CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2- Metastatic Breast Cancer

Purpose: In hormone receptor–positive (HRþ)/HER2- metastatic breast cancer (MBC), it is imperative to identify patients who respond poorly to cyclin-dependent kinase 4/6 inhibitors (CDK4/ 6i) and to discover therapeutic targets to reverse this resistance. Non-luminal breast cancer subtype and high levels of CCNE1 are candidate biomarkers in this setting, but further validation is needed. Experimental Design: We performed mRNA gene expression profiling and correlation with progression-free survival (PFS) on 455 tumor samples included in the phase III PEARL study, which assigned patients with HRþ/HER2- MBC to receive palbociclibþendocrine therapy (ET) versus capecitabine. Estrogen receptor–positive (ERþ)/ HER2- breast cancer cell lines were used to generate and characterize resistance to palbociclibþET. Results: Non-luminal subtype was more prevalent in metastatic (14%) than in primary tumor samples (4%). Patients with non-luminal tumors had median PFS of 2.4 months with palbociclibþET and 9.3 months with capecitabine; HR 4.16, adjusted P value < 0.0001. Tumors with high CCNE1 expression (above median) also had worse median PFS with palbociclibþET (6.2 months) than with capecitabine (9.3 months); HR 1.55, adjusted P value ¼ 0.0036. In patients refractory to palbociclibþET (PFS in the lower quartile), we found higher levels of Polo-like kinase 1 (PLK1). In an independent data set (PALOMA3), tumors with high PLK1 show worse median PFS than those with low PLK1 expression under palbociclibþET treatment. In ERþ/HER2- cell line models, we show that PLK1 inhibition reverses resistance to palbociclibþET. Conclusions: We confirm the association of non-luminal subtype and CCNE1 with resistance to CDK4/6iþET in HRþ MBC. High levels of PLK1 mRNA identify patients with poor response to palbociclib, suggesting PLK1 could also play a role in the setting of resistance to CDK4/6i.