New Mutation Found in the Estrogen Receptor May Cause Resistance to Breast Cancer Treatment
Most patients with estrogen receptor–positive metastatic breast cancer who initially respond to endocrine treatments will eventually develop resistance to the therapies. A study by Ido Wolf, MD, Head of the Oncology Department at the Tel Aviv Sourasky Medical Center in Israel, and colleagues has found that a novel mutation in the estrogen receptor called D538G may be the reason these patients become resistant to hormone therapies, such as tamoxifen. The study results are published in Cancer Research.
The researchers collected breast cancer samples from the breast and liver of 13 Israeli patients with estrogen receptor–positive metastatic infiltrating ductal carcinoma for whom multiple treatments had failed and submitted them for deep sequencing genetic analysis using the Foundation One platform, with the goal of identifying novel treatment options.
Study Findings
The researchers discovered that the estrogen receptor had the D538G mutation in five samples; this mutation was only present in the metastatic tumor samples taken from the liver and was not present in the primary tumor samples obtained from the breast. According to the study, the D538G mutation created a “conformational change that disrupts the interaction between the receptor and either estrogen or tamoxifen, but mimics the conformation of the activated receptor.”
With additional experiments using breast cancer cells in the laboratory, Dr. Wolf and his colleagues found that the change in the structure of the receptor caused it to function independently, resulting in the uncontrolled multiplication of the cancer cells, and making the tumors more aggressive and unresponsive to treatments. “Taken together, these data indicate the mutation D538G as a novel mechanism conferring acquired endocrine resistance,” wrote the researchers.
“Previous studies mostly looked at either the primary tumor or metastases before treatment, which may be why this mutation was never detected,” said Dr. Wolf in a statement. “We were able to detect it because we sampled tumors at the right time. Tumors evolve with treatments, and only the most recent sample can accurately represent the ‘new’ tumor. This finding needs to be examined in a larger cohort of patients at different time points of the disease.”
Since the only treatment available to breast cancer patients who have developed resistance to endocrine therapies is chemotherapy, which can cause more toxicity and be less effective than hormone therapies, new ways have to be found to inhibit the D538G mutation, said Dr. Wolf.
“This discovery may lead to the development of novel endocrine treatments for patients who develop resistance to currently available endocrine treatments,” concluded the researchers.
Dr. Wolf reported no conflicts of interest.
The study was funded by the Israel Cancer Association, The Margaret Stultz Foundation, the Slacker Faculty of Medicine, and the Israel Science Foundation.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
