Identifying Unmet Needs and Remaining Questions

The breast cancer treatment landscape encompasses 3 major therapeutic advances: oral SERDs with approved monotherapy for ESR1-mutant tumors and exciting combination development; CDK4/6 inhibitor strategies requiring better sequencing understanding, particularly with adjuvant exposure; and ADCs with 3 approved agents in estrogen receptor–positive disease expanding from late-line to first-line metastatic settings. Each area presents unique challenges and opportunities for improving patient outcomes through personalized treatment approaches.

Critical unmet needs include determining optimal sequencing strategies for CDK4/6 inhibitors following adjuvant exposure, developing effective combination regimens for oral SERDs and proteolysis-targeting chimeras to address resistance mechanisms, and understanding cross-resistance patterns between different ADCs with similar payloads. The field requires investigation of novel targets, including CDK4-specific inhibitors, CDK2 inhibitors, CAT6 inhibitors, and more specific PI3K inhibitors, to overcome existing resistance mechanisms.

Future developments will likely focus on precision medicine approaches incorporating molecular profiling, resistance mechanism identification, and treatment sequencing optimization. Emerging therapies, including B7-H4 ADCs, bispecific antibodies, and PD-L1/VEGF inhibitors, promise to further expand treatment options. The challenge lies in developing evidence-based guidelines for optimal treatment sequencing, combination strategies, and patient selection criteria while maintaining quality of life and avoiding overtreatment in this rapidly evolving therapeutic landscape.