Researchers have found a mutation in the estrogen receptor that is suspected to be one of the mechanisms that cause breast cancers that initially respond to hormone therapies, such as tamoxifen, to eventually become resistant Cancer Research (2013;73:6856-6864).
“Virtually all patients with metastatic breast cancer who initially respond to endocrine treatments eventually develop resistance to these treatments,” one of the study's coauthors, Ido Wolf, MD, Head of the Medical Oncology Department at the Tel Aviv Sourasky Medical Center in Israel, said in a news release. “We identified a new mutation in the estrogen receptor, which is the target for endocrine treatments, and the mutation makes the receptor more active and resistant to endocrine treatments. Importantly, we identified the mutation in 38 percent of our patients.”
The researchers (first author was Keren Merenbakh-Lamin) analyzed tumor samples of 13 patients with ERα-positive metastatic infiltrating ductal carcinoma who had initially received endocrine therapy, but subsequently did not respond to multiple lines of treatment. A novel mutation, A1613G, leading to the substitution D538G in ERα, was identified in liver metastases in five of the patients.
The mutation was not detected in the primary tumor of the patients, which had been obtained at diagnosis (prior the patients having received endocrine treatment). All five of those patients had received at least two lines of endocrine therapy for 67 to 97 months in the adjuvant or metastatic setting, prior to the development of endocrine resistance.
Further analysis of breast cancer cells in the laboratory showed that because of the mutation, the structure of the hormone receptor cells changed in such a way that those cells functioned independently and caused uncontrolled multiplication of the cancer cells—thus making the tumors more aggressive and resistant to treatment.
“Previous studies mostly looked at either the primary tumor or metastases before treatment, which may be why this mutation was never detected. We were able to detect it because we sampled tumors at the right time,” Wolf explained. “We now need to find ways to inhibit this mutated receptor and develop therapies that will be more effective and less toxic than chemotherapy [the only other treatment option currently available for patients who develop resistance to endocrine therapy].”
The study is also significant because the researchers were able to draw conclusions about “a very simple and straightforward mechanism of resistance”—by using modern deep sequencing techniques, he added. “Using these high-throughput techniques is likely to decipher simple mechanisms of treatment resistance and uncover many other mysteries.”