ACE inhibitors may be linked to breast cancer recurrence

Angiotensin-converting enzyme inhibitors may be associated with an increased risk for breast cancer recurrence, according to researchers at UCLA's Jonsson Comprehensive Cancer Center.

According to Patricia Ganz, MD, study researcher and director of cancer prevention and control research at the Jonsson Center, beta-blockers appear to have a protective effect by helping to prevent recurrence, and when used together, they appear to help improve the negative effect of angiotensin-converting enzyme (ACE) inhibitors.

Ganz and colleagues conducted a retrospective analysis using data from the Life After Cancer Epidemiology (LACE) study, which included 1,779 patients diagnosed with early-stage breast cancer. According to Ganz, their findings, recently published in Breast Cancer Research and Treatment, are "hypothesis-generating only" and require further validation in other, larger clinical databases.

However, the negative effect of ACE inhibitors on chances for recurrence is cause for caution.

"The message from this is we have to be aware of other chronic health problems and medications that patients take after their diagnosis of breast cancer," Ganz said in a press release. "We are learning that some medications, while they may be very helpful for treating cardiovascular disease and hypertension, may have an adverse effect on breast cancer survivors."

Patricia Ganz

In the study, Ganz said the key to the dissimilar effect of ACE inhibitors and beta-blockers on breast cancer recurrence may be explained by each working differently in the breast cancer microenvironment, affecting different pathways of inflammation.

Effects of stress

In September, data from a Jonsson Cancer Center study in mice demonstrated that chronic stress feeds breast cancer progression through inflammatory signaling and significantly accelerated the spread of disease.

The researchers discovered that stress was biologically reprogramming the immune cells trying to fight the cancer. The researchers reported a 30-fold increase in cancer spread throughout the bodies of stressed mice compared with those that were not stressed.

The animal study provided a model that demonstrated that stress can speed up cancer progression, and also detailed the pathway used to change the biology of immune cells that inadvertently promote metastasis.

The researchers documented the effects of stress on the spread of cancer and used beta-blockers to block the effects in stressed mice. The result was the nervous system's reprogramming of macrophages. The findings from the animal model experiments formed the basis to find a breast cancer patient sample in which to test whether exposure to beta-blockers could reduce the risk for breast cancer recurrence, according to the release.

Ganz worked with researchers at Kaiser Permanente Northern California to examine the influence of beta-blockers and ACE inhibitors on the risk for breast cancer recurrence in 1,779 women with early-stage breast cancer who were followed for an average of 8 years. Pharmacy data on the use of various medications was available for all patients. Information about cancer stage, treatments and other chronic conditions was also available.

Of these, 292 women experienced a breast cancer recurrence. In the release, Ganz said 23% of the women in the study were exposed to either a beta-blocker or an ACE inhibitor. The women taking these drugs were generally older, postmenopausal and had other health issues, such as being overweight and having hypertension or diabetes.

In analyses that controlled for these differences, Ganz found that women taking ACE inhibitors had a significantly increased risk for recurrence, whereas those taking beta-blockers had a lower risk for recurrence. Exposure to both beta-blockers and ACE inhibitors was associated with an intermediate risk for recurrence, suggesting that the beta-blockers may modify the increased risk associated with ACE inhibitors.

"The ACE inhibitor findings were not expected," Ganz said in the release. "These observations need to be confirmed and suggest that greater attention should be focused on the potential effect of these commonly used medications on recurrence and breast cancer survival."

Further research needed

Along with colleagues at the Jonsson Center, Ganz is now examining the effects of ACE inhibitors in a mouse model to better understand what is happening at the tissue level.

According to Ganz, understanding the biology of stress and inflammation at the cellular level is critical, as healthy lifestyle behaviors such as exercise and stress reduction techniques may also influence the same biological pathways in the tumor microenvironment. Those strategies may also be employed to help prevent recurrence.

"There is an increasing interest in the relationship between host lifestyle factors and the outcomes of cancer treatment," the researchers wrote. "Behavioral factors, comorbid conditions and noncancer-related pharmaceutical exposures may affect breast cancer outcomes."

In addition, Ganz is working with researchers in Denmark and Canada to examine these medications and their relationship to recurrence in larger samples of patients with breast cancer. She said she hopes to confirm the findings in this study within the next year to have a clearer picture of the effects of beta-blockers and ACE inhibitors on the risk for recurrence, according to the release. In the event that beta-blockers prove to be protective, prevention trials in women at high risk for recurrence, such as those treated for triple-negative breast cancer, may be warranted.

"If giving beta-blockers could help reduce risk of recurrence, [it] would increase the tools we have to fight this deadly form of breast cancer," Ganz said in the release. "There is only so much that treating the cancer cells can do. Up until recently, there's been a lot of focus on the cancer cell, but we need to understand that these malignant cells live in a microenvironment of growth signals and fat cells, insulin and inflammation, and these things may affect the way they behave."

Ganz also is beginning a phase 2, randomized trial in younger women with breast cancer using mindfulness meditation to reduce stress and evaluate its effects on healthful behaviors and the immune system.

"Instead of focusing on the cancer cell, what I'm doing is looking at the host lifestyle factors and how amenable those are to modification in an effort to prevent recurrence," Ganz said. "These cancer cells are not living in isolation."

For more information:

• Ganz PA. Breast Cancer Res Treat. 2011;doi:10.1007/s10549-011-1505-3.

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