AURORA US investigators have identified key molecular differences between primary tumors and their metastases that may contribute to the development and progression of metastatic breast cancer. Because metastasis remains a challenge to treating, identifying, and understanding molecular differences is critical to gain insights into the biology of disease progression and potentially reveal diagnostic and therapeutic biomarkers to impact and improve outcomes for patients. AURORA US and its counterpart AURORA EU are BCRF-supported initiatives established through the Evelyn H. Lauder Founder’s Fund for Metastatic Breast Cancer Research.
In Nature Cancer, AURORA US investigators report subtype changes involving the HER2 protein, decreased expression of estrogen receptor–mediated genes, microenvironmental changes particularly in immune cells, and modification of genes that results in lower immune cells in the tumor microenvironment of metastases compared to primary tumors.
The AURORA projects—the largest global effort to study metastatic breast cancer—compare primary tumors and matched metastases (from the same patient) to gain insights into the metastatic process. AURORA EU focuses on changes in breast tumors throughout the course of therapy to decipher what causes cancer to spread and how metastases specifically respond—or don’t—to therapy, while AURORA US drills down on the precise genomic changes that occur in the metastatic process including treatment resistance.
RELATED: BCRF-Supported AURORA-EU Study on Metastatic Breast Cancer Publishes First Findings (July 2021)
AURORA US is composed of two phases: phase one, a retrospective study that took a deep dive into a dataset of patients with primary tumors and multiple metastases, and phase two, a prospective study that will build on the trends observed in phase one to assess data as clinical trials progress.
“The AURORA projects are moving research forward with potentially practice-changing outcomes,” said BCRF Scientific Director Dr. Judy Garber. “By revealing the molecular mechanisms driving metastasis in some cases, this latest study uncovers new avenues of treatment for some of our most vulnerable patients living with stage IV breast cancer.”
Results from the first phase, reported here, showed changes between primary tumors and metastases, particularly between luminal-type tumors and basal-like tumors. From 55 patients with metastatic breast cancer, they obtained samples of 51 primary tumors and 102 matched metastases for in-depth analyses. This involved using three different cutting-edge technologies on each tumor and metastatic sample to identify possible drivers of metastasis.
“This study involved extensive collaboration among many institutions to advance our understanding of breast cancer,” said Dr. Charles Perou, the study’s corresponding author. “Our knowledge of breast cancer biology comes from studies of original tumors, but when people die of breast cancer, it is from the metastatic disease, so our lack of understanding of the biology of metastasis hinders patient care.”
Compared to primary tumor cells, metastases had fewer surrounding immune cells, particularly B and T cells that are typically mobilized to attack the tumor. Upon examination of metastases from different sites, AURORA US investigators found that liver and brain metastases had lower immune cell levels compared to lung metastases. This suggests that metastases may grow and progress in part by affecting the immune system’s ability to mount an adequate defense.
In 17 percent of metastases (especially in the brain and liver), they identified specific DNA deletions (focal deletions) in HLA-A, a gene that mediates an immune response. DNA modifications (hypermethylation, the addition of a specific chemical group to DNA) near HLA-A were also observed. These changes to DNA were also associated with lower immune cell levels, suggesting that during the progression from primary to metastatic, tumor cells can evade a robust immune response through specific DNA modifications.
DNA methylation also resulted in the downregulation (the process of turning a gene “off”) of estrogen receptor (ER)–mediated cell-to-cell adhesion genes in metastases. The ability of tumor cells to break from the initial tumor (i.e., no longer adhere to other tumor cells) is necessary for metastases.
These results support DNA methylation as a targetable mechanism to prevent the diminution of immune cells that mediate a strong immune response or stop primary tumor cells from leaving the initial tumor site and metastasizing. Ongoing studies will pursue ways to leverage these findings and improve outcomes for patients.
The tumor microenvironment encompasses several components including immune cells, epithelial cells, and fibroblasts (a cell type that provides the structural framework for tissues). In this study, differences in these components varied according to tumor subtype: ER-positive (also called luminal) breast cancer had lower fibroblast and endothelial content; and triple-negative breast cancer (also called basal) showed a decrease in B and T immune cells.
Ongoing studies will confirm these results and closely examine the tumor microenvironment’s possible impact on how metastatic breast cancers respond to treatments—ultimately moving us closer to more precise treatments for these breast tumors.
Changes in the biology of metastases compared to primary tumors were observed in 30 percent of the samples. In particular, the study team found that tumor subtype switching was especially frequent in ER-positive (luminal) breast cancer and involved changes in HER2 levels. This highlights the importance of assessing metastases by biopsy whenever possible since it is likely to have changed relative to the primary tumor, possibly warranting a different therapeutic strategy to effectively treat the metastases.
Although primary tumors generally maintain the same dominant genomic patterns in their metastases, this project has highlighted significant differences that may contribute to the poor prognosis associated with metastatic breast cancer. Recently, AURORA US launched a clinical trial to collect more samples and confirm their findings more broadly in a prospective study. The results will both confirm and extend the present results and provide valuable information that may guide and personalize treatment decisions for patients with metastatic breast cancer.
“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,” said BCRF Foundation Scientific Director Dr. Larry Norton. “AURORA is providing us a critical roadmap of the molecular abnormalities that underly the spread of breast cancer and is thereby getting us closer to better caring for—and ultimately curing—this most pressing public health problem.”
BCRF Chief Scientific Officer Dr. Dorraya El-Ashry said the AURORA projects highlighted BCRF’s unique ability to power collaborative scientific innovation.
“This study is a direct result of years-long efforts to foster a community of investigators working together toward resolving metastatic breast cancer—a goal that we are now one step closer to,” she said.
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