Dr. Wander on the Role of NF1 Mutations on CDK4/6 Resistance in Breast Cancer

Seth Wander, MD, PhD, medical oncologist, the Massachusetts General Hospital, instructor in Medicine, Harvard Medical School, discusses the investigation of resistance to CDK4/6 inhibitors and the role of NF1mutations in breast cancer.

At the 2022 San Antonio Breast Cancer Conference, investigators presented data on an institutional retrospective study, where they identified 26 patients metastatic hormone receptor (HR)–positive/HER2-negative breast cancer harboring NF1 mutations who had 1 or more circulating tumor DNA samples sequenced at variable time-points as part of routine care. They concluded that NF1 mutations may be associated with resistance to CDK4/6 inhibitors, and mutant NF1 allele fraction in HR-positive could be predictive of CDK4/6 inhibitor susceptibility.

The growing knowledge of the biology of HR-positive breast cancer has suggested that the genomic and molecular landscape of resistance to CDK4/6 inhibitors is heterogeneous, with a number of different potential driver alterations potentially affecting resistance, Wander explains. Many of these alterations fall into genomic or molecular changes that affect the mechanisms of cell cycle division and oncogenic signal transduction pathways, Wander adds.

The RAS/MAPK pathway may be a critical and common pathway that can be altered in patients who develop CDK4/6 inhibitor resistance, leading investigators to examine NF1 mutations as a potential route that the RAS/MAPK pathway can be activated, Wander explains.

New data continue to emerge on the use of CDK4/6 inhibitors in HR-positive/HER2-negative breast cancer, including information on the role that the immune system plays in interacting with different regulatory components that could affect response and resistance to CDK4/6 inhibitors, Wander says. Moreover, new data were also presented on different cellular models of resistance that may demonstrate unilateral resistance to one CDK4/6 inhibitor vs another. These data could help determine whether individual patients can respond to a different CDK4/6 inhibitor after developing resistance to a prior agent, Wander concludes.