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Metastatic ER+ Breast Cancers Acquire HER2 Mutations to Become Treatment Resistant

NEW YORK (GenomeWeb) – Metastatic breast cancer tumors that express the estrogen receptor often acquire HER2 mutations that make them resistant to treatments targeting the estrogen receptor.

About 80 percent of breast cancers are ER+, according to the National Institutes of Health. According to a team led by researchers at the Dana-Farber Cancer Institute, nearly all patients with ER+breast cancers that become metastatic develop resistance to treatments that target the estrogen receptor.

The researchers performed whole-exome sequencing on biopsies from 168 metastatic ER+ breast cancer patients who had undergone endocrine therapy. As they reported today in Nature Genetics, the investigators uncovered activating HER2 mutations in a subset of patients whose metastatic tumors had become treatment resistant and found that, in this cohort, these mutations appeared to be acquired. They further found that combining ER-directed therapies with an irreversible HER2 kinase inhibitor could overcome this resistance.

"Ultimately, the use of upfront combinations to preempt the emergence of HER2-mutant-resistant clones may lead to more durable responses in people with ER+ MBC," Dana-Farber's Nikhil Wagle and his colleagues wrote in their paper.

Within the biopsies from the 168 metastatic ER+ breast cancer patients, the researchers identified 12 patients with mutations in ERBB2, which encodes HER2. These mutations included ones affecting the kinase, extracellular, transmembrane and cytoplasmic domains. All the patients were treated with ER-directed therapies like tamoxifen, aromatase inhibitors, or fulvestrant before their metastatic tumors were biopsied.

For these eight of those 12 individuals, the researchers were able to obtain samples from their primary tumors for additional whole-exome sequencing. Six of those eight patients appeared to acquire HER2 alterations during therapy, as the mutations were not present in their primary tumors.

To determine whether these HER2 mutations influenced resistance to ER-directed therapies, the researchers expressed them in the ER+ HER2 breast cancer cell lines T47D and MCF7. T47D and MCF7 cells expressing HER2 with alterations to the kinase or transmembrane domains were resistant to estrogen deprivation in vitro, while wild-type HER2 provided modest resistance.

In particular, T47D and MCF7 cells expressing HER2 kinase domain and transmembrane domain mutations were completely resistant to tamoxifen, fulvestrant, and GDC-0810, while wild-type HER2 and alterations affecting the extracellular or cytoplasmic domains gave intermediate resistance.

The researchers also examined other mutations within these tumors, as ESR1 mutations are known to also be a means of developing aromatase inhibitor resistance in metastatic ER+ breast cancer. However, they found that none of the patients with acquired HER mutations had ESR1 mutations, suggesting they might be mutually exclusive alterations.

By qRT-PCR, they found that ESR1 transcript levels as well as the levels of the ER targets PGR and GREB were downregulated in HER2 mutant cells, though the ER target TFF1 was upregulated. They further found that the transcriptomes of cells expressing HER2 mutants clustered separately from cells expressing ESR1 mutants, further indicating the represent distinct methods to acquiring resistance to ER-directed treatments.

The researchers suggested that combining an ER-directed treatment with an irreversible kinase inhibitor like neratinib could restore sensitivity. When they treated HER2 mutant cells with neratinib, they observed decreased ERK and AKT phosphorylation. Then when they treated cells with both neratinib and fulvestrant, they found it repressed the pro-survival RAS/MAPK pathways.

They noted that the combination of fulvestrant with neratinib to treat breast cancer is current in phase 2 clinical trials and has had promising initial results.

"Identification of HER2 alterations in real time may help identify patients who will not benefit from ER-directed therapies or should be directed to clinical trials testing strategies to overcome this mechanism of resistance," the researchers wrote.