Prognostic impact of tumor recurrence dynamics in patients with HR+/HER2- advanced breast cancer treated with ET+CDK4/6i: Results from the multicenter, Italian study PALMARES-2.

1092 Background: Endocrine sensitivity/resistance (ES/ER) is a key prognostic and predictive factor in patients (pts) with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative advanced Breast Cancer (HR+/HER2- aBC). Cyclin Dependent Kinase 4/6 inhibitors (CDK4/6i)+Endocrine Therapy (ET) are standard 1 st line therapy for HR+/HER2- aBC pts regardless of tumor ES/ER status at diagnosis. However, the prognostic value of tumor recurrence dynamics within ES/ER groups has never been investigated. Methods: We conducted a pre-planned analysis of the multicenter, real-world, Italian study PALMARES-2 (NCT06805812) to evaluate the prognostic role of tumor recurrence dynamics, de novo aBC presentation and distant recurrence-free interval (DFRI) in pts with HR+/HER2- aBC treated with 1 st line ET+CDK4/6i between January 2016 and September 2024. DRFI was defined as the time from surgery to the detection of aBC. The primary endpoint was real-world progression-free survival (rwPFS), defined as the time between ET+CDK4/6i initiation and disease progression (PD) or patient death. Results were adjusted through Multivariable Cox regression for 16 relevant covariates. Results: Of 4,234 pts enrolled, 2,858 (67.5%) had ES and 1,376 (32.5%) had ER disease at aBC diagnosis. Median follow-up was 38.6 and 42.7 months, respectively. After adjustment, ER was associated with poorer rwPFS compared to ES (adjusted hazard ratio [aHR] 1.78, 95% CI 1.60-1.96). In the ER cohort, secondary tumor resistance with recurrence during years (y) 3-5 of adjuvant (adj) ET or <1 y from its end, and recurrence during extended adj ET or <1 y from its end, were associated with increasingly better rwPFS when compared to primary resistance (Table). In the ES cohort, pts with tumor recurrence >10 y from adj ET end had significantly longer rwPFS when compared to pts recurring <10 y from adj ET end, or pts with no prior adj ET or de novo aBC (Table). Among pts with recurrent disease (N=2,792), any additional y of DRFI resulted in 3% reduction in the risk of disease progression (aHR:0.97, 95% CI: 0.96-0.99). Conclusions: The current ES/ER classification fails to capture the whole spectrum of prognostic heterogeneity in HR+/HER2- aBC pts treated with 1 st line ET+CDK4/6i. Recurrence dynamics, including DRFI, improve prognostic classification and may inform treatment selection and personalised patient management in this clinical context. Clinical trial information: NCT06805812 . Recurrence dynamic N rwPFS (mo) aHR (95% CI) Primary resistant 334 13.4 Ref Secondary resistant-during 5 y adj ET 668 15.7 0.85 (0.72-0.99) Secondary resistant-during extended adj ET 375 19.4 0.73 (0.61-0.89) No adjuvant ET 288 30.0 0.46 (0.36-0.59) 1-5 y from adj ET end 453 29.3 0.54 (0.45-0.65) 5-10 y from adj ET end 377 32.6 0.50 (0.40-0.61) >10 y from adj ET end 275 45.2 0.30 (0.23-0.40) De novo aBC 1422 31.3 0.50 (0.42-0.59)