Preliminary results of an observational clinical trial underway at Roswell Park Comprehensive Cancer Center are shedding light on why some patients with an aggressive form of metastatic breast cancer fare better than others after receiving standard treatment with cyclin-dependent kinase (CDK) 4/6 inhibitors, a form of targeted therapy that prevents cancer cells from growing and multiplying.
The new study was published in the June 12, 2025 edition of NPJ Breast Cancer, part of the Nature network of academic journals.[1]
Results of the ongoing study (NCT04526587) in patients with this aggressive form of cancer — metastatic HR+/HER2- breast cancer — may support the development of therapies that combine different precision-based treatments to make CDK4/6 inhibitors more effective.
A research team led by Principal Investigator and study senior author Agnieszka Witkiewicz, MD, Professor of Oncology and Director of the Advanced Tissue Imaging Shared Resource at Roswell Park, identified factors that appear to impact progression-free survival (PFS) – the length of time post-treatment when the disease does not get worse – in patients treated with CDK4/6 inhibitors. The newly published work focuses on the association of immune infiltration and cell cycle markers with patients’ responses to this targeted form of treatment.
“Our imaging analyses revealed that cell cycle markers cyclin A and E were largely detected in tumors of patients with short progression-free survival and correlated with the presence of macrophages rather than T cells, another type of white blood cell. Understanding how tumor cell cycle expression associates with surrounding immune cell accumulation offers therapeutic opportunities for improving CDK4/6i durability,” says Stephanie Tzetzo, PhD, MA, Postdoctoral Research Affiliate at Roswell Park and first author of the new study.
Expression of cyclin A and E
The team examined patients’ immune profiles and cell-division activity before treatment, looking for differences between those who experienced PFS of less than six months and those with PFS longer than 23 months. They found that prior to treatment, the expression of cyclin A and E — cell-cycle regulators responsible for the division of cells — was significantly higher in the tumors of patients with shorter PFS. This was associated with the buildup of macrophages, immune cells that can promote tumor growth and metastasis.
Investigators also used tissue collected during treatment to study patients with long PFS. The study showed that gene enrichment for immune cell activation emerged during therapy, along with a reduction in cell cycle gene expression.
HR+/HER2- is the most common breast cancer sub-type, accounting for 68% of all cases. The prognosis is poor when the disease metastasizes, with only 32% of patients surviving five years.
Clinical trials
Biomarkers and Clinical Features of Metastatic Breast Cancer in Patients Treated With CDK4/6 Inhibitors – ClinicalTrials.gov ID NCT04526587
Reference
[1] Tzetzo SL, Schultz E, Wang J, Rosenheck HR, Mahan S, Knudsen ES, Witkiewicz AK. Baseline cell cycle and immune profiles indicate CDK4/6 inhibitor response in metastatic HR + /HER2- breast cancer. NPJ Breast Cancer. 2025 Jun 12;11(1):54. doi: 10.1038/s41523-025-00767-2. PMID: 40506447; PMCID: PMC12162882.
Featured image: Pink breast cancer awareness. Photo courtesy: 2019 Fotolia/Adobe. Used with permission.
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