SAN ANTONIO – Abemaciclib, both alone and in combination with anastrozole, significantly reduced Ki67 expression vs. anastrozole monotherapy after 2 weeks of treatment in the NeoMONARCH phase II neoadjuvant clinical trial of postmenopausal patients with hormone receptor–positive, HER2-negative early-stage breast cancer.
The findings, given that a change in Ki67 at 2 weeks in neoadjuvant studies appears to predict improved disease-free survival in adjuvant studies, support continued evaluation of the cyclin-dependent kinase-4 (CDK4) inhibitor for the treatment of patients with early-stage breast cancer, Sara Hurvitz, MD, reported at the San Antonio Breast Cancer Symposium.
“In hormone receptor–positive breast cancers, estrogen stimulates D-type cyclins, resulting in increased activity of CDK4 and CDK6, and then phosphorylate RB – the tumor suppressor protein retinoblastoma – which releases the E2F transcription factor,” explained Dr. Hurvitz of the University of California, Los Angeles.
This in turn ultimately leads to cell cycle progression from G1 to S.
“This increased rate of proliferation can be observed in tumor tissue samples by measuring the expression of Ki67. Blocking CDK4 and CDK6 should lead to a decrease in E2F expression, as well as a drop in the cell cycling and a drop in Ki67,” she said, adding that cell cycle arrest may induce senescence, which may also induce a phenotype that’s characterized by an immune cell infiltrate.
Indeed, in study subjects randomized to receive abemaciclib, treatment was shown to induce profound cell cycle arrest defined by decreased Ki67 and E2F targeted proliferation messenger RNAs, and reduction of expression of genes associated with senescence.
“Abemaciclib alone or in combination with anastrozole significantly reduced the Ki67 expression compared to anastrozole alone after 2 weeks of therapy, based on the geometric mean change and complete cell cycle arrest, and the study did meet its primary endpoint,” she said.
In a video interview, Dr. Hurvitz discussed the study methodology, results, and safety findings, as well as an intriguing observation regarding the effects of treatment on tumor differentiation and immune infiltrates over time.
This study was sponsored by Eli Lilly. Dr. Hurvitz has received renumeration for research and/or travel from Amgen, Bayer, BioMarin, Boehringer Ingelheim, Dignitana, Eli Lilly, Genentech, GSK, Medivation, Merrimack, Novartis, OBI Pharma, Pfizer, Puma Biotechnology, and Roche.