Dual therapy with fulvestrant and the irreversible HER2 kinase inhibitor neratinib reversed treatment-acquired hormone resistance in metastatic estrogen receptor (ER)–positive breast cancer cells.

Elaine Mardis, PhD, a spokesperson for the American Association of Cancer Research, hailed the research by Utthara Nayar, PhD, and colleagues as “groundbreaking and unexpected” during a briefing held in advance of the annual meeting of the American Association for Cancer Research. The lab experiments were part of a whole-exome sequencing study of metastatic ER-positive tumor biopsies from 168 patients, 12 of whom had acquired the HER2 mutations, said Dr. Nayar of the Dana-Farber Cancer Institute, Boston.

The findings have prompted a phase 2 trial of the combination, which is now recruiting patients, Dr. Nayar said. The 5-year study seeks 152 women with inoperable locally advanced or metastatic ER-positive breast cancer with a confirmed HER2-positive mutation. Patients will be randomized to the combination of neratinib and fulvestrant or to neratinib alone. The primary outcome is progression-free survival.

“We also hope to be able to develop upfront combinations to preempt the resistance and lead to more durable responses,” Dr. Nayar said.

All of the 168 patients who contributed metastatic tumor biopsy samples to the study had developed resistance to estrogen receptor treatments, including aromatase inhibitors, tamoxifen, and fulvestrant. Of these biopsies, 12 had HER2 mutations, 8 of which had been previously characterized as activating.

Dr. Nayar and colleagues examined the untreated primary tumors in five of these patients; there was no mutation in four, suggesting that the mutations were a response to treatment. “In these 80%, the mutations were acquired as tumors were exposed to treatment and not present in the original tumor,” Dr. Nayar said.

These acquired HER2 mutations were mutually exclusive with ER mutations, which suggested a different mechanism of resistance to ER-directed therapies, she noted in her abstract. The mutations conferred resistance to tamoxifen, fulvestrant, and palbociclib.

However, the combination of fulvestrant and neratinib, an irreversible HER2 kinase inhibitor, overcame resistance in these cells.

In addition to pioneering a potentially important therapy for treatment-resistant metastatic breast cancer, the study highlights the importance of gene sequencing metastatic tumors, said Nikhil Wagle, MD, Dr. Nayar’s colleague and deputy director of the Center for Cancer Precision Medicine at Dana-Farber.

“Our study highlights how important it is to profile resistant metastatic tumors since these tumors may harbor targetable mechanisms of resistance that were not present in the original tumor biopsy,” Dr. Wagle noted in a press statement. “Repeated sequencing of tumors can pinpoint new genetic changes that cause resistance to therapies. This in turn can enable physicians to personalize therapy depending on the specific genetic changes in a patient’s tumor over time.”

The study was supported by the Department of Defense, the National Cancer Institute, the Susan G. Komen Foundation, the Dana-Farber Cancer Center, and a number of other private funders. Dr. Wagle is a stockholder in Foundation Medicine. Dr. Nayar had no financial disclosure.

SOURCE: Nayer U et al. AACR 2018, Abstract 4952


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