Abstract P2-07-29: DNADX in advanced hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer following endocrine therapy with or without palbociclib: a correlative analysis from the GEICAM/2014-12 FLIPPER phase II randomized trial

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Abstract Background: DNADX, a novel machine learning-based approach, utilizes DNA copy-number aberration (CNA) data from tumor tissue or plasma to identify clinically relevant phenotypic tumor features and classify breast cancer into 5 groups (Prat et al. Nat Comm 2023). Here, we evaluated DNADX's ability to predict prognosis and treatment benefit in advanced HR+/HER2- breast cancer following endocrine therapy and a CDK4/6 inhibitor. Methods: FLIPPER (NCT02690480) was a multicenter phase 2 clinical trial which randomized 189 patients with HR+/HER2- advanced breast cancer to receive (1:1 ratio) first line fulvestrant with either palbociclib or placebo. DNADX was evaluated centrally in pre-treatment baseline plasma and tumor samples. Shallow whole genome sequencing (shWGS) was performed on ctDNA and tumor tissue DNA to determine the RB-LOH signature, and the 5 DNA-based groups (called Proliferative, Basal-related, Luminal-high, , CNA-flat, and TF-low [with a tumor fraction < 3%]). The primary objective was to evaluate the association of the RB-LOH signature and the DNADX subtypes determined in plasma and in tissue with progression-free survival (PFS). The secondary objective was overall survival (OS). Stratified Cox regression models were used to calculate hazard ratios (HRs) after adjusting for treatment arm and other potential prognostic factors. Results: DNADX information was obtained from 175 pre-treatment plasma samples and 111 tumor samples. In total, 183 patients, representing 96.8% of the FLIPPER population, had either baseline plasma or tumor samples available and were included in this study. Overall, DNADX identified 57.9% pts with TF-low (n=106), 0.5% with CNA-flat (n=1), 33.3% with Luminal-high (n=61), 7.7% with Proliferative (n=14) and 0.5% with Basal-related (n=1). The median PFS in pts classified as i) TF-low, ii) CNA-flat or Luminal-high and iii) Basal-related or Proliferative was 33.8m, 24.5m and 16.5m, respectively (HRs of 2.05 and 3.42, all p<0.001). Results remained consistent in patients treated with palbociclib or placebo and after adjusting for clinicopathological variables. The RB-LOH signature was significantly associated with PFS (HR=1.17, 95%CI 1.02-1.34, p=0.027). In terms of OS, the median OS in pts classified as i) TF-low, ii) CNA-flat or Luminal-high and iii) Basal-related or Proliferative was 79.0m, 55.1m and 45.5m, respectively (HRs of 2.4 and 3.9, all p<0.001). Results remained consistent in the multivariable analysis. The RB-LOH signature in plasma was also significantly associated with OS (HR=1.31, 95%CI 1.10-1.55, p=0.002). DNADX subtypes were significantly associated with PFS and OS in plasma but not in tissue samples. Conclusions: Liquid biopsy-based DNADX assay identifies substantial biological heterogeneity in advanced HR+/HER2- breast cancer and was a strong prognostic biomarker beyond standard clinical-pathological variables and treatment in the FLIPPER trial. Citation Format: Joan Albanell, Aleix Prat, Maria Teresa Martinez, Guillermo Villacampa, Lorena Paris, Sandra Cobo, Miriam O' Connor, Rosario Vega, Luis de la Cruz-Merino, Fara Brasó-Maristany, Ana Santaballa Bertrán, Francisco Pardo, Noelia Martínez-Jañez, Patricia Galván, Fernando Moreno, Oleguer Castillo, Isaura Fernández, Laia Paré, Jesús Alarcón, Judit Matito, Juan Antonio Virizuela, Juan de la Haba-Rodríguez, Pedro Sánchez-Rovira, Lucía González-Cortijo, Mireia Margelí, Alfonso Sánchez-Muñoz, Iria González Maeso, Antonio Antón, Juan Guerra, Ariadna Tibau, Manuel Ruíz-Borrego, Cinta Rosa Albacar, Coralia Bueno, Andrés García-Palomo, Yolanda Fernández, Sonia González, María Rodríguez de la Borbolla, Vega Iranzo, Catherine M Kelly, Maccon M Keane, Patrick G Morris, Conleth G Murphy, Charles M Perou, Jesús Herranz, Joel S Parker, Marta Portela, Patricia Villagrasa, Rosalia Caballero, Ana Vivancos, Federico Rojo. DNADX in advanced hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer following endocrine therapy with or without palbociclib: a correlative analysis from the GEICAM/2014-12 FLIPPER phase II randomized trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-07-29.

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