journal contribution
posted on 2024-09-03, 07:40 authored by Leonard Schmiester, Fara Brasó-Maristany, Blanca González-Farré, Tomás Pascual, Joaquín Gavilá, Xavier Tekpli, Jürgen Geisler, Vessela N. Kristensen, Arnoldo Frigessi, Aleix Prat, Alvaro Köhn-Luque Supplementary figures S1-S11
Funding
Horizon 2020 Framework Programme (H2020)
Norges Forskningsråd (Forskningsrådet)
Breast Cancer Research Foundation (BCRF)
Fundación Científica Asociación Española Contra el Cáncer (AECC)
Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR)
Fundación Fero (Fundació Fero)
Instituto de Salud Carlos III (ISCIII)
CRIS Cancer Foundation (CRIS Foundation)
History
ARTICLE ABSTRACT
Development of a computational biomarker to predict, prior to treatment, the response to CDK4/6 inhibition (CDK4/6i) in combination with endocrine therapy in patients with breast cancer.
A mechanistic mathematical model that accounts for protein signaling and drug mechanisms of action was developed and trained on extensive, publicly available data from breast cancer cell lines. The model was built to provide a patient-specific response score based on the expression of six genes (CCND1, CCNE1, ESR1, RB1, MYC, and CDKN1A). The model was validated in five independent cohorts of 148 patients in total with early-stage or advanced breast cancer treated with endocrine therapy and CDK4/6i. Response was measured either by evaluating Ki67 levels and PAM50 risk of relapse (ROR) after neoadjuvant treatment or by evaluating progression-free survival (PFS).
The model showed significant association with patient’s outcomes in all five cohorts. The model predicted high Ki67 [area under the curve; AUC (95% confidence interval, CI) of 0.80 (0.64–0.92), 0.81 (0.60–1.00) and 0.80 (0.65–0.93)] and high PAM50 ROR [AUC of 0.78 (0.64–0.89)]. This observation was not obtained in patients treated with chemotherapy. In the other cohorts, patient stratification based on the model prediction was significantly associated with PFS [hazard ratio (HR) = 2.92 (95% CI, 1.08–7.86), P = 0.034 and HR = 2.16 (1.02 4.55), P = 0.043].
A mathematical modeling approach accurately predicts patient outcome following CDK4/6i plus endocrine therapy that marks a step toward more personalized treatments in patients with Luminal B breast cancer.
