Gene Mutation Identified In Metastatic Breast Cancer

Dr. Ryan Hartmaier PhD Postdoctoral Associate Magee-Womens Research Institute (MWRI) and the University of Pittsburgh Cancer Interview with:
Dr. Ryan Hartmaier PhD
Postdoctoral Associate
Magee-Womens Research Institute (MWRI)
and the University of Pittsburgh Cancer Institute

Medical Research: What is the background for this study? What are the main findings?

Response: The inhibition of signaling through the estrogen receptor is a major target in breast cancer therapy. However, within recurrent disease others have recently identified point mutations within the estrogen receptor as a mechanism of resistance to this therapy.
We undertook a comprehensive study of breast cancer progression by applying many next-generation sequencing technologies to a collection of paired primary-metastasis tissue samples from 6 patients. We placed special emphasis on the identification of structural variants (i.e. translocations, duplications, inversions, and deletions) acquired in metastatic breast cancer. In one patient with recurrent disease while on endocrine therapy, we identified a fusion gene between ESR1 (estrogen receptor alpha) and DAB2 (disabled-2). In vitro functional studies indicate that this fusion is constitutively active and hormone independent.

Medical Research: What should clinicians and patients take away from your report?

Response: Although the DNA-binding domain of ESR1 is retained, the ligand binding domain is lost in the fusion. Since all our endocrine therapy drugs depend on the ligand binding domain, they will be ineffective against this fusion. Importantly, another ESR1 fusion was previously described by Matthew Ellis in a xenograft model with an identical breakpoint within the estrogen receptor (but a different 3’ fusion partner). This suggests that potentially this pattern of ESR1 fusion may occur as a more general mechanism of endocrine therapy resistance. Together with the previously described point mutations, it is safe to conclude that mutation of ESR1 in multiple manners is a common resistance mechanism of endocrine therapy.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: First, this illustrates how little we know about the mutational landscape of metastatic breast cancer. Although we are getting better at obtaining biopsies from recurrent disease, obtaining these samples remains a major hurdle. Continued efforts encouraging collaborations between oncologists, surgeons, and researchers in translational research efforts will help us to interrogate and eventually understand how breast cancers are sometimes able to subvert our best therapies.

Our work also illustrates that structural variants (i.e. translocations, deletions, inversions, duplications) remain an understudied source of mutation complexity in . More work needs to be done to explore this understudied form of mutation, especially in metastatic disease, with appropriate genetic and informatic tools.

Citation: Abstract presented at the

2014 San Antonio Breast Cancer Symposium.

Newly-identified gene mutation could help explain how breast cancer spreads

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Last Updated on January 7, 2015 by Marie Benz MD FAAD