Identifying mutations in the estrogen receptor (ER) gene can help clinicians choose effective therapies for patients with metastatic breast cancer, according to recent research co-authored by Northwestern Medicine scientist Massimo Cristofanilli, MD. The findings were published in the Journal of Clinical Oncology.
About 75 percent of breast cancers are ER-positive, which means the cancer cells contain proteins that receive signals from the hormone estrogen to promote cell growth. Aromatase inhibitors, which block the enzyme that produces estrogen, are the standard of care for this type of cancer, but patients with metastatic cancer often become resistant to those drugs.
The new study focused on patients with advanced ER-positive breast cancer that had progressed despite aromatase inhibitor therapy. The investigators wanted to know if patients in this group who had mutations in the ER gene (ESR1) would be more or less sensitive to additional hormone therapies.
“We evaluated whether ER mutations detected in plasma of patients enrolled in two clinical trials could indicate the most effective treatment. Mutations were studied in circulating tumor DNA of blood specimens collected before patients started treatment,” explained Cristofanilli, a professor of Medicine in the Division of Hematology/Oncology and associate director for Precision Medicine and Translational Research at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.
By analyzing DNA from plasma, the fluid part of blood, the investigators determined that about 40 percent of patients enrolled in a study called the SoFEA trial had ESR1 mutations. That trial compared therapeutic strategies involving two different hormone treatments, the drugs fulvestrant and exemestane. Cristofanilli and colleagues discovered that patients with the mutations had better rates of survival after taking the drug fulvestrant compared to the drug exemestane, while patients without the mutations had similar results on both regimens.
A second study called the PALOMA3 trial, led by Cristofanilli, compared fulvestrant plus a placebo to fulvestrant plus the drug palbociclib. The latter strategy improved survival for patients with the mutation and patients without it.
“The evidence shows that when there’s an ER mutation in a patient with metastatic breast cancer, it’s more appropriate to use fulvestrant than aromatase inhibitors,” Cristofanilli said.
The findings suggest that clinicians should use molecular diagnostic tests to find out if a patient has ER mutations before making a decision about the best hormone therapy to pursue.
“Our study strongly suggests that checking for these mutations should be a standard of care,” Cristofanilli said. “It’s very important to carefully select the patients who would benefit most from a targeted therapy. This kind of precision medicine approach increases a patient’s chance of responding to treatment.”
In future research, Cristofanilli and colleagues will analyze the implications of other genetic mutations in patients with advanced breast cancer. They are also designing studies that incorporate upfront screening of mutations in genes like ESR1 when testing new targeted therapies.
This study was supported by The Royal Marsden Cancer Charity – Le Cure Fund; Medical Research Council grant MR/N002121/1; Breast Cancer Now with support from the Mary-Jean Mitchell Green Foundation; Cancer Research UK grant C30746/A16642; and Pfizer.
