A new study from researchers at Baylor College of Medicine brings hope for a more personalized approach to treat estrogen receptor-positive (ER+) breast cancer, the most common type of this cancer. The team identified a biomarker in preclinical ER+ breast cancer models that indicates that the tumor is more likely to respond to treatment with CDK4/6 inhibitors. The findings support further clinical studies to determine whether this marker may help identify patients who could benefit from CDK4/6 inhibitors. The study appeared in Science Translational Medicine .
ER+ breast cancers rely on estrogen to grow and are typically treated by endocrine therapies that block the effects of estrogen. To improve outcomes, drugs called CDK4/6 inhibitors, such as abemaciclib and ribociclib, are added to endocrine therapy to prevent relapse. As a result, many patients are exposed to prolonged treatment with CDK4/6 inhibitors (up to three years) and adverse effects without a clear understanding of which patients truly benefit from these agents.
The research team discovered that approximately 20% of ER+ breast cancers have low levels of a tumor suppressor protein called neurofibromin, encoded by the NF1 gene. These cases were less responsive to endocrine therapy drugs but more responsive to CDK4/6 inhibitors in preclinical experiments of animal models derived from patient tumors (PDX) and clinical trial data.
This study was led by Drs. Ze-Yi Zheng, Anran Chen, Matthew Ellis (now at Guardant Health) and Eric Chang at the Lester and Sue Smith Breast Center at Baylor. Their work was inspired by clinical data showing that tumors with reduced NF1 had unusually high CDK4/6 activity, which suggests sensitivity 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."
Responding to this need, the Chang lab developed immunohistochemistry- and mass spectrometry-based tests to directly measure NF1 protein abundance. These promising tools could help identify patients most likely to benefit from CDK4/6 inhibitors so that these drugs can be more selectively prescribed.
The research was a collaborative effort that also involved Eric J. Jaehnig, Meenakshi Anurag, Jonathan T. Lei, Long Feng, Chenwei Wang, Diana Fandino, Purba Singh, Hilda Kennedy, Ghazal Yadav, Craig T. Vollert, Jill Tsai, Xi Chen, Yi Li, Bora Lim, Alastair Thompson, Charles E. Foulds and Bing Zhang, all at Baylor College of Medicine, and Shunqiang Li, at Washington University School of Medicine in St. Louis.
This work was supported by National Institutes of Health grants P50CA186784, U54CA233223, P30CA125123; Department of Defense grants W81XWH-21-1-0106, W81XWH-21-1-0634, HT94252410103 and Cancer Prevention & Research Institutes of Texas awards RR160027 and RP210227.
