Abstract PS2-07: Intrinsic Subtype at Progression to CDK4/6 Inhibitors Plus Endocrine Therapy in Hormone Receptor-Positive/HER2-Negative Metastatic Breast Cancer (MBC)

Background: Biomarkers after progression to CDK4/6 inhibitors plus endocrine therapy (CDKi+ET) are needed to guide the use of ET-based therapies versus chemotherapy (CT). Here, we explored the prognostic and predictive value of the 4 major intrinsic subtypes (IS) of breast cancer (i.e., Luminal A [LumA], Luminal B [LumB], HER2-enriched [HER2E], Basal-like [BL]) in tumor samples of patients with HR+/HER2- MBC progressing to CDKi+ET. Methods: This retrospective/prospective observational study included 63 patients with HR+/HER2- MBC treated at the Hospital Clinic of Barcelona between 2018-2024 with at least one line after CDKi+ET and an available tumor biopsy obtained at progression from CDK4/6 inhibition. The primary objective was to determine the progression-free survival (PFS) and overall survival (OS) after CDKi+ET, according to IS determined at progression from CDKi+ET. PFS and OS within luminal (Lum) vs. non-Lum IS according to type of therapy was explored. A paired biopsy (before starting CDKi+ET and at progression to CDKi+ET) was available in 39 (61.9%) cases. IS was assessed using a research-based PAM50 assay on the nCounter platform. Survival analyses were conducted with the Kaplan-Meier method and Cox regression models. Significance was established at p≤0.05. Results: The median age was 57.6 years. Overall, CDKi+ET had been administered in 1st, 2nd and ≥3rd line in 65.1%, 14.8% and 20.1% cases, with 54.0% patients progressing to ribociclib as CDKi and 57.1% progressing to letrozole as ET. Median PFS to CDKi+ET was 13.6 months (95% CI 10.2-19.2). In tumor samples obtained at CDKi+ET progression, 27 (42.9%) were Lum (LumA+LumB) and 36 (57.1%) non-Lum (HER2E+BL+normal-like). With a median follow-up of 35.2 months (95% CI 22.5-53.3) after progressing to CDKi+ET, PFS was 5.5 months (95% CI 3.8-7.9), and OS was 21.3 months (95% CI 16.8-28.7). Subtypes at progression to CDKi+ET were prognostic for PFS (p<0.001) and OS (p=0.004) with LumA tumors displaying the best median PFS (7.9 months) and OS (43.3 months), followed by LumB (5.4 and 23.8 months), HER2E (4.8 and 21.4), and BL (4.6 and 10.3). The PFS and OS hazard ratios (HR) between LumA versus others, adjusted for post-CDKi treatment, were 0.39 (p=0.032) and 0.49 (p=0.202), respectively. Patients with non-Lum tumors received more CT +/- targeted therapy (63.9% vs 18.5%) and less ET-based therapies (25.0% vs 66.6%) than patients with Lum tumors (p<0.01). Type of therapy (CT-based versus ET-based) was not found significantly associated with PFS (p=0.585) and OS (p=0.516). However, CT-based therapies within non-Lum disease showed better PFS compared to ET-based therapies (HR=0.44, p=0.039). No difference in OS was observed (p=0.266). Within Lum disease no difference in PFS and OS was observed according to therapy. Finally, in 39 paired tumor samples, subtype switching occurred in 61.9% of the cases. Tumor samples obtained at progression to CDKi+ET were significantly enriched in HER2E disease (51.3% vs 35.9%) and showed less Lum IS (41.0% vs 56.4%), with a consistent increase in the HER2E PAM50 score (p=0.005) and mRNA levels of genes associated to proliferation or HER2E biology, e.g. MKI67 (p=0.009) and FGFR4 (p=0.035), despite no ERBB2 mRNA levels’ changes (p=0.841). Similar findings were observed in a subgroup of baseline Lum tumors shifting to HER2E. Conclusions: Subtype switching towards less ET-sensitive IS, especially the HER2E, occurs under CDKi+ET and has prognostic value. Post-CDKi LumA disease showed the best outcomes, regardless of treatment type. This group of patients might be the ideal group to be treated with ET-based therapies. Non-Lum IS performed better with CT-based approaches. Overall, these findings suggest the necessity to profile tumor samples at progression to CDKi+ET to better tailor treatments. Citation Format: Isabel Garcia-Fructuoso, Fara Brasó-Maristany, Olga Martínez-Sáez, Raquel Gómez-Bravo, Sabrina Nucera, Elia Seguí, Oleguer Castillo, Paula Blasco, Valeria Sirenko, Angela Aguirre, Natalia Lorman-Carbó, Patricia Galván, Benjamín Walbaum, Esther Sanfeliu, Blanca Gonzalez-Farre, Tomás Pascual, Barbara Adamo, Maria Vidal, Montserrat Muñoz, Aleix Prat, Francesco Schettini. Intrinsic Subtype at Progression to CDK4/6 Inhibitors Plus Endocrine Therapy in Hormone Receptor-Positive/HER2-Negative Metastatic Breast Cancer (MBC) [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 PS2-07.