Prognostic Value of Estrogen Receptors Versus Progesterone Receptors in Early Breast Cancer: An Analysis of Clinical...

The accurate determination of hormone-receptor status is foundational to risk stratification and therapeutic decision-making in breast oncology. While the estrogen receptor (ER) is universally recognized as the primary predictive biomarker for a tumor's response to endocrine therapy, the independent prognostic value of the progesterone receptor (PR) remains a subject of ongoing clinical debate. This study evaluates the relative prognostic weight of PR expression compared to ER expression in early-stage breast cancer, clarifies the biological mechanisms driving PR loss, and assesses the diagnostic reproducibility of single hormone receptor-positive phenotypes using primary clinical and translational data synthesized from 2004 to 2026. A systematic assessment of primary scientific literature was conducted to isolate original clinical validation cohorts and translational molecular studies published from 2004 to 2026. Eligible studies were required to evaluate original data from primary operable, non-metastatic early-stage invasive breast cancer (Stage I to IIIA). Studies were categorized by methodology into clinical cohorts or mechanistic investigations. Methodological variations in immunohistochemical percentage cutoffs across different cohorts were evaluated via prespecified sensitivity analyses. The data tracking protocol was registered under the PROSPERO identifier CRD420251274985. The systematic literature search identified a cohesive pool of 18 eligible original studies published between 2004 and 2026 for quantitative synthesis and structural categorization. Within the synthesized clinical cohorts, higher PR expression was generally associated with improved disease-free survival (DFS) and significantly lower late recurrence rates in multivariate testing. Conversely, the loss of PR expression, resulting in the ER-positive/PR-negative (ER+/PR-) phenotype, was generally associated with endocrine resistance and a more aggressive clinical course. Furthermore, interassay reproducibility analyses revealed that the ER-negative/PR-positive (ER-/PR+) subtype is highly unstable, as a substantial proportion of cases were reclassified on secondary central pathology review, indicating that this phenotype frequently reflects an immunohistochemical technical artifact rather than a distinct biological entity. PR expression is not merely a surrogate marker for ER activity; it functions as a critical independent prognostic indicator and a molecular modulator in early breast cancer. The quantitative assessment of PR expression levels is essential for accurate risk stratification, particularly within luminal-like disease. Single hormone receptor-positive tumors, particularly the ER-/PR+ phenotype, require highly cautious clinical interpretation and validation via repeat immunohistochemical testing to prevent suboptimal treatment allocation.