The approach to ESR1 and PIK3CA mutations in patients with hormone receptor–positive metastatic breast cancer continues to evolve. What role does circulating tumor DNA (ctDNA) play in treatment decisions? How should oncologists best approach patients with PIK3CA mutations who subsequently develop ESR1 mutations? VK Gadi, MD, PhD, professor and director of medical oncology and deputy director of the University of Illinois Cancer Center in Chicago, discusses with Robert A. Figlin, MD, the interim director of Cedars-Sinai Cancer in Los Angeles and Steven Spielberg Family Chair in Hematology-Oncology, how recent data are informing care for patients with comutations. “We now have at least one ESR1-targeting drug out there, and more to come,” Dr. Gadi explains. “Elacestrant is the drug I’m of course referencing, and that is used essentially like a single agent and works well for those patients. Even when they have, for example, PIK3CA mutations present.” He and Dr. Figlin consider when to act on ctDNA findings and potential future strategies. Dr. Gadi reported no relevant financial relationships. Dr. Figlin reported various financial relationships.