Abstract PS2-07-11: The improved long-term outcome in denosumab-treated postmenopausal women with early luminal breast cancer in Abcsg 18 is driven by progesterone receptor-positive tumors

Abstract Background: The biological effects of progesterone are mediated through the RANK/RANK-ligand system, which promotes tumor growth and malignant behavior in breast cancer models. In the large prospective, double-blind, placebo-controlled, phase 3 ABCSG 18 trial we have demonstrated that the addition of the RANK ligand denosumab dramatically reduces fractures compared to placebo, but also improves disease-free survival (DFS), and overall survival (OS) in aromatase inhibitor-treated postmenopausal patients with early luminal breast cancer. Patients and Methods: Tumor histological grade, as well as immunohistochemically quantified Ki-67, estrogen receptor (ER), and progesterone receptor (PR) data were collected from 2,026 patients. ER and PR were assessed according to the Allred score and considered positive if ≥3. Disease-free survival (DFS), distant recurrence-free (DRFS), and overall survival (OS) data were prospectively collected during a median follow-up (FU) of 8.1 years as part of the ABCSG 18 study. Cox Models were used to evaluate the association with outcome. Results: Overall, luminal A-like tumors had a better DFS, DRFS, and OS than luminal B-like tumors, but PR expression per se was not prognostic in this large prospective clinical trial. Patients with PR positive tumors, however, who were treated with denosumab, enjoyed a considerably better long-term outcome than patients who had been randomized to the placebo arm (HR for DFS: 0.80; 95% CI 0.65-0.98; HR for DRFS: 0.68; 95% CI 0.51-0.90; HR for OS 0.63; 95% CI 0.46-0.88). In contrast, in patients with PR-negative tumors, no differences in long-term outcomes between the denosumab or placebo arm of the trial were observed (HR for DFS: 0.87; 95% CI 0.46-1.64; HR for DRFS: 1.19; 95% CI 0.53-2.66; HR for OS 0.99; 95% CI 0.37-2.65). While the HR for DFS in denosumab vs placebo patients remained stable with increasing Allred scores, HRs for DRFS and OS improved with increasing Allred scores, thereby suggesting that the efficacy of denosumab depends on the degree of intra-tumoral PR expression. Conclusion: Our results indicate that the long-term outcome benefit for adjuvant denosumab in this large prospective randomized placebo-controlled trial is driven by patients with PR-positive tumors. The disruption of PR signaling, either via PR antagonization or by RANKL inhibition, could therefore be a promising therapeutic strategy in luminal breast cancer. Citation Format: C. Singer, D. Hlauschek, D. Egle, A. Reiner, G. G. Steger, G. Huber, R. Greil, G. Rinnerthaler, F. Fitzal, C. Brunner, C. Suppan, G. Pfeiler, S. P. Gampenrieder, M. Seifert, S. Kacerovsky-Strobl, C. Deutschmann, K. Wimmer, M. Balic, R. Jakesz, C. Fesl, H. Fohler, M. Gnant. The improved long-term outcome in denosumab-treated postmenopausal women with early luminal breast cancer in Abcsg 18 is driven by progesterone receptor-positive tumors 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 PS2-07-11.