Precision oncology in rare tumors: Have the orphans been adopted?

Oncology has shifted from organ- or histology-based therapy toward precision medicine, guided by molecular and immune targets. This paradigm change is especially impactful in rare cancers, which may be defined by unusual histology, anatomical site, or uncommon molecular subtypes of common tumors. The emergence of tumor-agnostic, histology-independent classifications has added new molecularly defined rare tumor groups. Biomarker-based therapies mark a turning point in personalized medicine, with several gene- and immune-targeted drugs now approved by the US Food and Drug Administration (FDA). Tissue-agnostic approvals typically rely on trials showing high response rates and durable benefit across diverse cancers driven by rare molecular alterations. This approach is crucial for the ∼200 types of histologically rare cancers, where trials in tiny patient subsets are unfeasible. Finally, the complexity and variability of tumor genomics between patients highlight the need for individualized, n-of-1 therapeutic combinations as the next step in optimizing cancer treatment.