Dr Ma on Mechanisms of Resistance to CDK4/6 Inhibitors in HR+ Breast Cancer

Cynthia X. Ma, MD, PhD, professor of medicine, Division of Oncology, Section of Medical Oncology, Washington University School of Medicine, St. Louis, Missouri, discusses the mechanisms of resistance and current unmet needs associated with the use of CDK4/6 inhibitors in the treatment of patients with hormone receptor–positive breast cancer.

Ma emphasizes that understanding the mechanisms of resistance to CDK4/6 inhibitors is vital, especially for patients who experienced early disease progression on these agents. Identifying appropriate treatment strategies following progression on CDK4/6 inhibitors is a significant unmet need. She notes that the mechanisms of resistance to CDK4/6 inhibitors is likely heterogenous, and these mechanisms can help influence subsequent treatment decisions. Using the mechanisms to inform personalized treatment decisions should be addressed in future research, Ma says.

For example, patients who experience early disease progression, treatment options currently include chemotherapy, antibody-drug conjugates (ADCs), immunotherapy, and other targeted therapies, Ma says, adding that more needs to be learned about this specific subgroup of patients.

Moreover, Ma underscores the importance of exploring targeted therapies following disease progression on CDK4/6 inhibitors in patients who do not harbor mutations in the AKT pathway or ESR1 mutations. For example, capivasertib (Truqap) plus fulvestrant (Faslodex) is approved by the FDA for the treatment of adult patients with HR–positive, HER2-negative, locally advanced or metastatic breast cancer harboring 1 or more PIK3CA, AKT1, or PTEN alterations after progression on at least 1 endocrine-based regimen in the metastatic setting or recurrence on or within 12 months of completing adjuvant therapy. Additionally, the regulatory agency previously approved elacestrant (Orserdu) for the treatment of postmenopausal women or adult men with estrogen receptor–positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy. However, an unmet need remains for patients without these alterations, Ma says.

Determining whether patients without these mutation would benefit more from alternative targeted therapies or a switch to systemic chemotherapy remains a critical question, Ma continues. Future studies should aim to refine patient selection criteria for these therapeutic approaches to optimize outcomes, she concludes.