But there are concerns, he says, around lead time bias—did patients simply do better because they were given a drug sooner rather than later? There is also the question of whether a different therapy should be used so quickly. “Are you sure you want to run through your therapies?” he asks. And changing progression-free survival is not the same as changing overall survival.
Then there are challenges with implementation. “There are concerns we don’t have health care that’s set up to do this,” Dr. Lee says. The cost of testing would be prohibitive on such a large scale; there are also matters of physician time, effort, and education. “This is one gene,” he says. “Imagine we’re screening for 30 genes conferring resistance to five drugs.” And without a good clinical decision support system, physicians could become overwhelmed.
Moreover, there’s the matter of accuracy of testing for early resistance. “What happens if you get that wrong?” Dr. Lee says. “There is a lower limit of detection for these mutations. What if it’s ‘bouncing around’ stochastically above it? That could lead to switching therapy prematurely.”
Gregory Bean, MD, PhD, associate professor of pathology, Stanford Medicine, calls the SERENA-6 data exciting because “we have known about the development of ESR1 mutations for many years” when resistance to aromatase inhibitors develops.
“But this way we’re able to catch that point earlier,” without waiting for radiologic or clinical evidence of disease progression. “That’s the new part—being able to use this as a dynamic biomarker” and act more quickly, Dr. Bean says.
“And we now have better drugs targeting resistance mechanisms than we used to,” he adds. Though the firstline therapies do their job in blocking estrogen signaling, he says, after a period of time they can lose effectiveness in patients who develop a new mutation in the ER protein. “We’ve known that these patients need to switch therapies.” And the newer drugs, including camizestrant, can be taken orally.
His enthusiasm is shared by Rohit Bhargava, MBBS, professor of pathology, University of Pittsburgh, and chief of pathology, UPMC Magee-Womens Hospital. “ESR1 mutations have been known to occur as a response to therapy for years,” Dr. Bhargava says. “But the recent interest has been ignited because there’s a therapy that our clinical colleagues can use to overcome this resistance. And there are others in the pipeline.” In many ways, the story is similar to that of HER2 gene amplification, he says—interest in examining the tissue protein was renewed with the approval of trastuzumab. And being able to act sooner, before radiologic detection—the mutation can be detected in ctDNA approximately six months before disease progression—would be a big shift.
The impact could be considerable. ER-positive breast cancers account for 70 to 80 percent of cases, depending on the patient population, says Dr. Bhargava. “But in primary breast cancers, this is extremely rare,” he continues, which is why no one recommends looking for ESR1 mutations at time of initial diagnosis. “The routine standard of care of endocrine therapy is excellent therapy, and most patients, obviously, are not going to recur.” But when they do, it’s usually late in the course of disease. And while aromatase inhibitors seem to be the better choice of treatment in postmenopausal women, he says, they’re susceptible to resistance in a subset of patients. The SERENA-6 authors note that ESR1 mutations are found in less than five percent of HR-positive/HER2-negative cases at the start of firstline therapy; however, for patients who receive an aromatase inhibitor and a CDK4/6 inhibitor, mutations emerge in 40 percent of patients at time of disease progression.