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BCRF Researchers Identify New Drivers of Drug Resistance in Metastatic Estrogen Receptor-Positive Breast Cancer

By BCRF | April 11, 2018

ESR1 gene fusions drive resistance to endocrine therapies in some tumors and are a new potential target to develop drugs to overcome resistance

Understanding how metastatic breast cancers initially respond to, and then become resistant to, treatment is critical to developing more effective treatments to improve length and quality of life in women and men living with metastatic breast cancer.  Drs. Adrian Lee, Steffi Oesterreich and colleagues have been studying the underlying causes of resistance to treatment in metastatic estrogen receptor-positive breast cancer. In a recent BCRF-funded study, they reported a new way in which these cancer cells can evade anti-estrogen treatments.  

Estrogen receptor-positive (ER+) breast cancer, cancer fueled by the hormone estrogen, is the most common type of breast cancer and accounts for about 70% of newly diagnosed breast cancer cases each year. After treatment with anti-estrogen therapies, in addition to surgery or chemotherapy, many women and men are cured. However, a subset of cancers will return, and spread to other organs in the body – called metastatic breast cancer. Often, when these ER+ breast cancers return they have developed a resistance to the anti-estrogen therapies that worked before.

To understand how the cancer develops resistance, Dr. Lee performed genomic sequencing of primary and metastatic tumors from 6 breast cancer patients as well as 51 unrelated metastatic samples and performed additional validation studies in previously banked samples.  They identified “gene fusions” in the ESR1 gene that are a recurrent driver of anti-estrogen therapy resistance. ESR1 fusions were originally identified by BCRF funded investigator Dr. Matthew Ellis, and the study by Dr Lee’s group adds important clinical significance to this growing area of research into anti-estrogen resistance.

“Our study findings are important because these ESR1 fusions are completely resistant to endocrine therapy,” Dr Lee said“Future directions for this work will be to determine how these ESR1 fusions function and if they point to alternative therapies for these cancers”. Importantly, several of the ESR1 fusions were detected in blood, commonly known as a liquid biopsy, allowing for less invasive detection.

Dr. Lee’s identification of a new mechanism of cancer cell resistance to treatment is an exciting new advance from a team at the University of Pittsburgh.  BCRF is committed to making progress in metastatic breast cancer as rapidly as possible. That’s why we’ve committed over a 1/3 of our research portfolio to metastasis and sponsored an international workshop of experts calling for “a cooperative, worldwide effort” to better understand the issues of late recurrence and treatment resistance.