Abstract Background: The existence of estrogen receptor-negative (ER-), progesterone receptor-positive (PR+) breast cancer is rare, biologically confusing, and often attributed to technical artifact. Previous national analyses found no benefit from endocrine therapy (ET) in ER-/PR+ tumors, but more recent data suggest a survival benefit. To explore this inconsistency, we analyzed the association between receiving ET and survival in ER-/PR+ early-stage breast cancer treated with chemotherapy over time. Methods: We used the National Cancer Database (NCDB) to identify women age 40 and older diagnosed with stage I-III, ER-/PR+ breast cancer from 2010 to 2020 who received chemotherapy. Multivariate logistic regression evaluated factors associated with ET omission. Multivariate Cox regression analyzed the association between ET receipt and three-year overall survival (OS), stratified by diagnosis period (2010-2017 vs. 2018-2020) based on 2018 changes for prognostic staging and NCDB site-specific factors. Analyses adjusted for stage at diagnosis, age, comorbidity, HER2 status, race/ethnicity, grade, facility type, and zip code income. Robustness was tested using propensity score matching (PSM), landmark analysis, and HER2-negative subgroup analysis. Results: We identified 24,198 (0.94%) cases of ER-/PR+ breast cancer, of which 18,788 (77.6%) were stage I-III at diagnosis. Of these, 13,957 (74.3%) received chemotherapy, and 11,558 with complete covariate data were analyzed. Most cases were HER2-negative (60.2%) and high grade (75.1%). Stage distribution was 38.5% stage I, 43.5% stage II, and 18.0% stage III. Two-year overall survival was 93.3% for patients diagnosed from 2010-2017 and 92.9% for 2018-2020. ET was omitted in 33.8% of patients (median age 58 vs. 57 among ET recipients). In multivariate logistic regression, factors associated with omission of ET were diagnosis from 2018-2020 (adjusted odds ratio aOR 1.95, 95% CI 1.75-2.17, p0.001), increasing age (age 70-80 vs. 40-50: aOR 1.34, 95% CI 1.16-1.55, p0.001), and high grade (aOR 1.15, 95% CI 1.03-1.28, p=0.02). In multivariate Cox regression, receiving ET was associated with improved three-year OS for patients diagnosed from 2010-2017 (n=7,517; adjusted hazard ratio aHR 0.54, 95% CI 0.47-0.62, p0.001) and 2018-2020 (n=4,041; aHR 0.60, 95% CI 0.48-0.77, p0.001). Interaction testing for diagnosis period and ET benefit was not significant (p=0.59). After PSM by all covariates, OS benefit remained for both 2010-2017 (n=5,696; aHR 0.55, 95% CI 0.47-0.65, p0.001) and 2018-2020 (n=2,344; aHR 0.64, 95% CI 0.48-0.86, p=0.003). Conclusions: Omission of ET in ER-/PR+ early-stage breast cancer treated with chemotherapy was associated with worse overall survival, both before and after 2018. The biological and technical uncertainty of this subtype remains unresolved, but these findings warrant further investigation. Citation Format: S. M. Doss, P. Raval. The mystery of ER-negative/PR-positive breast cancer: revisiting the endocrine therapy controversy using national data abstract. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-08-03.
Doss et al. (2026) studied this question.