Karen Titus
May 2026—When it comes to cancer mutations, there are big fish in little ponds, and little fish in big ponds, and big fish in big ponds, and little fish in little ponds.
The ESR1 mutation and its emergence in advanced breast cancer is still deciding what stripe of fish it is—or rather, breast specialists, researchers, and the FDA are in the midst of figuring out potentially important uses of testing for the mutation to monitor and direct therapy.
Intriguingly, patients who were found to have an ESR1 mutation but no radiologic progression, and who were then randomized to switch to camizestrant—a selective estrogen-receptor degrader and complete ER antagonist—instead of an aromatase inhibitor (with both groups continuing the CDK4/6 inhibitor), had significantly longer progression-free survival than those who continued with standard treatment.
“This is a disruptive trial, with disruptive results,” says Adrian Lee, PhD, professor of pharmacology and chemical biology, UPMC Hillman Cancer Center, and the Pittsburgh Foundation chair and director of the Institute for Precision Medicine, University of Pittsburgh and UPMC.
He should know. He oversees the Lee-Oesterreich laboratory, along with Steffi Oesterreich, PhD, and has been looking at mechanisms of resistance to endocrine therapy for some two decades. In the past 10 years, ESR1 mutations have emerged as the mostly likely driver of endocrine resistance. And it has become well established that these mutations can be picked up in circulating tumor DNA in liquid biopsies. The mutations are not oncogenic driver mutations; rather, they’re classic resistance mutations that evolve during therapy, Dr. Lee says.
In the SERENA-6 trial, patients were tested for ESR1 mutations with a circulating tumor DNA assay (Guardant360 CDx) every two to three months during the surveillance period. “It’s one of the first examples of dynamic monitoring of evolution of resistance in cancer, and then acting on a molecular resistance,” he says. “It excites physicians and scientists because we do think that maybe tackling that resistance earlier will [improve] outcomes.”
But for all the excitement around SERENA-6, Dr. Lee says, “The trial was controversial.”
The reason? “It raises a lot of challenges,” he says. “This isn’t naturally what we do, so it’s caused a lot of angst over the interpretation of it.”
He continues: “Most people feel, moving forward, that this will be the way we treat cancer—with dynamic, real-time monitoring with a liquid biopsy, and then more rapid interventions and changing of therapy.”