Editor’s Note: Estrogen receptor (ER)–positive breast cancer has long been regarded as a relatively “indolent” subtype. However, during disease progression, a subset of patients experience loss of ER expression, converting from ER-positive to ER-negative status. This transformation not only alters tumor biology but may also reshape therapeutic strategies and prognosis. At the 2025 San Antonio Breast Cancer Symposium (SABCS), Professor Wang Biyun and her team from Fudan University Shanghai Cancer Center presented a study based on ^18F-FES PET/CT imaging (poster PS5-03-16), which for the first time systematically compared clinical outcomes between patients with functional ER loss and those with de novo triple-negative breast cancer (TNBC).Study Overview
Title Clinical Outcomes of ER-Positive to Negative Conversion Versus De Novo Triple-Negative Breast Cancer: Evidence from an ^18F-FES PET/CT–Guided Study
Background During the course of disease, patients with ER-positive breast cancer may experience ER loss, resulting in ER-negative conversion. ^18F-fluoroestradiol positron emission tomography/computed tomography (^18F-FES PET/CT) enables noninvasive, whole-body assessment of functional ER status across metastatic lesions, particularly valuable when biopsies are difficult or infeasible. However, differences in clinical outcomes between patients with ER conversion and those with de novo TNBC have not been clearly defined.
Methods This retrospective study included 808 patients with recurrent or metastatic breast cancer initially diagnosed as ER-positive/HER2-negative who underwent ^18F-FES PET/CT at Fudan University Shanghai Cancer Center between 2017 and 2023. Among them, 82 patients with functional ER loss confirmed by FES-PET prior to first-line treatment for recurrence or metastasis constituted the study group. A contemporaneous cohort of 115 patients with de novo TNBC served as the control group. Propensity score matching was applied to balance baseline characteristics, including number of metastatic sites, history of visceral, liver, lung, or bone metastases, and prior taxane exposure.
Results After propensity score matching, 59 patients were included in each group, achieving good balance in baseline characteristics. Concordance between FES-PET and immunohistochemistry for ER status was 71.7%.
As of June 5, 2025, the median follow-up was 24.64 months (interquartile range [IQR] 12.62–41.72) in the ER conversion group and 28.75 months (IQR 14.98–48.84) in the TNBC group. There were 46 progression-free survival (PFS) events in the ER conversion group and 40 in the TNBC group.
After matching, median PFS differed significantly between groups. Compared with TNBC, patients with ER-positive to ER-negative conversion had a shorter PFS of 6.7 months versus 12.0 months, with a hazard ratio of 1.55 (95% CI 1.01–2.37, P = 0.042). The objective response rate was also significantly lower in the ER conversion group at 15.3% compared with 37.3% in the TNBC group, and the disease control rate was 72.9% versus 84.7% (P = 0.044).
Biomarker analyses revealed that, among evaluable patients, androgen receptor (AR) positivity was markedly higher in the ER conversion group than in the TNBC group, at 88.0% versus 25.0% (P < 0.0001), suggesting a potential role of AR signaling in this subgroup.
In terms of treatment patterns, 47.5% of patients in the ER loss group received first-line chemotherapy, most commonly capecitabine-based regimens. In contrast, 57.6% of patients in the TNBC group received platinum-based chemotherapy, with some also treated with PD-1 or PD-L1 inhibitors.
Conclusions Using ^18F-FES PET/CT to identify functional ER loss, this study demonstrates that patients who convert from ER-positive to ER-negative status have poorer outcomes than those with de novo TNBC. This unfavorable prognosis may be related to insufficient treatment intensity and activation of AR signaling pathways. These findings suggest that patients with functional ER loss should be considered a high-risk subtype and may warrant treatment strategies comparable in intensity to those used for TNBC. Further studies are needed to elucidate underlying mechanisms and to evaluate the therapeutic potential of AR-targeted treatments in this population.
Investigators’ Perspective
Highlighting the Prognostic Impact of Dynamic ER Changes and the Need for Vigilance in Clinical Practice This study is the first to systematically evaluate functional ER loss during breast cancer progression using ^18F-FES PET/CT and to show that these patients have an even worse prognosis than those with de novo TNBC. The findings underscore that ER status is not static and highlight the importance of dynamic assessment of ER function, particularly in patients with endocrine resistance or metastatic disease. Functional imaging, rather than reliance on a single biopsy, allows a more comprehensive assessment of tumor heterogeneity and facilitates identification of this high-risk subgroup, thereby informing subsequent treatment decisions.
ER Conversion and Molecular Subtypes: Insights from the Fudan Classification The Fudan classification subdivides TNBC into luminal androgen receptor, immunomodulatory, basal-like immunosuppressed, and mesenchymal subtypes to enable more precise therapeutic stratification. The very high AR positivity rate observed in patients with ER loss in this study suggests that many of these tumors may correspond to the luminal androgen receptor subtype. This subtype is characterized by a higher frequency of PI3K/AKT/mTOR pathway alterations and may be sensitive to AR- and pathway-targeted therapies.
^18F-FES PET/CT as a Tool for Dynamic ER Monitoring and Treatment Guidance Traditionally, treatment decisions in breast cancer rely heavily on immunohistochemical findings from the initial biopsy. By enabling whole-body, noninvasive, and dynamic assessment of ER function, ^18F-FES PET/CT offers a complementary approach to tumor classification and evaluation. For patients with endocrine resistance or suspected ER loss, ^18F-FES PET/CT may serve as an important adjunctive diagnostic tool to guide a timely transition to more aggressive chemotherapy or combination treatment strategies.
Professor Wang Biyun
Department of Medical Oncology, Fudan University Shanghai Cancer Center
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