ER negative PR positive breast cancer: Revisiting a rare and controversial molecular subtype

Estrogen receptor-negative/progesterone receptor-positive (ER-/PR+) breast carcinoma is a rare and controversial subtype that challenges conventional understanding of hormone receptor biology in breast cancer. Traditionally, the expression of progesterone receptors is considered a downstream effect of estrogen receptor activity, making the presence of PR in the absence of ER biologically puzzling. This discordant profile accounts for a small percentage of breast cancers and has raised questions regarding its reproducibility, prognostic significance, and therapeutic implications. Several studies have questioned the validity of the ER-/PR+ phenotype suggesting it may result from technical artifacts in immunohistochemical testing or heterogeneous tumor sampling. Nonetheless, when consistently identified, ER-/PR+ tumors have been observed to exhibit more aggressive clinicopathologic features than ER+ cancers, such as higher grade and increased proliferation rates. Despite this, they tend to have a better prognosis and overall survival compared to ER-/PR- tumors, suggesting some degree of hormone sensitivity. Therapeutic management of ER-/PR+ tumors remains a subject of debate. While some clinicians consider them hormone receptor-positive and advocate for endocrine therapy, others are cautious due to the absence of ER expression, which is traditionally viewed as the primary target of such treatments. As a result, treatment strategies often vary, underscoring the need for further research and standardized guidelines. In conclusion, ER-/PR+ breast carcinoma represents a biologically intriguing and clinically challenging subtype. Clarifying its molecular mechanisms, improving diagnostic accuracy and establishing evidence-based treatment approaches are essential for optimizing outcomes in this uncommon subtype of breast carcinoma.