Abstract CT039: Cyclin E1 (CCNE1)expression associates with benefit from palbociclib in metastatic breast cancer (MBC) in the PALOMA3 trial

BACKGROUND : The CDK4/6 inhibitor palbociclib in combination with fulvestrant (F) improved progression-free survival (PFS) vs F alone in previously-treated MBC. Prior pre-clinical research, and the NeoPalAna window study, identified high CCNE1 expression as a potential palbociclib resistance marker. We conducted large panel gene expression analysis of baseline tumor tissue to identify biomarkers (BMs) that predicted the relative benefit of palbociclib. METHODS : The PALOMA3 trial randomized 521 patients (pts) with endocrine-pretreated MBC to receive palbociclib + F or placebo (PBO) + F. All pts, except bone only or early relapse, provided FFPE tissue taken from recurrent disease. EdgeSeq Oncology BM Panel (HTG Molecular Diagnostics) was used for mRNA profiling, assessing 2534 cancer related genes. Primary objective was to evaluate the association of cell cycle pathway with palbociclib + F vs F alone treatment effect by using gene expression as a continuous variable or dichotomization by median level with Cox regression analysis. RESULTS : 302 pts had tumor tissue analyzed (194/347 [56%] palbociclib + F; 108/174 [62%] PBO+F). The BM and overall populations had similar treatment effect. Benefit from palbociclib was greater in patients with low tumor CCNE1 expression (median PFS: palbociclib + F 14.1 mo vs PBO+F 4.8 mo, HR 0.32) than high tumor CCNE1 expression (palbociclib + F 7.6 mo vs PBO+F 4.0 mo; HR 0.85) (interaction p=0.0024). Similar results were observed with CCNE1 as a c ontinuous variable (interaction p=0.0008). Expression levels of CDK4, CDK6, cyclin D1 and RB1 did not associate with benefit from palbociclib, and both luminal A and B tumors derived benefit from palbociclib. In exploratory analysis, high E2F-regulon expression predicted for relative resistance to palbociclib. CONCLUSION : Higher expression of CCNE1 was associated with relative resistance to palbociclib, although all biomarker groups derived benefit from treatment. This data supports CDK2 as the key bypass kinase of CDK4/6 inhibition, and potential to target CDK2 to subvert resistance. Sponsor : Pfizer Citation Format: Nicholas C. Turner, Yuan Liu, Zhou Zhu, Sherene Loi, Marco Colleoni, Sibylle Loibl, Angela DeMichele, Nadia Harbeck, Fabrice Andre, Zhe Zhang, Carla Giorgetti, Cynthia Huang Bartlett, Massimo Cristofanilli. Cyclin E1 ( CCNE1) expression associates with benefit from palbociclib in metastatic breast cancer (MBC) in the PALOMA3 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT039.