Researchers at Baylor College of Medicine have identified a biomarker in preclinical models of estrogen receptor-positive (ER+) breast cancer that could help predict which tumors are more likely to respond to CDK4/6 inhibitor therapy. The findings, published in Science Translational Medicine, may pave the way for more personalized treatment strategies for ER+ breast cancer, which is the most common form of the disease.
ER+ breast cancers depend on estrogen for growth and are commonly treated with endocrine therapies that block estrogen’s effects. In recent years, drugs known as CDK4/6 inhibitors—such as abemaciclib and ribociclib—have been added to these therapies to reduce relapse rates. However, it remains unclear which patients will benefit most from extended use of these inhibitors, which can last up to three years and carry risks of adverse effects.
The study found that about 20% of ER+ breast cancers show low levels of neurofibromin, a tumor suppressor protein encoded by the NF1 gene. Tumors with reduced NF1 were less responsive to endocrine therapy but showed greater sensitivity to CDK4/6 inhibitors in both animal models derived from patient tumors and clinical trial data.
This research was led by Drs. Ze-Yi Zheng, Anran Chen, Matthew Ellis (now at Guardant Health), and Eric Chang at Baylor’s Lester and Sue Smith Breast Center. Their investigation followed clinical observations indicating that tumors with diminished NF1 exhibited increased CDK4/6 activity—a sign they might be more receptive to CDK4 inhibition.
“Molecular data from patient samples can guide lab research in important new directions,” said Chang, professor at the Breast Center and member of the Dan L Duncan Comprehensive Cancer Center at Baylor.
“When a CDK4/6 inhibitor was added to fulvestrant, (an estrogen blocker), we readily observed durable tumor regressions in PDX animal models,” Chang said. “These preclinical results were further supported by analysis of serial biopsy samples from patients treated before surgery with an aromatase inhibitor (another estrogen blocker) alone, followed by the addition of the CDK4/6 inhibitor palbociclib.”
“More clinical studies are needed to validate our findings,” Ellis said. “A major challenge has been to develop a reliable clinical test to determine NF1 levels in patient samples so that confirmatory clinical trials can proceed.”
To address this issue, researchers developed immunohistochemistry- and mass spectrometry-based tests aimed at directly measuring NF1 protein abundance. These tools could help clinicians identify patients most likely to benefit from CDK4/6 inhibitors and tailor treatments accordingly.
The collaborative study included scientists from Baylor College of Medicine and Washington University School of Medicine in St. Louis. It received funding support from several National Institutes of Health grants, Department of Defense grants, and awards from the Cancer Prevention & Research Institutes of Texas.
