Development of a multiparametric prognostic score based on PAM50, in patients with HR+/HER2- advanced breast cancer (aBC) treated with endocrine therapy (ET) plus cyclin dependent kinase 4 and 6 inhibitors (CDKi), within the CDK-PREDICT (SOLTI-1801) study and HCB cohort.
Authors: Pablo Tolosa Ortega, Tomás Pascual, Olga Martínez-Sáez, Cristina Hernando, Sonia Servitja, María Fernández-Abad, Fara Brasó-Maristany, Esther Sanfeliu Torres, Javier Benítez, Laura Lema, Yolanda Ruano, Isabel García-Fructuoso, Adela Rodríguez, Lucia Parrilla, María Ángeles Cobos-Fernández, Guillermo Villacampa, Jordi Canes, Fernando Salvador, Aleix Prat, Eva Ciruelos
Journal: Journal of Clinical Oncology (2024)

1061 Background: CDKi + ET combinations have demonstrated efficacy in improving progression-free survival (PFS) and overall survival (ribociclib) in HR+/HER2- aBC in the first-line setting. Intrinsic subtypes (IS) are prognostic and predict benefit from CDKi + ET. The multiparametric PAM50MET score has demonstrated prognostic value prior to the widespread use of CDKi in HR+/HER2- aBC patients. Here we developed a new prognostic score based on PAM50 assay from metastatic baseline biopsies prior to CDKi + ET within the CDK-PREDICT (SOLTI-1801) study and the Hospital Clinic de Barcelona (HCB) cohort. Methods: RNA from FFPE tumors was analyzed at the nCounter (Nanostring Technologies) using a 72 custom gene panel including the PAM50 genes. Intrinsic subtyping (luminal A, luminal B, HER2-enriched, basal-like, and normal-like) was performed using the research-based PAM50 IS predictor. The following parameters were used to develop the predictive score: PAM50 subtype assignments, PAM50 subtype expression signatures (PAM50 scores), expression of 72 individual genes included in the custom panel (PAM50 and no PAM50 genes) and 14 clinical variables. Parameters were assessed individually and all in combination. The most parsimonious model with the highest Harrel C-index (C-index) was selected. The prognostic value of the new model was assessed using multivariable Cox regression models (adjusting by endocrine sensitivity, visceral disease, and de novo metastatic disease) as a continuous variable and as a categorical variable. Results: Between May 2020 and May 2022, 185 patients (113 from CDK-PREDICT study and 72 from HCB cohort) diagnosed with HR+/HER2- aBC were evaluated. The combined model (CDK-SCORE) that achieved the highest C-index (table) included 4 clinical variables (ECOG, liver metastases, progesterone receptor expression and Ki-67), 6 genes as a continuous variable (AR, BRCA1, CCND1, CCNE1, PGR and FGFR4) and HER2-enriched and basal-like subtypes PAM50 scores. CDK-SCORE as a continuous variable was associated with PFS (aHR: 2.77, 95% CI 2.12 – 3.61). The median PFS of CDK-SCORE LOW patients was 32.9 months (95% CI 23.3 – NA) vs 16.3 months (95% CI 12.1 – 19.7) in CDK-SCORE HIGH patients (aHR: 2.76, 95% CI 1.74 – 4.37). CDK-SCORE was also categorised by tertiles and quartiles and mPFS and Kaplan-Meier curves will be presented. Conclusions: The combined CDK-SCORE demonstrates prognostic value in patients diagnosed with HR+/HER2- aBC and treated with ET+CDKi in the first-line setting. Future plans include conducting an external validation of the CDK-SCORE. [Table: see text]