Abstract Background: Understanding prognosis in de novo metastatic breast cancer (dnMBC) requires accounting for both where the disease first spreads and the tumour’s molecular subtype, yet recent population level studies that analyse these two determinants together are uncommon. Objectives: To determine, in a recent nationwide cohort, how the first metastatic organ and the tumour molecular subtype jointly influence breast cancer specific survival (BCSS) among women diagnosed with dnMBC between 2010 and 2022. Methods: Using the US SEER-17 Research database (diagnoses 2010-2022), we identified women presenting with dnMBC (N = 38,078). Molecular subtype was derived from estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) status and classified as hormone receptor positive/HER2-negative (HR+/HER2-), HR+/HER2+, HR-/HER2+, or triple negative breast cancer (TNBC). The first metastatic organ was coded from SEER Combined Mets at Diagnosis (bone, brain, liver, lung, multiple, other/unspecified). BCSS was estimated with Kaplan Meier curves, and multivariable Cox models adjusted for age, race/ethnicity and grade generated adjusted hazard ratios (aHRs) with 95% confidence intervals (CIs). Reference categories were bone only (site) and HR-/HER2+ (subtype). Sensitivity analysis excluded unknown organ codes. Results: Spread pattern: Bone only metastasis predominated (59% overall; 73% in HR+/HER2-). Liver only, lung only and brain only spread accounted for 20%, 14% and 7%, respectively; 28% presented with ≥ 2 metastatic organs. TNBC showed the highest lung or multi-site involvement (≥ 35%). Survival: Five year BCSS differed markedly by site (log-rank p 0.001): bone 31%, liver 12%, lung 14%, brain 5%, multiple 8%. Adjusted prognosis: Brain only metastasis carried the poorest outlook versus bone only (aHR 1.78, 95% CI 1.60-1.98), closely followed by multi organ dissemination (1.81, 1.76-1.87). Liver only disease conferred intermediate risk (1.33, 1.26-1.41), whereas lung only spread did not differ significantly from bone (1.03, 0.98-1.07; p = 0.30). Relative to HR-/HER2+ tumours, HR+/HER2+ showed the most favourable prognosis (0.75, 0.71-0.79); HR+/HER2- provided a modest benefit (0.88, 0.83-0.92); and TNBC more than doubled the risk of breast-cancer death (2.27, 2.14-2.40). All aHRs shifted by 5% after excluding unknown sites. Conclusions: The first metastatic organ and tumour molecular subtype independently determine prognosis in dnMBC. Brain involvement and multi organ dissemination portend the worst survival, whereas lung only disease is comparable to bone only after adjustment. HR+/HER2+ tumours confer the most favourable subtype profile, while TNBC remains high risk. These findings support subtype guided imaging and site specific eligibility stratification in metastatic clinical trials. Citation Format: P. Jain, R. Patel, N. Ganatra, M. Patel, A. Jamal, S. Patel, S. Modi, T. Naqvi. Organ specific metastasis and survival across molecular subtypes in de novo stage IV breast cancer: A population based retrospective cohort study, 2010-2022 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 PS1-09-28.
Jain et al. (Tue,) studied this question.