Resistance Mutations Identified in ER-Positive Metastatic Breast Cancer

Two independent research groups have identified resistance mutations in the gene that encodes the estrogen receptor in some cases of metastatic breast cancer.

Two independent research groups have identified resistance mutations in the gene that encodes the estrogen receptor in some cases of metastatic breast cancer. Reporting in Nature Genetics, both teams sequenced tumor samples from women with estrogen receptor–positive metastatic breast cancer resistant to hormonal therapy. The mutations were identified in metastatic breast cancer samples but not in primary tumor samples.

The results show that signaling through the estrogen receptor remains important even in advanced breast cancer treated with multiple drugs that target the estrogen pathway.

“Estrogen receptor signaling is still important even once metastatic breast cancer has progressed and is not responsive to multiple estrogen-targeted drugs,” said the lead author of one of the studies, Arul M. Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology. “The breast cancer cells find a way to maintain estrogen signaling.” These studies suggest that estrogen receptor antagonists can have therapeutic benefits in some metastatic estrogen receptor–positive breast cancer cases.

As many as 70% of breast cancer patients are diagnosed with estrogen receptor–positivedisease and receive estrogen-targeted therapy. A small fraction have de novo resistance to these therapies, but the majority of patients initially respond, and then develop acquired resistance as their disease progresses. These studies are among the first to identify the molecular cause of this resistance.

“These findings are a huge step forward in our understanding of mechanisms of anti-estrogen resistance,” said Todd Miller, PhD, assistant professor of pharmacology and toxicology at the Geisel School of Medicine at Dartmouth College in New Hampshire, who was not affiliated with the studies.

Chinnaiyan and colleagues used whole-exome sequencing and transcriptome analysis on 11 metastatic estrogen receptor–positive breast cancer samples and identified mutations in the estrogen receptor alpha 1 (ESR1) gene in 6 of the tumors. All patients had been treated with anti-estrogen and estrogen-deprivation treatments including aromatase inhibitors. The study identified five different mutations in the part of the receptor that binds to estrogen. In cell lines, the mutations resulted in constitutive activation of the estrogen receptor even in the absence of estrogen. These mutated receptors were still partly responsive to anti-estrogen therapy, however.

Sarat Chandarlapaty, MD, PhD, medical oncologist and breast cancer specialist at Memorial Sloan-Kettering Cancer Center in New York, and colleagues analyzed two independent cohorts of patients, identifying similar mutations in the ESR1 gene in 14 of 80 metastatic samples. The authors also analyzed samples from patients who took part in the BOLERO-2 clinical trial that enrolled metastatic breast cancer patients whose cancer had progressed while on aromatase inhibitor therapy. Of 44 metastatic samples, 5 (11%) had an ESR1 mutation.

The mutations were identified only in estrogen receptor–positive breast tumors and not in estrogen receptor–negative samples.

Both groups demonstrated that the mutation forms of the estrogen receptor continue to drive estrogen receptor–dependent transcription and proliferation in the absence of the receptor’s ligand, estrogen.

Cell lines expressing the ESR1 mutations were still sensitive to endoxifen, tamoxifen, and fulvestrant, direct estrogen receptor-targeting therapies used to treat women with estrogen receptor–positive breast cancer. But, higher doses of these drugs were necessary to achieve inhibition. This result along with structural modeling conducted by the Sloan-Kettering group suggest that these drugs may not be potent enough to work in patients. Rather, more selective or active drugs may be needed to inhibit these mutated estrogen receptors.

The actual frequency of these mutations in patients treated with estrogen therapies will need to await analysis of additional patient samples. Chinnaiyan estimates that the frequency of these mutations is somewhere between 20% and 40%, and could be as high as 50%. “We think the frequency will vary depending on how you select for patients-which therapy they received and for how long.” Still, a range of other resistance mechanisms can also develop and researchers are actively working to identify these and how they relate to the specific treatment.

These findings will have clinical utility in the future: clinicians may be able to anticipate resistance to aromatase inhibitor therapy by monitoring for mutations in the ESR1 gene, said both study authors. Detection of the mutation would then result in modifying or changing therapy.

Chinnaiyan and colleagues are now trying to better estimate the general prevalence of the ESR1 mutations in aromatase inhibitor-treated advanced cancer patients.

“These results don’t argue against using estrogen therapies, which are proven to be beneficial,” said Chandarlapaty. “But what it suggests is an incredible dependence, in certain tumors, on [estrogen receptor] signaling.”

These results emphasize the ability of broad sequencing studies to identify important and potentially common mechanisms of resistance to therapies. “It is import to sequence patients in real time because their mutational landscape changes over time,” said Chinnaiyan. Retrospective samples of primary tumor or tumor samples prior to treatment exposure are likely not to be informative about the current molecular state of the tumor.