The evolving landscape of breast cancer treatment, particularly for hormone receptor (HR)-positive, HER2-negative disease, is marked by the increasing use of CDK4/6 inhibitors and antibody-drug conjugates (ADCs). This progress, however, brings forth new challenges in treatment eligibility, resistance mechanisms, and optimal sequencing strategies. Yuan Yuan, MD, PhD, Director of Breast Oncology at Cedars-Sinai Medical Center, shared insights on these emerging treatment options and the importance of personalized approaches.
CDK4/6 Inhibitors: Expanding Options and Unanswered Questions
Several large, phase 3 randomized trials have established the role of CDK4/6 inhibitors in the post-surgical breast cancer setting. The monarchE trial led to the FDA approval of abemaciclib (Verzenio) plus endocrine therapy for patients with HR-positive, HER2-negative early breast cancer. Similarly, the NATALEE trial evaluated ribociclib (Kisqali) in the adjuvant setting, securing FDA approval in September 2024 for high-risk, stage II and III early breast cancer.
While both trials have expanded treatment options, differences in patient populations raise questions. According to Dr. Yuan, the monarchE data cannot be applied to patients with clinically nodal-negative disease, whereas the NATALEE regimen can be considered for high-risk, nodal-negative, T2 disease. The long-term benefits and risk/benefit ratio of CDK4/6 inhibition in high-risk, nodal-negative patients require further investigation, especially considering the potential for side effects like hair thinning and fatigue.
Precision Medicine After CDK4/6 Inhibitor Progression
For patients who progress on CDK4/6 inhibitors, a precision medicine approach is crucial. This involves considering molecular features such as ESR1, PIK3CA, AKT, and BRCA mutations to guide treatment decisions. The phase 3 CAPItello-292 trial has provided a less toxic treatment option for patients with PIK3CA mutations. However, questions remain regarding the sequencing of PIK3CA/AKT inhibitors, particularly for patients who have previously received alpelisib (Vijoice).
Novel PIK3CA inhibitors like inavolisib (GDC-0077), in combination with endocrine therapy and a CDK4/6 inhibitor, are under evaluation for high-risk patients with PIK3CA-mutated, HR-positive, HER2-negative breast cancer who have relapsed during or after endocrine therapy. Additionally, oral selective estrogen receptor degraders (SERDs) like elacestrant (Orserdu) are being investigated in ongoing trials to address their broader application.
Personalized Radiation Therapy
The traditional approach of administering 6 to 6 1/2 weeks of radiation to all patients is evolving. Personalized radiation therapy involves shorter treatment schedules, such as 15 to 20 fractions over 3 to 4 weeks or even 5 fractions within 1 week, tailored to the patient's disease risk. This approach aims to minimize toxicity while maintaining efficacy, particularly in early-stage patients.
Antibody-Drug Conjugates: A New Era in Breast Cancer Treatment
Antibody-drug conjugates (ADCs) have emerged as a major breakthrough in breast cancer treatment. The focus has expanded from HER2-positive to HER2-low and HER2-ultralow disease, raising questions about the clinical significance of HER2 expression levels. Beyond HER2 and TROP2, numerous ADCs targeting other targets like HER3 are in development, creating a crowded space with diverse options.
A critical area of focus is understanding drug resistance. Determining whether to immediately use another HER2-targeted therapy with a different payload after progression on a HER2-targeted therapy, or to switch to a TROP2-targeted agent, requires further research. A deeper understanding of how ADCs work and how tumors develop resistance is essential for optimizing their use.
