Researchers at the University of Michigan Comprehensive Cancer Center have sequenced the DNA and RNA sequences of patients with advanced cancer to identify all the genetic mutations involved in causing cancer.
The study analyzed 11 patients with metastatic breast cancer, that was classified as estrogen receptor positive, where the cancer is influenced by the hormone estrogen. This is the most common type of breast cancer. All patients were treated with an aromatase inhibitor a drug that blocks estrogen production. Six patients had mutations in the estrogen receptor, and the mutations were not present before the patients started their treatment.
“This is the tumor’s way of evading hormonal therapy. These mutations activate the estrogen receptor when there is no estrogen — as is the case when a patient takes an aromatase inhibitor. It’s essentially an on-switch for the estrogen receptor,” says lead study author, Dan Robinson, Ph.D., research assistant professor of pathology at the U-M Medical School.
The on-switch essentially circumvents the effects of the aromatase inhibitor, preventing estrogen receptor signaling from being shut down. That’s when patients become resistant to the therapy, which leaves them with few other treatment options. Some 40,000 people will die from breast cancer this year in the United States, with the majority having estrogen receptor positive tumors.
“We’ve been trying for a long time to understand why people become resistant to anti-hormone therapy. This finding sheds an entirely new light onto the problem. Now, we can look at how these estrogen receptors function and begin to develop drugs to shut down or attack this mutation,” says study co-author Anne F. Schott, M.D., associate professor of internal medicine at the U-M Medical School.
“Precision medicine approaches will allow us to understand how targeted therapies are working, but another important challenge is to understand the mechanisms by which tumors become resistant to these treatments so that we can prevent the resistance or develop strategies to overcome it,” says senior study author Arul Chinnaiyan, M.D., Ph.D., director of the Michigan Center for Translational Pathology and S.P. Hicks Professor of Pathology at the U-M Medical School.
Dan R Robinson, Yi-Mi Wu, Pankaj Vats, Fengyun Su, Robert J Lonigro, Xuhong Cao, Shanker Kalyana-Sundaram, Rui Wang, Yu Ning, Lynda Hodges, Amy Gursky, Javed Siddiqui, Scott A Tomlins, Sameek Roychowdhury, Kenneth J Pienta, Scott Y Kim, J Scott Roberts, James M Rae, Catherine H Van Poznak, Daniel F Hayes, Rashmi Chugh, Lakshmi P Kunju, Moshe Talpaz, Anne F Schott, Arul M Chinnaiyan. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nature Genetics, 2013; DOI: 10.1038/ng.2823