Rosiane Batista Mastelari, Tiago Veiras Collares
Second primary cancers (SPCs) are an important challenge in cancer survivorship, yet their heterogeneous biological origins cannot be reduced to treatment exposure. Inherited susceptibility shared environmental and tissue-field effects, ageing, pre-existing somatic mosaicism and treatment-associated mutagenesis contribute to SPC risk. High-resolution studies show that therapy can alter somatic selection, clonal architecture and persistent immune or stromal states in normal tissues. We propose the therapy-conditioned host as a State-Transition framework integrating these observations in survivorship. In this framework, a pre-treatment host state (H0) is perturbed by therapy (P), generating evolving post-treatment states H(t), defined by interacting genomic, clonal, immune and stromal/tissue features. H(t) describes biological state at time t, whereas the sequence H0→H(t1)→H(t2)… defines the host trajectory. Equivalent exposures may generate different trajectories, while distinct treatments may converge on similar biological states. Treatment history is therefore an imperfect proxy for biological consequence. The framework does not imply that all SPCs are therapy-induced, that post-treatment conditioning is inherently carcinogenic, or that clonal expansion is equivalent to malignant progression. It proposes that the magnitude, direction and persistence of treatment-associated changes may influence the evolutionary opportunities of normal and premalignant cells. We outline testable predictions and a translational pathway requiring longitudinal validation, incremental predictive value beyond baseline susceptibility and treatment history, clinical actionability and evidence that intervention improves outcomes without disproportionate harm. The central question is not only what treatment a survivor received, but what biological state it produced, how that state evolves over time, and whether its trajectory meaningfully alters subsequent cancer risk.