Combination Treatment Options for Patients With ESR1 Mutation and Comutations

Treatment selection for patients harboring both ESR1 mutations and PI3K/AKT/PTEN pathway alterations requires individualized approaches based on disease characteristics and progression patterns. For patients with slow-growing tumors, bone-only disease, and minimal symptoms, single-agent elacestrant may be appropriate given its approval status and manageable toxicity profile. However, patients with more aggressive disease, visceral involvement, or faster progression rates warrant consideration of combination therapies.

Current combination options include fulvestrant plus alpelisib for patients with PI3K mutations, though the role of CDK4/6 inhibitors in this setting when patients have prior CDK4/6 exposure remains uncertain. Emerging data suggest promising approaches with imlunestrant plus abemaciclib, showing activity regardless of PI3K pathway alteration status. Novel PI3K-specific inhibitors are under development alongside selective estrogen receptor degraders (SERDs), with early data on agents such as gedatolisib showing impressive results in PI3K wild-type tumors.

The treatment landscape is rapidly evolving toward doublet therapies targeting both the estrogen receptor and PI3K pathways simultaneously. Future combination strategies may include CDK4/6 inhibitors with oral SERDs for patients without recent CDK4/6 exposure or novel PI3K inhibitors with enhanced specificity and tolerability profiles. The goal is to develop targeted combinations that address multiple resistance mechanisms while maintaining acceptable toxicity profiles for patients with complex molecular profiles.