Computational Model Predicts Patient Outcomes in Luminal B Breast Cancer Treated with Endocrine Therapy and CDK4/6 Inhibition

被引:3
作者
Schmiester, Leonard [1 ]
Braso-Maristany, Fara [2 ]
Gonzalez-Farre, Blanca [2 ,3 ]
Pascual, Tomas [2 ,4 ,5 ]
Gavila, Joaquin [5 ,6 ]
Tekpli, Xavier [7 ]
Geisler, Jurgen [8 ,9 ]
Kristensen, Vessela N. [7 ,8 ]
Frigessi, Arnoldo [1 ]
Prat, Aleix [2 ,3 ,10 ]
Kohn-Luque, Alvaro [1 ,11 ]
机构
[1] Univ Oslo, Fac Med, Oslo Ctr Biostat & Epidemiol, Oslo, Norway
[2] August Pi & Sunyer Biomed Res Inst IDIBAPS, Translat Genom & Targeted Therapies Solid Tumors, Barcelona, Spain
[3] Hosp Clin Barcelona, Dept Pathol, Barcelona, Spain
[4] Hosp Clin Barcelona, Dept Med Oncol, Barcelona, Spain
[5] SOLTI Canc Res Grp, Barcelona, Spain
[6] Inst Valenciano Oncol, Dept Med Oncol, Valencia, Spain
[7] Univ Oslo, Oslo Univ Hosp, Dept Med Genet, Oslo, Norway
[8] Univ Oslo, Inst Clin Med, Fac Med, Oslo, Norway
[9] Akershus Univ Hosp, Dept Oncol, Oslo, Norway
[10] Univ Barcelona, Dept Med, Barcelona, Spain
[11] Oslo Univ Hosp, Oslo Ctr Biostat & Epidemiol, POB 1122 Blindern, N-0317 Oslo, Norway
关键词
CLINICAL-IMPLICATIONS; PALBOCICLIB; MULTICENTER; RESPONSES; SUBTYPES;
D O I
10.1158/1078-0432.CCR-24-0244
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: 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.Experimental Design: 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).Results: 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].Conclusions: 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.
引用
收藏
页码:3779 / 3787
页数:9
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