A genomic analysis study by Rutgers Cancer Institute of New Jersey investigators and other colleagues has identified recurrent genomic alterations in a subset of breast cancer that are typically associated with a form of thyroid cancer and an intestinal birth defect known as Hirschsprung disease. Data from the study, conducted in conjunction with the Avera Center for Precision Oncology in South Dakota and Foundation Medicine in Massachusetts, are being presented as part of a poster presentation during the 2016 San Antonio Breast Cancer Symposium.
"The precision medicine approach involving DNA sequencing to pinpoint specific alterations that can be targeted with anti-cancer therapies is becoming an alternate treatment avenue for those with resistant cancers. But there are still some subsets of disease that are elusive to this approach. Such is the case for triple-negative and recurrent breast cancer," notes the study's lead investigator Kim M. Hirshfield, MD, PhD, medical oncologist at Rutgers Cancer Institute and assistant professor of medicine at Rutgers Robert Wood Johnson Medical School. With that, investigators wanted to apply a new genomic sequencing approach to help identify a subset of breast cancers that may respond to therapies already-approved for the treatment of patients with other cancers. At focus are powerful drivers of cancer growth known as 'fusion genes' that are often missed by standard sequencing approaches.
"Breast cancer contains many complex genomic rearrangements - almost like shifting words in a sentence. The new sentence will pass the 'spell check,' as all the words are correct, but now there is a whole new meaning to the sentence," notes Rutgers Cancer Institute Associate Director for Translational Science, Chief of Molecular Oncology and Omar Boraie Chair in Genomic Science Shridar Ganesan, MD, PhD, who is another investigator on the study. "These genes may be targeted with the right therapies, but we need to identify them first."
Using advanced genomic sequencing techniques, 8,119 breast cancer cases were examined for 315 cancer-related genes. Arrangements in a gene known as RET were identified in 22 cases and further evaluated for tumor development and treatment response in laboratory models. Mutations and rearrangements in RET are typically associated with subsets of thyroid cancer. Similar and newly-described RET rearrangements were observed in this breast cancer cohort. Expression of these rearrangements in normal cells caused the cells to form tumors. They cause activation of cellular pathways that support tumor growth and survival. Like thyroid cancers with these alterations, RET- altered breast cells were also killed by RET-targeting drugs. The effect was related to the specific type of rearrangement present. Treatment of a patient with a RET-altered breast cancer with a RET-targeting drug caused a rapid clinical response, supporting the idea that these alterations are targetable in breast cancer.
"Even if these actionable genes are only found in a minority of breast cancer cases, the clinical impact may still be quite powerful, and we can get to work on developing therapeutic clinical trials," notes Dr. Ganesan, who is also an associate professor of medicine and pharmacology at Rutgers Robert Wood Johnson Medical School. Dr. Hirshfield agrees. "By further pinpointing certain nuances of aggressive and lethal forms of breast cancer, there is an opportunity to save more lives."
Other investigators on the work include Bhavna S. Paratala and Sonia C. Dolfi of Rutgers Cancer Institute; Bahar Yilmazel, Alexa Schrock, Laurie Gay, Siraj M. Ali and Jeffrey S. Ross of Foundation Medicine, Cambridge, Massachusetts; Casey B. Williams and Brian Leyland-Jones of Avera Center for Precision Oncology, Sioux Falls, South Dakota; and Antreas Hindoyan and Praveen Nair of Molecular Response, LLC, San Diego, California.
The work was supported in part by a National Institutes of Health Cancer Center Support Grant (P30CA072720) and by a generous gift to the Genetics Diagnostics to Cancer Treatment Program of the Rutgers Cancer Institute of New Jersey and RUCDR Infinite Biologics. Other support comes from the Val Skinner Foundation, AHEPA, and the Ruth Estrin Goldberg Memorial for Cancer Research.