ESR1 Testing Is Crucial in Second-line HR+, HER2- Metastatic Breast Cancer

Elacestrant has played a vital role in the treatment of ESR1-mutant metastatic breast cancer.

The second-line treatment of HR-positive, HER2-negative metastatic breast cancer has drastically evolved in recent years, putting a focus on ESR1 mutation monitoring at center stage, explained Dana J. Tolman, MSN, APRN, FNP-C.

“The very first medication that we started out with [for this patient population] was the SERM, tamoxifen. That was in the late 1970s and clearly, we have come a long way,” said Tolman, who is a nurse practitioner at Baptist Health Miami Cancer Institute.

Tolman led a community case forum on the evolving treatment landscape in HR-positive, HER2-negative metastatic breast cancer.

Testing for ESR1 Mutations After Disease Progression

A major concern in treating this patient population is the development of an ESR1 mutation.

ESR1 mutations are rare before patients undergo treatment for metastatic breast cancer, and typically emerge after a patient is exposed to endocrine therapy. Additionally, ESR1-mutant disease has fewer treatment options as it is usually resistant to treatment with an aromatase inhibitor, tamoxifen, and fulvestrant.

“[ESR1] has a decreased affinity for ligands, for example, the estrogens, the SERMs and the SERDs, and the ligand independent tumor growth, resulting in cancer proliferation, metastasis, and resistance,” Tolman explained.

Both the American Society for Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN) recommend that patients are tested for ESR1 mutation via blood-based ctDNA tests, after each time they experience disease progression on endocrine therapy.

Treatment With Elacestrant

Once it is determined that the disease is ESR1-mutant, the standard treatment is elacestrant (Orserdu), an oral drug that was approved in January 2023 for men and postmenopausal women with estrogen receptor (ER)–positive, HER2- negative ESR1-mutated advanced or metastatic breast cancer who experienced disease progression after endocrine therapy.

Elacestrant’s FDA approval was based on findings from the phase 3 EMERALD trial (NCT03778931), which showed that the drug improved progression-free survival (PFS) rates over standard of care (SOC). At 6 months, the PFS rates were 34.3% and 20.4% in the elacestrant and SOC groups, respectively. For patients specifically with an ESR1 mutation, 6-month PFS rates were 40.8% in the elacestrant group and 19.1% in the SOC group. Further, at 12 months, the PFS rates were 22.3% and 9.4%, respectively, in the entire study population and 26.8% vs 8.2% in the ESR1-mutant population.

However, treatment decisions may become a bit more complicated if a patient’s disease has both an ESR1 mutation as well as another targetable mutation, such as PIK3. Such was the case for one of the attendees at the case-based forum.

“I'm pretty sure she was on a PIK3 inhibitor. We were waiting [to switch her to elacestrant] because she was doing really well on a PIK3CA inhibitor,” the attendee said.

“You also have to think of what the patient would tolerate better,” another attendee responded. “So in our case, if a patient would tolerate any other medication better, typically we would gear toward that route.”