A couple of years ago, Kathryn Moore, the director of the Cardiovascular Research Center at NYU Langone Health, came across a study that made her pause. Researchers had tracked the cardiovascular outcomes of breast cancer patients and found that among women with only one or two risk factors—such as family history, hypertension, or diabetes—30 percent experienced a cardiovascular event, a troubling statistic that jumped to 50 percent among women with three or four risk factors. Given how frequent these events were, “I wondered whether having a heart attack affected their cancer,” says Moore, “and I was surprised to find that no one had looked at this.”
Research has long supported a link between cancer treatments such as chemotherapy that can weaken the heart and subsequent cardiovascular disease in patients. The effectiveness of modern treatments means “patients are living longer, but they’re also experiencing complications,” says Moore, and far less work has been done investigating how cancer responds in turn to a heart attack, also known as a myocardial infarction (MI). A new study by Moore and her colleagues, published today (July 13) in Nature Medicine, reports that breast cancer patients who experience a heart attack are 60 percent more likely to die from their cancer than patients who don’t.
The team’s experiments in mice explain why that might be. Tumors in mice that experienced a simulated heart attack grew larger than those in mice that did not, and a subsequent analysis of immune cells taken from bone marrow, plasma, and tumors revealed a large-scale epigenetic reprogramming of their genomes that allowed the cancer to thrive.
“This study is relevant because quite a lot of oncology patients are having these events during their cancer treatments,” says Alex Lyon, a consulting cardiologist at the Royal Brompton Hospital who was not involved in the study. Modeling these cancer systems in mice, he adds, can be “very technically challenging and complex,” but he says he feels the study will prompt needed discussions among cardiologists and oncologists about screening for cancer following a cardiovascular event.
To investigate whether cardiovascular events were negatively affecting cancer outcomes in patients, Moore’s team first looked retrospectively at the outcomes of more than 1,700 women with early-stage breast cancer over the course of 12 years. Women who experienced a cardiovascular event such as a heart attack or stroke had a nearly 60 percent increased risk of their cancer returning more aggressively, and a 60 percent higher chance of dying from that cancer than patients who didn’t have such complications. During the 12 years, 168 women died from their breast cancer.
To address the molecular mechanisms underlying this observation, Moore and her colleagues turned to mouse models. They first injected cancer cells into the mammary fat pads of mice and simulated a heart attack by closing one of the heart’s two coronary arteries. A subset of mice was also injected with cancer but underwent a sham surgery to control for the effects of the procedure itself.
Mice that experienced an MI developed tumors that grew to be twice as large after 20 days as those in mice that underwent the sham surgery. When the researchers analyzed the cellular makeup of MI tumors, they found a higher proportion of Ly6Chi monocytic immune cells recruiting into the tumor, accounting for 30 percent of the tumor cells compared to 16 percent in mice subjected to a sham surgery. Monocytes form in the bone marrow before differentiating into either dendritic cells or macrophages, both of which are involved in the body’s innate ability to recognize and destroy foreign cells, including cancer. But Moore’s group found that around 20 percent of the Ly6Chi monocytes in the tumors were not differentiating, remaining instead as immature myeloid-derived suppressor cells (mMDSCs) that block cytotoxic T cells from attacking tumors, resulting in a suppressed immune response to cancer compared to control mice.
An analysis of the transcriptomes of Ly6Chi monocytes in the bone marrow and blood, as well as from the mMDSCs in the tumor, showed that this immunosuppressive state was present in cells throughout the body. Under MI conditions, 235 genes had altered expression patterns compared to the control population of mice. Genes associated with tumor growth were elevated, while many genes that prompt immune system activation and function were downregulated.
That these changes were observed in the bone marrow, where the monocytic cells are first formed, points to an epigenetic effect—the cells were being manufactured in their immunosuppressive state, rather than being reprogrammed later, the researchers concluded. Moore attributes these changes in gene expression to a tightening of the chromatin, making genes that code for important immunological and inflammatory proteins less accessible to expression. “The transcription factors that are needed to get in there to turn those genes on just can’t get in,” Moore says.
Moore and her colleagues plan to investigate the factors that prompt these epigenetic changes after an MI and possible ways of minimizing risk in patients. The implication, Moore says, is that breast cancer patients will need to be aggressively managed to control for cardiovascular risk, including both medical treatments and lifestyle changes such as exercise.
Shannon Armbruster, a gynecological oncologist at Virginia Tech who was not involved in the study, credits Moore’s study for starting with an analysis of human patients, even if it was retrospective. A common critique of studies that use animal models, she says, is whether the results can be clinically meaningful. Armbruster, who studies behavioral interventions for improving cancer outcomes, also supports the authors’ plans to pursue exercise as a possible management strategy, pointing to a 2016 study that linked exercise with lower risks of developing 13 types of cancer, including breast cancer. “Quality of life has been shown, really time and time again, to be improved” when patients commit to moderate exercise goals, Armbruster says.
G.J. Koelwyn et al., “Myocardial infarction accelerates breast cancer via innate immune reprogramming,” Nature Medicine, doi:10.1038/s41591-020-0964-7, 2020.