Advancing Treatment Strategies for HR-Positive Metastatic Breast Cancer

Recent findings presented at San Antonio Breast Cancer Symposium 2025 highlight the critical role of ESR1 mutations, which occur in approximately 40% of patients treated with aromatase inhibitors and CDK4/6 inhibitors. These mutations drive resistance to standard endocrine therapies (ETs), necessitating the development of more effective, targeted treatments.

Traditional ETs, including the first-generation SERD fulvestrant, have shown limited efficacy against ESR1-mutated cancers. Fulvestrant’s intramuscular administration restricts its exposure, and efforts to develop an oral formulation have been unsuccessful. However, the discovery of ESR1 mutations has spurred innovation in oral SERDs, which target and degrade mutant and wild-type estrogen receptors.

The phase 3 EMERALD trial demonstrated the superiority of the oral SERD elacestrant over standard ET in patients with ESR1 mutations. Building on this success, the EMBA3 trial evaluated the second-generation oral SERD imlunestrant in combination with standard ET and abemaciclib, a CDK4/6 inhibitor. The trial revealed promising results, with improved progression-free survival (PFS) in patients with ESR1 mutations. Although the study lacked the statistical power to confirm overall survival benefits, the findings suggest a positive trend.

The data further underscore the limitations of single-agent ETs in patients progressing on CDK4/6 inhibitors. Studies like CAPItello-291 highlight that patients with prior CDK4/6 inhibitor exposure experience significantly reduced PFS on subsequent single-agent treatments, emphasizing the need for combination approaches.

Adding targeted therapies to oral SERDs shows promise. Trials combining SERDs with agents targeting PI3KCA and other relevant pathways are underway, with early evidence suggesting potential synergies. For example, everolimus, an mTOR inhibitor, has seen renewed interest due to its combination with newer agents like SERDs. Recent trials have shown that combining everolimus with emerging therapies may offer improved outcomes, despite past concerns about toxicity.

A key question remains: when should ESR1 mutations be targeted? Current strategies focus on treating ESR1 mutations at disease progression, as seen in the SERENA-6 study, which showed improved outcomes by switching therapies upon detection of emerging ESR1 mutations in circulating tumor DNA. However, some researchers propose targeting ESR1 mutations earlier, potentially as part of a first-line treatment strategy to prevent resistance from developing.

The role of co-mutations in pathways like PI3KCA, AKT1, and PTEN also remains an area of active investigation. Understanding these interactions could help refine treatment strategies and identify patients most likely to benefit from targeted combinations.

The field of hormone receptor–positive metastatic breast cancer treatment is rapidly evolving. With new therapies targeting ESR1 mutations and novel combinations in development, the future holds promise for patients facing this challenging disease. As we await data from ongoing first-line studies, researchers are optimistic that these advancements will reshape the standard of care, offering more durable responses and improved outcomes for patients.

Source: Turner N. Expanding therapeutic options in hormone receptor positive metastatic breast cancer. Presented at: San Antonio Breast Cancer Symposium 2025. December 12, 2025; San Antonio, TX. Presentation GS3-10.