Abstract INTRODUCTION: Hormone receptor (HR) positive HER2 negative breast cancer (BC) is the most common cancer affecting women in general as well as women with a pathogenic/likely pathogenic (P/LP) germline variant in TP53 (TP53-associated BC). However, while most HR+/HER2- BC in the general population has a good prognosis, early HR+/HER2- invasive BC in TP53 carriers seems to have a worse prognosis in comparison to other BC subtypes.2 To investigate the prognostic value of HR expression in TP53-associated BC, we analyzed real-world data from a large international cohort of TP53 germline P/LP women with BC and comprehensive treatment data and follow-up. METHODOLOGY: Women (age ≥18 years) with a first invasive nonmetastatic TP53-associated BC, diagnosed between 2000 and 2020, were identified from an international multicenter database created in 2022. This ongoing international collaboration involves 10 institutions from USA, Brazil, France, and Italy. Restrospective and prospective data are collected. For this analysis, patients with a P/LP germline variant in other BC genes, TP53 variants confirmed as clonal hematopoiesis of indeterminate potential, and tumors with unknown HR status were excluded. Tumor size, nodal involvement and tumor features were based on pathological staging and final surgical specimens. For patients who received neoadjuvant therapy, we used clinical staging and pathology reports from the initial biopsy. Recurrence free survival in 5 years (5y-RFS) was estimated by Kaplan-Meier method according to HR status and BC subtype (combined HR and HER2 status). Log-rank test was reported. RFS was defined as time from primary diagnosis of the first BC to first recurrence (local, regional, distant) or death. Patients without events were censored at last follow-up date. Univariate analyses included age, year of diagnosis, tumor size, grade, nodal involvement, HER2 status, type of breast surgery, radiation therapy and neo/adjuvant chemotherapy. Chi-square test was used for comparison of type of recurrence events by HR status and BC subtype. Results: Among 463 patients from the database, 250 met criteria for this analysis. Median age of first BC diagnosis was 34.5 years (range 19.0-81.0), 74.0% were HR+, and 72% of the cohort received BC treatment between 2011-2020. Most tumors were HR+/HER2- (41.6%), followed by HR+/HER2+ (30.0%) and HR-/HER2+ (18.4%). T1 and T2 represented 44.8% and 40.0% of tumors, respectively. Approximately half of the cohort had nodal involvement at diagnosis (N1 32.4%, N2 11.2%, N3 4.8%). Regarding tumor grade, 51.6% were G3 and 34.0% G2. Regarding BC treatment, 75.6% of patients received mastectomies, 81.2% chemotherapy, 37.2% radiation therapy, and 66.4% endocrine therapy. Fifty-six patients had recurrences, 26 isolated locoregional and 30 distant events. With a median follow-up of 7.2 years (IQR 4.7-13.4), the 5-yr RFS was 79% (95%CI: 74%-85%). In the univariate analysis, age, year of diagnosis, tumor size, grade, nodal involvement, surgery type, chemotherapy and radiation therapy were not associated with RFS in this cohort. RFS was not statistically different between HR+ vs HR- tumors. HER2- tumors were associated with a worse outcome in comparison to HER2+ tumors (5y-RFS rate 72% vs 85%, p.01). By BC subtype, HR+HER2- tumors also had a worse outcome in comparison to other subtypes (5y-RFS rate 70% vs 86%, p.001), and relapsed more frequently as distant metastasis (66.7% vs 36.4%, p=0.027). Conclusion: In this large cohort of TP53-associated BC, we confirmed a worse outcome for HR+/HER2- tumors. The higher rate of distant relapse after appropriate treatment in this group suggest more aggressive biology. Immune mechanisms are also considered. REFERENCE: 1. Sandoval RL, et al. J Natl Cancer Inst. 2024 Aug 1;116(8):1246-1254. Citation Format: R. Sandoval, L. Tianyu, M. Bottosso, R. Delgado, C. Orr, S. Cahil, A. Rodriguez Hernandez, N. Polidorio, B. Bychkovsky, B. Verret, O. Caron, M. Imbert-Bouteille, C. Noguès, P. Rochefort, E. Barbieri, A. Gennari, N. Tayob, M. Achatz, K. Mawell, F. André, J. Garber. The prognosis of invasive early hormone receptor positive HER2 negative breast cancer in women harboring a pathogenic or likely pathogenic TP53 germline variant 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 PD4-10.
Sandoval et al. (Tue,) studied this question.