ESR1 Fusions and Metastasis in Estrogen Receptor–Positive Breast Cancer
Estrogen receptor–positive breast cancer is the most common type of breast cancer, but resistance to therapy is common, and eventual development of metastatic disease is a leading cause of death. In research published by Lei et al in Cell Reports, researchers from Baylor College of Medicine and Washington University in St. Louis identified estrogen receptor alpha gene (ESR1) translocation events that drive not only therapeutic resistance, but also trigger estrogen receptor–positive breast cancer cells to metastasize.
“Breast cancer is not generally thought to be a disease driven by chromosomal translocations—when two separate genes break in two and then the ends find each other to create a chimera, or fusion, protein that is encoded by the front half of one gene and the back half of another,” said first author Jonathan Lei, a graduate student in translational biology and molecular medicine at Baylor. “However, we detected through RNA-sequencing the presence of ESR1 fusion transcripts in [estrogen receptor–positive] breast cancer, but we weren’t sure how they contributed to disease progression.”
Study Methods and Findings
The research team studied ESR1 fusions identified in both treatment-naive primary breast tumors as well as in late-stage, endocrine therapy-resistant, metastatic estrogen receptor–positive breast cancer patients. From the metastatic patients, the researchers found two different ESR1 fusion events that generated very active estrogen receptor fusion proteins and went on to study their biologic properties in detail.
These two hyperactive fusion proteins, part estrogen receptor and part fusion partner protein, caused profound endocrine therapy resistance because the part of the estrogen receptor that interacts with estrogen and with the breast cancer drug tamoxifen was replaced with a protein fragment from the partner gene, which caused unregulated growth. More surprising was that the ESR1 fusions also could promote cell motility and cancer spread though the activation of a metastasis program called epithelial-to-mesenchymal transition. This potentially explains why these active ESR1 fusion genes have been found only in advanced breast cancer cases so far—they are the actual cause of metastasis.
The researchers also found a way to suppress ESR1 fusion–driven growth at primary and metastatic sites using existing U.S. Food and Drug Administration–approved breast cancer drugs that target cyclin-dependent kinase 4 and 6 (CDK4/6) cell-cycle proteins—palbociclib (Ibrance) and abemacicilib (Verzenio).
“These findings are important because they help explain how endocrine therapy drug resistance and metastasis are linked lethal processes. Our studies should drive more dedicated efforts to identify and characterize additional ESR1 fusions in early and late-stage [estrogen receptor–positive] breast cancer,” Mr. Lei added.
More ESR1 fusions are being detected in metastatic breast cancer, and many precision medicine programs are now including RNA sequencing in patient care plans as sequencing technologies continue to improve and become more cost-effective.
“From the clinical perspective, this study suggests that the diagnosis of an active ESR1 fusion could guide treatment by selecting CDK4/6 inhibitor monotherapy for patients with highly endocrine therapy–resistant, metastatic, [estrogen receptor]-positive disease where traditionally, chemotherapy has been the standard of care,” said Matthew Ellis, MB, BChir, BSc, PhD, FRCP, McNair Scholar and Director of the Lester and Sue Smith Breast Center, part of the Dan L Duncan Comprehensive Cancer Center at Baylor, and senior author on the paper. “This research adds to the catalog of clinically actionable changes in the breast cancer genome,” Dr. Ellis added.
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®.
