HER-2 mutations appeared associated with resistance to hormone therapy among women with ER-positive metastatic breast cancer, according to a study scheduled for presentation at American Association for Cancer Research Annual Meeting.
However, this resistance can be treated with fulvestrant (Faslodex, AstraZeneca), a hormone therapy, and neratinib (Nerlynx, Puma Biotechnology), a HER-2 kinase inhibitor.
“ER-positive metastatic breast cancer is the most common cause of breast cancer mortality in the U.S., accounting for over 20,000 deaths per year,” Utthara Nayar, PhD, research fellow in medicine at Dana-Farber Cancer Institute and Harvard Medical School, said during a press conference. “Drugs that target the ER are the mainstay of therapy for patients with ER-positive metastatic breast cancer. These drugs include aromatase inhibitors, tamoxifen and selective ER-degraders. [Although] therapy is initially effective, virtually all of these patients will go on to develop resistance and stop responding to these drugs.”
ER mutations exist in about 25% to 30% of patients treated with aromatase inhibitors. However, mechanisms of resistance are currently unknown.
Nayar and colleagues studied whole-exome sequencing from tumor biopsies of 168 patients with ER-positive metastatic breast cancer with resistance to hormone therapies. Twelve patients had HER-2 mutations; eight of those patients had mutations previously identified to be activating.
After examining pretreatment primary biopsies, the researchers found four of five patients with activating mutations had no evidence of pre-existing HER-2 mutations, suggesting these mutations were acquired as a result of hormone therapy.
“[Because] HER-2 mutations appear to be mutually exclusive with those bearing ER mutations, we hypothesized that the HER-2 mutations may serve as an alternate mechanism of resistance to anti-ER agents,” Nayar said. “We tested this mutation in the lab using functional assays, which showed that the activating mutations identified in this study conferred strong resistance to aromatase inhibitors. Unlike ER mutations, the HER-2 mutations also conferred strong resistance to tamoxifen and fulvestrant, two other standard of care therapies for which we don’t know resistance mechanisms.”
Researchers also found patients with hormone therapy resistance could be effectively treated with neratinib and fulvestrant in vitro.
“We found that activating HER-2 mutations are a distinct mechanism of acquired resistance to multiple forms of anti-ER therapy in metastatic breast cancer that can still be overcome by an irreversible kinase inhibitor,” Nayar said.
“The finding of acquired activating mutations that can be targeted highlights the importance of profiling tumors at multiple stages of a patient’s disease and not just initially, as is the current standard,” she added. “Patients found to have these mutations will need to be directed away from anti-ER therapy alone and to enroll in clinical trials with combinations that are more likely to work.”
In the future, researchers hope to develop novel upfront combinations that can prevent HER-2 mutations from occurring. – by Cassie Homer
Nayar U, et al. Abstract 4952. Scheduled for presentation at: American Association for Cancer Research Annual Meeting; April 14-18, 2018; Chicago.
Disclosures: Nayar reports no relevant financial disclosures. Please see the abstract for all other authors’ relevant financial disclosures.