HER2-Negative and HER2-Low mBC: Key Takeaways

Future Directions and Closing Perspectives on Hormone Receptor–Positive Breast Cancer Treatment

The hormone receptor–positive breast cancer treatment landscape has undergone remarkable transformation, with multiple oral SERDs approaching approval and the emergence of diverse ADC options. Oral SERD therapy represents a significant advance in patient convenience and quality of life, with current approvals limited to ESR1-mutant disease populations but future development potentially expanding to broader patient groups. The mechanistic basis of SERD therapy through estrogen receptor degradation suggests applicability beyond ESR1 mutations, with ESR1 status serving more as a prognostic marker than a truly predictive biomarker.

Combination therapy development remains a priority, with ongoing trials exploring oral SERD combinations with various targeted agents to expand treatment eligibility and efficacy. Novel therapeutic approaches, including radioligand therapy, cancer vaccines, and Aurora kinase inhibitors, offer additional future directions. The critical clinical challenge involves determining optimal timing for transitioning from endocrine-based therapy to chemotherapy, requiring continued refinement of biomarker strategies and clinical assessment tools.

The ADC resistance question demands urgent attention, with the need for alternative payloads beyond topoisomerase I inhibitors becoming increasingly apparent. Current evidence suggests payload resistance rather than antigen resistance as the primary limitation, supporting development of ADCs with novel mechanisms of action. The “sandwich approach” of separating similar ADCs with alternative therapies represents a pragmatic interim strategy while awaiting next-generation agents with different payloads and resistance profiles.