ER^-/PR⁺ breast cancer: from diagnostic discordance to precision therapy

Estrogen receptor-negative/progesterone receptor-positive/human epidermal growth factor receptor 2-negative (ER^-/PR⁺/HER2^-)breast cancer is a rare, controversial type that makes up about 0. 3% of all breast cancer cases and does not follow the traditional ER→PR regulatory hierarchy. This review synthesizes the available evidence on the diagnostic evaluation, clinicopathological characteristics, molecular mechanisms, prognosis, and treatment of ER^-/PR⁺/HER2^-(ER^-/PR⁺) breast cancer. Although there are false-negative ER staining results and pre-analytical/analytical factors, a number of clinical and transcriptomic data support the existence of a reproducible ER^-/PR⁺subgroup with molecular heterogeneity. These tumors often have a high histological grade, elevated Ki-67 expression, TP53 alterations, and basal-like features, and are closer to triple-negative breast cancer than luminal disease. Potential drivers include ER-independent non-canonical PR activation, epigenetic dysregulation, kinase-mediated receptor phosphorylation, membrane-associated progesterone signaling and receptor network reprogramming. Direct subtype-specific evidence remains limited, and the effectiveness of conventional endocrine therapy is unknown. Current guidelines classify these tumors as hormone receptor-positive/HER2-negative, obscuring clinically relevant heterogeneity. Standardized repeat testing and multi-omic characterization are thus required. Future studies should prioritize prospective multicenter cohorts with paired pre-treatment and post-treatment receptor testing, spatial or single-cell characterization, biomarker-guided stratification and adaptive clinical trials. A PR-oriented precision-medicine framework may improve diagnostic classification and help identify therapeutic vulnerabilities in biologically distinct patient subsets. In addition, this rare phenotype may serve as a useful model for investigating lineage plasticity and endocrine resistance.