In survivors of early breast cancer, cardiovascular events significantly increased the risk of cancer recurrence and cancer death, a review of 1,700 patients showed.
The risk of breast cancer recurrence increased by 59% and cancer-specific death by 60% in patients who had a heart attack, stroke, or heart failure after cancer diagnosis and treatment. Laboratory studies involving a preclinical model of breast cancer showed that experimental myocardial infarction had an immunosuppressive effect on a type of bone marrow cell, reducing the body’s ability to recognize and attack cancer cells.
The findings put a new spin on a large volume of evidence showing that cancer and the adverse effects of chemotherapy and radiotherapy may weaken the immune system and predispose cancer survivors to cardiovascular disease (CVD) and events, as reported in Nature Medicine. The results also have immediately applicable implications for patients and clinicians.
“I think one of the most important things for breast cancer survivors to understand is that there is this link between breast cancer and heart disease and that they are at increased risk for heart disease after surviving breast cancer,” co-author Kathryn Moore, PhD, of NYU Langone Health in New York City, told MedPage Today. “After surviving breast cancer, they should speak with their healthcare providers about closely monitoring for cardiovascular risk factors.”
“[Breast cancer survivors] definitely want to avoid getting to the point where you might have a heart attack, because our data suggest that after a heart attack, there is this reciprocal relationship with cancer, where cancer is more likely to come back, and if it does, women are 60% more likely to die of their cancer.”
A long history of breast cancer research documented that survivors have a significantly higher risk of CVD and clinical events as compared with the general population. Studies showed that chemotherapy and radiation therapy adversely affected the heart, blood vessels, and the immune system to increase breast cancer survivors’ risk of heart attack, stroke, and heart failure.
Whether the reverse was also true — a cardiovascular event adversely affected cancer outcomes — had not been investigated, according to Moore and first author Graeme J. Koelwyn, PhD, also of NYU Langone Health. To address the issue, they and their co-authors performed a combination of clinical and preclinical studies to investigate the impact of cardiovascular events on cancer course in survivors of early-stage breast cancer.
The preclinical research focused on the impact of MI on the pathophysiology of breast cancer. Investigators implanted breast cancer cells in mice and then surgically induced MI or performed a sham operation. The results showed that animals with experimentally induced MI had a twofold increase in the growth rate and volume of the cancer cells as compared with the mice who had sham operations. Echocardiography showed no evidence that post-MI cardiac remodeling or changes led to accelerated cancer growth.
Additional studies focused on potential systemic effects of MI on cancer cell growth, specifically whether MI altered immune cell composition. The studies showed that MI led to a persistent increase in a type of immune cell known as Ly6Chi monocytes. Moreover, MI had the effect of “reprogramming” Ly6Chi monocytes to become immunosuppressive. Recruitment of the reprogrammed cells into tumors was associated with accelerated tumor cell growth and expansion. Conversely, depletion of Ly6Chi monocytes was associated with reduced MI-related tumor growth.
RNA sequencing of immune cells from breast tumors showed that MI altered the expression of 235 genes, particularly downregulation of genes involved in restricting cancer pathogenesis. Investigators also found that MI altered the makeup and function of chromatin, which plays a key role in DNA replication and gene expression.
“The pattern we were seeing was that for those genes that are required to mount an effective immune response, the chromatin was more closed, suggesting they couldn’t be turned on,” said Moore. “We think that heart attack is somehow causing this epigenetic reprogramming across the genome.”
Collectively, the laboratory findings provided a biological mechanism for an adverse effect of MI on breast tumor growth. Next, the investigators wanted to see how the clinical data matched up with the preclinical data. They retrospectively analyzed data from two prospective case cohort studies of patients with early-stage breast cancer to evaluate relationships between post-cancer diagnosis cardiovascular events (including MI, stroke, and heart failure) and cancer outcomes.
After exclusion of patients with pre-existing CVD or risk factors, 1,724 patients remained for the analysis. Follow-up averaged 11.7 years from cancer diagnosis. The primary outcomes were breast cancer recurrence and breast-cancer specific mortality (BCSM).
Recurrence data were available for all 1,724 patients, of whom 270 had a CV event. In multivariable analysis, patients with an MI, stroke, or heart failure after breast cancer diagnosis had a hazard ratio for recurrence of 1.59 compared with patients who did not have a CV event (95% CI 1.23-2.05, P=0.0004). The BCSM analysis included 1,544 patients, 168 of whom had a CV event and yielded a hazard ratio of 1.60 (95% CI 1.15-2.22, P=0.0045).
Moore said the findings probably are applicable to other types of cancer. Future studies will focus on further clarifying how MI reprograms the immune system and extending the studies to the human immune system.
Last Updated July 16, 2020
Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow
The authors reported having no relevant relationships with industry.
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