Evidence and gaps in tumor-agnostic therapies for breast cancer: a narrative review.

Abstract

Background and objective: Tumor-agnostic therapies enable treatment selection based on shared molecular alterations rather than tissue of origin and represent a central advancement in precision oncology. Since 2017, multiple U.S. Food and Drug Administration (FDA) approvals have validated this biomarker-driven framework across solid tumors. Clinical applicability in breast cancer is limited by the low prevalence of actionable tumor-agnostic biomarkers and minimal representation of breast tumors in pivotal registrational trials. This review evaluates the biological rationale, clinical evidence, and relevance of tumor-agnostic therapies in breast cancer.

Methods: A structured literature search was conducted using PubMed/MEDLINE, Embase, ClinicalTrials.gov, and FDA regulatory documents from database inception through November 2025. Search terms included tumor-agnostic, tissue-agnostic, basket trials, and biomarker-specific therapies. Inclusion was restricted to FDA-approved tumor-agnostic therapies supported by prospective clinical or registration-enabling data.

Key content and findings: Nine FDA-approved tumor-agnostic therapies across multiple mechanistic classes were identified. Breast cancer representation in pivotal datasets was limited or absent in most approvals. Several therapies were supported by datasets that included no breast cancer patients, while others included only one to three cases. The largest breast cancer subgroups included fewer than fifteen patients. Clinical activity was observed in select contexts, particularly NTRK fusion-positive tumors and hypermutated cancers treated with immune checkpoint inhibitors. Most available evidence in breast cancer is derived from extrapolation across non-breast tumor types.

Conclusions: Tumor-agnostic therapies represent a biologically valid treatment strategy for rare molecular subsets of breast cancer. Clinical implementation is constrained by low biomarker prevalence, limited disease-specific evidence, and absence of robust survival data. A selective, guideline-informed approach using comprehensive genomic profiling in metastatic disease is appropriate. Expansion of breast-specific evidence through histology-enriched trials, prospective registries, and standardized molecular diagnostics is required to define the role of tumor-agnostic therapies in breast oncology.