42556070].

The conceptual leap is real: moving from “remove the tumor and watch” to “train the immune system so it does not let the next one grow.”

What does this mean in clinical practice?

Three practical ideas for the oncologist:

1. Do not underestimate adjuvant endocrine therapy as a prevention tool, not just treatment. The contralateral breast is a preventable SPC.
2. Ask about Lynch syndrome in CRC. If the molecular profile places them at risk, aspirin makes sense as continued prevention, not only antiplatelet.
3. Do not prescribe metformin/statins/GLP-1 “just in case” thinking of cancer prevention. Today’s evidence does not justify it outside a clinical trial.

The road ahead

The review is clear: the future is not broad chemoprevention, but risk-adapted and biology-guided prevention — dedicated SPC trials, patient selection by biomarker, long-term safety evaluation, and integration into “cancer interception” programs [PMID: 42556070].

Meanwhile, the best prevention of second cancers remains what we already control: treat the first one well, and do not forget adherence to what already works.

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Link to paper: https://doi.org/10.1016/j.ctrv.2026.103200 (PMID: 42556070)

— This analysis was generated by ANGIE (Always Next to Guide, Inspire and Empower), an artificial intelligence system with SOUL profiles, designed by Dr. Javier Pumares Pérez.

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