Clinical Decision-Making: Co-occurring Mutations in ESR1 and Other Actionable Targets
Panelists discuss that for patients with both ESR1 and PIK3CA mutations after progression on CDK4/6 inhibitors, single-agent elacestrant shows meaningful clinical activity and is often favored in the second line due to its efficacy and tolerability, with more toxic combination regimens typically reserved for later treatment lines.
As treatment options for hormone receptor–positive, HER2-negative metastatic breast cancer expand, selecting the right agent in the right sequence becomes increasingly complex. A particularly challenging scenario is when patients harbor both ESR1 and PIK3CA mutations following progression on first-line endocrine therapy, plus a CDK4/6 inhibitor. While this dual mutation scenario isn’t the most frequent—occurring in roughly 12% to –15% of cases—it presents a strategic dilemma, given the multiple targeted agents now available, including oral SERDs, PI3K inhibitors, and AKT inhibitors.
Existing data suggest that single-agent elacestrant remains an effective option even in the presence of PIK3CA co-mutations. Subgroup analyses from the EMERALD trial and real-world datasets indicate median progression-free survival of approximately 5 to 5.5 months for patients with both mutations, aligning closely with outcomes seen in trials using combinations like such as fulvestrant plus alpelisib. While this does not provide definitive guidance on sequencing, it reinforces that elacestrant has clinically meaningful activity in this co-mutated group and could be a reasonable second-line choice.
Ultimately, clinical decision-making often hinges on factors beyond mutation status. Disease tempo, patient comorbidities, and tolerance for side adverse effects all weigh heavily. Given the toxicity profiles of PI3K and AKT inhibitors—ranging from hyperglycemia to rash and diarrhea—many clinicians lean toward using single-agent elacestrant in the second line, reserving combination regimens for later lines. Until we have head-to-head sequencing data, this approach offers a balance of efficacy and tolerability, especially when clinical trial participation is also an option. Looking forward, the goal remains to extend second-line progression-free survival beyond six 6 months, and continued innovation in targeted combinations will be key to achieving that.
