Markers of Resistance to CDK4/6 Inhibition Among Patients with HR-Positive, HER2-Negative Metastatic Breast Cancer

Non-luminal subtype, high CCNE1, and high PLK1 expression were found to be associated with resistance to the CDK4/6 inhibitor palbociclib among patients with metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer.

While non-luminal breast cancer subtype and high levels of CCNE1 have already been identified as candidate biomarkers for poor response to CDK4/6 inhibitors, Ángel Guerrero-Zotano, MD, Valencian Institute of Oncology, Valencia, Spain, and colleagues stated, “further validation is needed.”

In this study, 455 HR-positive, HER2-negative metastatic breast cancer tumor samples were collected from the phase 3 PEARL study population. In the PEARL trial, patients with HR-positive, HER2-negative metastatic breast cancer were randomized to receive either palbociclib plus endocrine therapy or capecitabine. The tumor samples underwent mRNA gene expression profiling and correlation with progression-free-survival (PFS).

The non-luminal subtype was more prevalent in metastatic tumor samples (14%) compared with primary tumors (4%), and patients with non-luminal tumors in the palbociclib plus endocrine therapy arm had a median PFS of 2.4 months vs 9.3 months in the capecitabine arm (hazard ratio [HR] 4.16, adjusted P-value < .0001). Tumors with high CCNE1 expression, defined as above median, also had worse median PFS when treated with palbociclib plus endocrine therapy vs capecitabine (6.2 months vs 9.3 months, respectively; HR 1.55, adjusted P-value = .0036).

With an independent data set from the PALOMA3 trial, a worse median PFS with palbociclib plus endocrine therapy was seen in tumors with high PLK1 compared with those with low PLK1 expression. Using estrogen receptor-positive/HER2-negative cell line models, the study authors found “PLK1 inhibition reverses resistance to palbociclub [plus endocrine therapy].”PFS was not affected in patients treated with capecitabine, whether PLK1 expression was high or low (10.35 vs. 9.4 months, respectively; adjusted HR = 0.89; 95% CI 0.65 to 1.21; P = .4535).

Dr Guerrero-Zotano, et al concluded these data "confirm association of non-luminal subtype and CCNE1 with resistance to CDK4/6 [inhibitors plus endocrine therapy]” in this patient population. They added the potential of high levels of PLK1 mRNA to identify patients with poor response to palbociclib, noting therefore, “PLK1 could also play a role in the setting of resistance to CDK4/6 [inhibitors].”

Source:

Guerrero-Zotano Á, Belli S, Zielinski C, et al. CCNE1 and PLK1 mediates resistance to palbociclib in HR+/HER2- metastatic breast cancer. Clin Cancer Res. Published online: February 7, 2023. doi:10.1158/1078-0432.CCR-22-2206