Abstract OT3-02-06: Utilizing multiomic advanced diagnostics to identify CDK4/6 inhibitor response predictors and a post-treatment multiomic signature for patients with ER+/HER2- metastatic breast cancer (SIDEOUT-3)
Authors: Abu-Khalaf MM , Pierobon M , Denduluri N , Valdes-Albini F , Forero-Torres A , Clark A , Yung R , Mita M , Christensen S , Awerkamp K , Dunetz B , Murphy R , Hatzis C , Zelterman D , Liotta L , Petricoin E 
Published: May 2019

Abstract
Background: Palbociclib, ribociclib and abemaciclib are 3 cyclin-dependent kinase (CDK) 4/6 inhibitors (inh) approved by the FDA for treatment of patients (pts) with hormone receptor–positive (HR+) metastatic breast cancer (MBC). We hypothesize that measuring the signaling architecture of CDK 4/6 kinase signaling network will predict response to CDK 4/6 inh and identify pts who are unlikely to respond to CDK4/6 inh and can be treated with other FDA approved drugs or a clinical trial. Patients who develop disease progression on CDK 4/6 inh within 12 months of starting therapy are eligible for a unique mulit-omic based molecular analysis that can be used as a therapeutic decision support tool.
Trial design: This is an open label, multicenter study prospectively evaluating the phosphoprotein-based CDK 4/6 kinase network within the tumors of 100 pts with HR + MBC who are candidates for standard 1st line treatment with a CDK 4/6 inh plus endocrine therapy (ET). Eligible pts must have pretreatment tissue from a metastatic lesion sufficient to complete baseline biomarker analysis using a novel Laser Capture Microdissecton (LCM) reverse phase protein array (RPPA) coupled approach to quantitatively analyze 8 specific proteins/phosphoproteins within the CDK 4/6 kinase signaling network (Total Rb; phospho Rb (S780); total Cyclin D1; phospho Cyclin D1 (S286); total p16INK; total p27KIP; phosphop27KIP (T187); phosphoFoxM1 (T600). Pts who develop disease progression within 12 months of starting CDK4/6 inh plus ET will be eligible for an optional biopsy of a soft tissue or bone metastatic lesion at time of disease progression for molecular analysis using a multi-omic CAP/CLIA laboratory assays to analyze post-therapy biopsies by RPPA, IHC analysis, RNA-Seq, and targeted exome sequencing. A molecular tumor board then provides the results to the treating physician as a therapeutic decision support tool outlining potential targets and possible therapies which may be used for further treatment. The primary objective is to demonstrate a correlation between one-year progression-free survival (PFS) and pre-treatment phospho RB levels. Secondary endpoints will examine the association between one-year PFS and 7 pre-specified CDK 4/6 signaling network markers. Thirteen of planned 100 patients have been enrolled. The study will be conducted at 12 centers.
Clinical trial registry number 03195192
Citation Format: Abu-Khalaf MM, Pierobon M, Denduluri N, Valdes-Albini F, Forero-Torres A, Clark A, Yung R, Mita M, Christensen S, Awerkamp K, Dunetz B, Murphy R, Hatzis C, Zelterman D, Liotta L, Petricoin E. Utilizing multiomic advanced diagnostics to identify CDK4/6 inhibitor response predictors and a post-treatment multiomic signature for patients with ER+/HER2- metastatic breast cancer (SIDEOUT-3) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT3-02-06.