ER Loss Requires Vigilance—Evidence Shows Poor Prognosis in Patients with ER Positive-to-Negative Conversion**
Editor’s Note:Estrogen receptor (ER)–positive breast cancer has traditionally been regarded as a relatively indolent subtype. However, during disease progression, a subset of patients experience loss of ER expression, transitioning from ER-positive to ER-negative status. This biological shift may profoundly alter tumor behavior, treatment strategies, and clinical outcomes.
At the 2025 San Antonio Breast Cancer Symposium (SABCS), Professor Biyun Wang and colleagues from Fudan University Shanghai Cancer Center presented a study (Poster No. PS5-03-16) based on ¹⁸F-FES PET/CT, which for the first time systematically compared the clinical outcomes of patients with functional ER loss and those with de novo triple-negative breast cancer (TNBC).
Study Overview
The study, entitled Clinical Outcomes of ER-Positive to Negative Conversion Versus TNBC: Evidence from an ¹⁸F-FES PET/CT–Guided Study, addresses an unresolved clinical question regarding whether ER-positive tumors that lose ER expression behave similarly to, or more aggressively than, primary TNBC.
Background
During disease evolution, ER-positive breast cancer may undergo ER loss, resulting in ER-negative conversion. ¹⁸F-fluoroestradiol positron emission tomography/computed tomography (¹⁸F-FES PET/CT) provides a noninvasive and whole-body method to assess ER functional status across all tumor lesions, particularly valuable in patients for whom repeated biopsies are impractical or infeasible.
Despite growing recognition of ER dynamics, the prognostic implications of ER-positive–to–negative conversion compared with de novo TNBC remain poorly defined, prompting the present investigation.
Methods
This retrospective analysis included 808 patients with recurrent or metastatic breast cancer whose primary tumors were ER-positive/HER2-negative and who underwent ¹⁸F-FES PET/CT at Fudan University Shanghai Cancer Center between 2017 and 2023. Among them, 82 patients were confirmed by FES-PET to have functional ER loss prior to first-line treatment for recurrence or metastasis and were assigned to the ER-loss cohort. A contemporaneous cohort of 115 patients with newly diagnosed TNBC served as the control group.
To minimize confounding, propensity score matching was applied to balance baseline characteristics between the two cohorts, including the number of metastatic sites, history of visceral, liver, lung, or bone metastases, and prior exposure to taxane-based chemotherapy.
Results
After propensity score matching, 59 patients were included in each group, with well-balanced baseline clinical features. Concordance between ER status determined by FES-PET and immunohistochemistry was 71.7%.
With a median follow-up of 24.64 months in the ER-positive–to–negative group and 28.75 months in the TNBC group, progression-free survival (PFS) events occurred in 46 and 40 patients, respectively. Following matching, median PFS was significantly shorter in the ER-loss group than in the TNBC group (6.7 months vs 12.0 months; HR 1.55, 95% CI 1.01–2.37; P = 0.042). In addition, both the objective response rate (15.3% vs 37.3%) and disease control rate (72.9% vs 84.7%) were significantly lower in patients with ER loss.
Biomarker analysis revealed a striking difference in androgen receptor (AR) expression. Among evaluable patients, AR positivity was observed in 88.0% of the ER-loss cohort, compared with only 25.0% of the TNBC cohort (P < 0.0001), suggesting a potentially important role of AR signaling in this subgroup.
Treatment patterns also differed between groups. Nearly half of the ER-loss patients received first-line chemotherapy, most commonly capecitabine, whereas a greater proportion of TNBC patients received platinum-based chemotherapy, with some also treated with PD-1/PD-L1 inhibitors.
Conclusions
Using ¹⁸F-FES PET, this study is the first to identify a population of breast cancer patients with functional ER loss and to demonstrate that their prognosis is inferior to that of patients with de novo TNBC. These findings suggest that ER-loss tumors may represent a distinct high-risk subtype, potentially driven by inadequate treatment intensity and activation of the AR pathway. Clinically, such patients may warrant treatment strategies comparable to those used for TNBC. Further mechanistic studies and clinical trials are needed to evaluate AR-targeted therapies in this setting.
Researchers’ Perspective
This work underscores the prognostic significance of dynamic changes in ER status. By employing functional imaging rather than relying solely on single-site biopsy, the study highlights intratumoral and interlesional heterogeneity and emphasizes the need for ongoing assessment of ER functionality, particularly in patients with endocrine resistance or metastatic disease. Identification of this high-risk subgroup may enable earlier treatment escalation and more rational therapeutic decision-making.
Molecular Interpretation and the Fudan Classification
Within the framework of the Fudan classification, TNBC is subdivided into luminal androgen receptor (LAR), immunomodulatory, basal-like immune-suppressed, and mesenchymal subtypes. The exceptionally high AR positivity observed in ER-loss patients suggests that many may correspond to the LAR subtype, which is characterized by frequent PI3K/AKT/mTOR pathway alterations and potential sensitivity to AR- and pathway-targeted therapies.
Clinical Implications of ¹⁸F-FES PET/CT
Traditionally, treatment decisions in breast cancer rely heavily on immunohistochemical assessment at initial diagnosis. This study demonstrates that ¹⁸F-FES PET/CT enables noninvasive, whole-body, and dynamic evaluation of ER function, offering a valuable adjunct for disease classification and treatment planning. In patients with suspected ER loss or endocrine resistance, FES PET/CT may support timely transition to more aggressive systemic therapies or combination regimens.
Professor Biyun Wang
