The treatment of cancer is growing more and more specialized, as researchers and pharmaceutical companies test strategies designed to attack very specific types of tumors. A success of this approach received an avalanche of publicity this past week at the American Society for Clinical Oncology meeting in Chicago – two new drugs that target mutations associated with some forms of melanoma. But the history of cancer treatment is marked by many happy accidents, and two papers published shortly before the ASCO meeting revealed a potential new bit of cancer-fighting serendipity. In this case, a drug class used for decades to treat hypertension and heart disease may play a previously-unanticipated role in improving the outcome of patients with breast cancer by interfering with the more general phenomenon of stress.
Beta blockers are a group of drugs named for their inhibition of the beta-adrenergic receptors, where the hormone known as adrenaline or epinephrine binds and activates the sympathetic nervous system. Drugs that block these receptors can lower a patient’s heart rate and blood pressure, making them valuable tools for fighting cardiovascular disease. Those effects would seemingly have little to do with treating cancer. But animal and tissue culture studies have suggested a role for beta-adrenergic receptors in promoting tumor growth and metastasis, and human data implicating lifestyle factors such as social stress and obesity in cancer outcomes have also suggested a role for the sympathetic nervous system.
Those were enough clues for two groups of researchers to test whether beta-blockers affected the usual course of breast cancer. Using retrospective data on thousands of patients from the United States or Ireland, the two groups compared patients who were taking beta-blockers (for reasons unrelated to cancer) and women who were not on the drugs. While retrospective studies aren’t always the best way to measure the effect of an intervention – due to an inability to control what data was collected, which beta blocker was used, how much of the drug was given, etc. – it was a fast way to see whether promising signs were apparent in a large population.
In spite of these limitations, both studies (published in late May in the Journal of Clinical Oncology) found favorable effects of beta blockers in breast cancer patients. In the United States study, led by former Medical Center fellow Amal Melhem-Bertrandt and co-authored by professor of medicine Suzanne Conzen, women with triple-negative breast cancer who were on beta-blockers during their cancer treatment exhibited a longer relapse-free survival, despite no dramatic differences in initial tumor response to chemotherapy. The effect on patient’s cancer-free survival was particularly notable, since triple-negative breast cancer is a form of the disease especially prone to relapse and death.
“It seems to be particularly affecting those tumor cells that are left behind after chemotherapy and surgery, those that grow back after the initial therapy and return as recurrences,” Conzen said. “It suggests that the beta-adrenergic pathway has something important to do with tumor growth and the stress responsiveness of the tumor cells themselves.”
The study using breast cancer data from Ireland found benefits of beta-blockers using slightly different measures. Women who were on beta-blockers were initially diagnosed with less severe tumor types and displayed significantly lower breast-cancer related mortality than the no-drug controls, the authors reported. Intriguingly, they also determined that one type of beta blocker, propranolol, produced these protective effects while a more specific version, called atenolol, did not show an effect.
The authors of an editorial appearing alongside the two articles were convinced enough to call for “proof-of-concept” trials to more carefully test the value of beta blockers in treating breast cancer. But Conzen said the star of the show was not necessarily the drugs themselves, but the identification of a stress response pathway with an impact upon cancer outcomes. With professor of psychology Martha McClintock, Conzen’s laboratory is studying the relationship between stress and breast cancer in animal models, and the new studies add an intriguing piece to that puzzle.
“It fits our hypothesis that a patient’s chronically heightened stress responsiveness resulting from exposure to unrelenting stressors is associated with increased breast cancer growth,” Conzen said. “We think that the new beta-blocker results reflect the beneficial effect of antagonizing part of this pathway.”
Blocking the effects of stress on breast cancer progression may not require beta blockers or other drugs, she said. A more supportive social environment, lifestyle changes, or cognitive/behavioral therapy designed to reduce stressors and hence the patient’s heightened response to stress may accomplish the same benefits as adding another drug to cancer therapy – in fact, studies of those approaches are already underway.
“There are more and more studies being done that are randomizing early stage breast cancer patients to exercise and/or stress reduction and seeing if there’s a difference in recurrence rates. It’s looking like there is,” Conzen said. “But the beta-blocker research is still very interesting, as we may have unearthed a potential physiological link between those sorts of lifestyle changes and the reduction in the risk of the recurrence.”
Melhem-Bertrandt A, Chavez-Macgregor M, Lei X, Brown EN, Lee RT, Meric-Bernstam F, Sood AK, Conzen SD, Hortobagyi GN, & Gonzalez-Angulo AM (2011). Beta-Blocker Use Is Associated With Improved Relapse-Free Survival in Patients With Triple-Negative Breast Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology PMID: 21632501