Abstract P2-05-18: Molecular Effects of Short Pre-Operative Endocrine Therapy in Hormone Receptor-Positive and HER2-negative Early Breast Cancer

Background: The identification of biomarkers for evaluating sensitivity to endocrine therapy in early breast cancer (EBC) is critical. Assessing the dynamic biological changes in the tumor caused by brief pre-operative endocrine therapy (POET) can guide decisions on reducing or intensifying treatment. In this study, we examined the molecular changes induced by short-term POET and their correlation with the treatment's effectiveness. Methods:This is a retrospective study of paired samples from patients (pts) with hormone receptor-positive and HER2-negative (HR+/HER2-) EBC treated at Hospital Clinic of Barcelona between 2014 and 2023 and from the letrozole arm of SOLTI-1501 VENTANA trial (Adamo et al. BCR 2019; NCT02802748). All pts received POET for 2 to 12 weeks prior to surgery, with tamoxifen or aromatase inhibitors (AI), administered according to menopausal status. RNA expression was assessed in baseline and surgery samples, including PAM50 and HER2DX signatures. Treatment response was defined as a value of Ki67≤10% at surgery. Logistic regression models explored the association between baseline gene expression and response. Gene expression changes were analyzed using paired SAM analysis and t-tests. Results: A total 111 pts with both baseline and surgery samples available were included. Median age was 63 years-old (61.8-66.4) and most of the tumors were cT1 (68.5%) and cN0 (97.3%) at diagnosis. 19 pts (17.1%) were premenopausal and 92 (82.9%) postmenopausal. The median baseline Ki67 was 18% (14-25%). After POET, the median Ki67 value was 4% (1-10). 81 pts (73%) reached Ki67≤10% at surgery and 41 (37%) Ki67≤ 2.7% (complete cell cycle arrest). At baseline, PAM50 molecular subtype distribution was: 79 pts (71.2%) Luminal A, 23 (20.7%) Luminal B, 4 (3.6%) HER2-enriched, 3 (2.7%) Normal-like, 2 (1.8%) Basal-like. At surgery, there were 82 (73.9%) Luminal A, 23 (20.7%) Normal-like, and 6 (5.4%) Basal-like tumors. In the univariate analysis, baseline clinicopathological variables associated with response were age (odds ratio [OR]=1.04, p=0.028), percentage of estrogen receptor (OR=1.03, p=0.025), Ki67 value (OR=0.95, p=0.003) and type of endocrine therapy (tamoxifen vs AI, OR=0.17, p<0.001). In terms of baseline gene expression, high Luminal A signature (OR=7.72, p<0.001) and luminal-related genes (e.g.: FOXA1 [OR=1.46, p=0.021] or ESR1 [OR=1.38, p=0.001]) were associated with response, while high Basal-like (OR=0.19, p=0.009), PAM50 proliferation (OR=0.30, p=0.005) and HER2DX proliferation (OR=0.24, p=0.037) signatures and proliferation-related genes (e.g.: MYBL2 [OR=0.58, p<0.003] or MKI67 [OR=0.71, p=0.004]) were associated with no response. After POET, all genes and signatures were up- or downregulated significantly. In particular, we observed a significant decrease of the PAM50 Luminal and proliferation signatures, as well as the HER2DX proliferation and luminal signatures, with an increase of the HER2DX immune (IGG) and HER2 amplicon signatures, both in responders and non-responders (FDR<5%). Conclusion: POET is a simple and secure treatment that can be administrated before surgery in HR+/HER2- EBC. The molecular profiling and dynamic evaluation of biological changes induced by POET could offer opportunities for a better understanding of the tumor´s sensitivity to endocrine therapy and could help guide and optimize treatment strategies in HR+/HER2- EBC. Citation Format: Raquel Gómez-Bravo, Barbara Adamo, Benjamin Walbaum, Esther Sanfeliu, Blanca González-Farré, Francesco Schettini, Olga Martínez-Sáez, Elia Seguí, Isabel García-Fructuoso, Paula Blasco, Oleguer Castillo, Ángela Aguirre, Valeria Sirenko, Pol Giménez, María Rey, Jordi Canes, Patricia Galván, Tomás Pascual, Maria Vidal, Adela Rodriguez Hernandez, Eva Ciruelos, Meritxell Bellet, Aleix Prat, Montserrat Muñoz, Fara Brasó-Maristany. Molecular effects of short pre-operative endocrine therapy in hormone receptor-positive and HER2-negative early breast cancer [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 P2-05-18.