Dr Ma on Questions Regarding Treatment Sequencing in CDK4/6 Inhibitor–Resistant Breast Cancer

Cynthia Ma, MD, PhD, medical oncologist, Siteman Cancer Center, Washington University Medical Campus, discusses unanswered questions and remaining unmet needs regarding the optimization and sequencing of therapy for patients with metastatic hormone receptor (HR)–positive, HER2-negative breast cancer who develop resistance to CDK4/6 inhibitors.

The mechanism of resistance to CDK4/6 inhibitors in breast cancer is likely to be heterogeneous, Ma begins. Accordingly, this necessitates a nuanced approach to treatment decision-making in patients who experience disease progression following treatment with a CDK4/6 inhibitor, she says.

Research into individualized therapy based on specific resistance mechanisms is critical for advancing patient care, Ma says, adding that understanding the best subsequent treatment options for patients experiencing early progression or those who rapidly progress on prior CDK4/6 inhibitors is particularly essential. Potential treatment strategies for this patient population include chemotherapy, antibody-drug conjugates, immunotherapy, and other emerging therapies, Ma details.

In patients without PI3K pathway mutations or those harboring ESR1 mutations, research is also needed to identify alternative pathways to target, Ma continues. Several targeted therapies, such as CDK2 inhibitors and CDK7 inhibitors, are currently in development to potentially address this need, she reports. Determining the most appropriate settings and patient subsets for these agents is another important area of ongoing research, Ma reiterates.

For patients who progress on therapies targeted against the PI3K pathway, identifying the most effective agents before switching to chemotherapy is vital, Ma emphasizes. Future studies should focus on these areas to provide more precise and personalized treatment options for patients who develop resistance to initial targeted therapies, she adds.

Overall, developing comprehensive resistance profiles and integrating them into clinical decision-making will enhance the ability to select the most appropriate subsequent therapies for patients with HR-positive, HER2-negative breast cancer, ultimately leading to better patient outcomes in the post-CDK4/6 inhibition setting.