Breast Oncologist Dr. Sheheryar Kabraji: A Message For His Colleagues On ESR-1 Testing Timing

In conversation with SurvivorNet Dr. Sheheryar Kabraji discussed how emerging data are prompting clinicians to reconsider when—and how—to test for ESR-1 mutations in advanced breast cancer, an area where practice patterns remain unsettled.

Dr. Kabraji shared his views on the following areas of open discussion :

• Should ESR-1 testing happen earlier? 
• Is molecular progression underdiagnosed? 
• How are clinical trials shaping new forms, frequency and feasibility of ESR-1 testing?

Framing the issue, Dr. Kabraji noted that while somatic mutation testing is recommended by guidelines in advanced disease, the optimal timing remains unclear. “The question is, should ESR-1 testing be moved up earlier and when is the optimal time to do this,” Dr. Kabraji asks. “There’s actually a variety of opinions and I’ll describe what the landscape of practice looks like today,” he said. “So we know that for advanced breast cancer, what’s called somatic testing of mutations–which means analyzing the tumor to find mutations that could be targeted–is recommended by guidelines. But, the optimal timing of this is not yet clear.”

Interest in earlier testing, he explained, has been driven largely by results from the SERENA-6 trial evaluating the not yet FDA approved oral SERD camizestrant. In that study, patients underwent blood-based screening every three months to detect emerging ESR-1 mutations. “When that ESR-1 mutation was discovered in the SERENA-6 Trial, they actually put patients into two groups,” Dr. Kabraji said. One group remained on standard endocrine therapy plus CDK four six inhibition, while the other switched endocrine therapy to an oral SERD. “And, what was found was that there was significant improvement of disease control with this early molecular switch,” he explained.

Importantly, he noted, the benefit appeared before radiographic progression. “This is before the tumors looked like they were progressing on scans,” Dr. Kabraji said. “And, much more importantly, there appeared to be a significant improvement in patient’s symptoms including things like fatigue and pain with this earlier switch [to camizestrant] compared to standard therapy.”

The Impact of the SERENA-6 Trial on ESR-1 Testing

Although the oral SERD studied in the SERENA-6 Trial is not yet FDA approved, Dr. Kabraji said the study has raised important questions about current practice. “Because typically now ESR-1 mutation testing happens after someone has progressed on an endocrine therapy plus CDK-4-6 inhibitor by scans,” he said. “But it raises the question, should this testing happen earlier?”

At present, he emphasized, practice patterns vary widely. “My own practice has actually been to start testing sooner for a few reasons,” Dr. Kabraji said, citing patient-reported outcome data from SERENA-6. “It suggests that this idea of molecular progression may be underdiagnosed in many of our patients and where, for example, their disease is progressing, but we don’t actually see that on scans. But, it’s making them feel unwell and knowing that is very important for patient quality of life.”

The Evolution of ESR-1 Testing

Dr. Kabraji also outlined how ESR-1 testing is evolving technically. “So ESR-1 testing or somatic mutation testing can happen in sort of two primary ways,” he said, either through tumor tissue or via liquid biopsy. Blood-based circulating tumor DNA testing, he added, “is much more feasible than solid tumor testing because a blood test is more accessible, it’s less invasive and potentially allows for serial testing.”

Still, he cautioned that the evidence base remains limited. “There’s still no clear data to show that earlier more frequent testing is necessarily superior apart from in terms of outcomes, apart from the Serena six study,” he said. While liquid biopsy may ultimately complement or even reshape how progression is detected, “the exact test we use or whether it’s a combination of tests and combination of tests with imaging is still under research.”