CDK 4/6 drug target activation mapping of HR+/HER2- metastatic breast cancer for treatment selection and response prediction.

e13029 Background: Despite the fact that a number of CDK 4/6 inhibitors have become FDA approved as the main frontline therapy for HR+/HER2- metastatic breast cancer (MBC), there are no validated predictive markers of response to this class of drugs. Additionally, approximately 30-40% of patients (pts) have little to no response to these agents, with disease progression occurring in weeks to a few months after therapy initiation. We have initiated a clinical trial (NCT03195192) to utilize cutting edge proteomic technologies to map the functional activation of the signaling architecture of tumors taken from HR+/HER2- MBC pts at diagnosis. We plan to correlate these functional phosphoprotein-based signaling patterns with PFS intervals to identify candidate markers associated with response to CDK 4/6 inhibitor therapy. Methods: Pre-treatment diagnostic FFPE biopsy material from 26 individuals enrolled on study were analyzed by an LCM- reverse phase protein array workflow. Quantitative measurements of a focused set of 8 qualifying (pre-hypothesized) protein/phosphoprotein CDK 4/6 kinase pathway biomarkers, total Rb, Rb (S780), total Cyclin D1, Cyclin D1 (S286), total pI6INK, total p27, p27 (T187), FoxM1 (T600) were measured. Results: Baseline tumor tissue was successfully analyzed for 26 pts, 17 (65%) White, 8 (31%) African American, and 1 (4%) Asian; average age 62 (range 36-79); 4 pts (15%) had prior endocrine therapy and 4 (15 %) had chemotherapy in the adjuvant setting. Seven pts remain on study treatment. Unsupervised analysis revealed substantial concordance between a number of the total-phosphoprotein paired biomarkers, with 8/26 (31%) patients having relatively low activation/expression pattern (within the bottom quartile of the data range of the 8 markers) and 6/26 (23%) having relatively high activation/expression pattern within the top quartile of the data range of the 8 markers). Conclusions: Functional CDK 4/6 drug target pathway mapping analysis is possible from the pre-treatment diagnostic FFPE material and revealed sub-populations of patients who had systematically low and high levels of CDK 4/6 kinase substrate proteins and phosphoproteins that indicate overall drug target activity. Correlations of those patterns with PFS outcome data is ongoing with final analysis planned for Summer 2020. Clinical trial information: NCT03195192 .