Researchers have identified unique molecular features responsible for the development and progression of metastatic breast cancer, according to a novel study published by Garcia-Recio et al in Nature Cancer. They discovered that one of the key features involves changes in the immune system that are due, in part, to methylation of the HLA-A gene. Focal deletions were also found and were mutually exclusive from samples with DNA methylations. In this study, methylation and focal deletions resulted in the reduced amount of immune cells available to attack cancer cells.
Study Methods and Results
In the multi-institutional, national study—one of the first to use multiple genomic platforms to analyze primary (original) tumors and their paired metastases—the researchers collected tumor tissue that represented 51 primary cancers and 102 paired metastases in 55 patients with metastatic breast cancer. Most earlier studies examined primary cancers, or metastases, in isolation from each other.
“This study involved extensive collaboration among many institutions to advance our understanding of breast cancer,” highlighted corresponding study author Charles M. Perou, PhD, the May Goldman Shaw Distinguished Professor of Molecular Oncology and Co-Director of the Lineberger Comprehensive Cancer Center’s Breast Cancer Research program at the University of North Carolina at Chapel Hill. “Our knowledge of breast cancer biology comes from studies of original tumors, but when [patients] die of breast cancer, it is from the metastatic disease, so our lack of understanding of the biology of metastasis hinders patient care.”
The researchers found that T cells and B cells were notably fewer in metastases. They also looked at differences between various sites of metastasis; liver and brain metastases showed lower levels of immune cell response compared to levels of immune cells found in lung metastases.
“We found that around 17% of metastatic tumors had reduced expression of a gene that affects cellular immunity and showed a reduced ability of immune cells to infiltrate their environment and fight off cancer cells,” explained lead study coauthor Susana Garcia-Recio, PhD, Assistant Professor of Genetics at the Lineberger Comprehensive Cancer Center’s Breast Cancer Research program at the University of North Carolina at Chapel Hill.
AURORA US Metastasis Network Project
The research in this study was made possible by the AURORA US Metastasis Network Project—which has a major component at the University of North Carolina at Chapel Hill. AURORA utilized three different genetic technologies on each tumor and metastatic specimen to help elucidate key differences between primary and metastatic tumors.
“This finding represents but the first half of the AURORA US Metastasis Network Project, as researchers have recently launched a clinical trial to help collect more samples,” revealed Nancy E. Davidson, MD, Executive Vice President of Clinical Affairs; and Senior Vice President, Director, and Professor of the Division of Clinical Research at the Fred Hutchinson Cancer Center; as well as Cofounder of AURORA. “Results of analyses of the samples from the trial will be added to the current data, thereby enabling better detection of genomic changes to truly enhance our understanding of the disease.”
Conclusions
“We saw changes in biology in about 30% of patients—including loss of immune activation, especially in liver and brain metastases,” underscored study author Lisa A. Carey, MD, ScM, FASCO, the L. Richardson and Marilyn Jacobs Preyer Distinguished Professor of Breast Cancer Research at the University of North Carolina School of Medicine as well as Deputy Director of Clinical Sciences at the Lineberger Comprehensive Cancer Center. “Many of these changes occurred through mechanisms that can be reversed or treated. For this reason, we are very excited about the potential for improved treatment of metastatic disease, or even prevention of metastases themselves, based on this effort.”
“This crucial study—which identifies a new target for potentially controlling metastatic disease—demonstrates the value of broad-based collaborative research by people united by their dedication to a vital mission,” emphasized Larry Norton, MD, Founding Scientific Director of the Breast Cancer Research Foundation; as well as Senior Vice President of the Office of the President, Medical Director of the Evelyn H. Lauder Breast Center, and Norna S. Sarofim Chair in Clinical Oncology at the Memorial Sloan Kettering Cancer Center.
“We owe our patients a tremendous round of thanks for helping us advance these research efforts and for any contributions they make in the future,” Dr. Perou concluded, adding that “We are currently mimicking a lot of these genetic findings in our mouse models, where we are testing new treatments and making real progress—which we hope will pay off for patients in the near future.”
Disclosure: The research in this study was funded in large part by the Breast Cancer Research Foundation through the Evelyn H. Lauder Founder’s Fund for Metastatic Breast Cancer Research. For full disclosures of the study authors, visit nature.com.
