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Long-term use of calcium-channel blockers may raise breast cancer risk
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Use of calcium-channel blockers for 10 years or more was associated with higher risk for ductal breast cancer and lobular breast cancer, according to findings from a large, population-based, case-control study.
Christopher I. Li, MD, PhD, and colleagues observed no link between breast cancer and other classes of antihypertensive medications.
“Our results do suggest that long-term current use of calcium-channel blockers is associated with an increased risk of both [invasive ductal carcinoma] and [invasive lobular carcinoma] and that these associations do not vary according to [estrogen receptor] status,” Li, of the division of public health sciences at the Fred Hutchinson Cancer Research Center, Seattle, and colleagues wrote.
Previous studies exploring the relationship between antihypertensive medications and breast cancer returned inconsistent findings, according to the study background. Most studies were small, with the largest ones dating back to the 1990s, and were unable to assess the impact of long-term medication use, the researchers wrote.
The study included women aged 55 to 74 years from the Seattle metropolitan area who had no prior history of cancer and were diagnosed with a primary invasive breast cancer between January 2000 and December 2008. They interviewed 916 patients with ductal breast cancer, 1,068 patients with lobular breast cancer and 902 women from a control group. All women were asked about their history of hypertension, CVD and use of antihypertensive medications. Medication classes discussed included ACE inhibitors, angiotensin receptor blockers, beta-blockers, calcium-channel blockers (CCBs), diuretics and combination preparations.
The researchers found no association between either type of breast cancer and use of any class of antihypertensive medication for less than 10 years. However, there was an association between current use of CCBs for ≥10 years and increased risk for ductal breast cancer (OR=2.4; 95% CI, 1.2-4.9) and lobular breast cancer (OR=2.6; 95% CI, 1.3-5.3). No other antihypertensive medication classes were associated with either type of breast cancer when used for ≥10 years.
Further research is needed “to confirm this finding and to evaluate potential underlying biological mechanisms,” Li and colleagues wrote.
In a related editorial, Patricia F. Coogan, ScD, of Slone Epidemiology Center at Boston University, called the study “first-rate” because of its size, high response rate and use of best practices in determining participants’ current and prior medication use. She said bias from confounding by indication was unlikely because the researchers conducted a subanalysis of the participants who reported a history of hypertension. She also said that recall bias was unlikely because it would likely have extended to all medication classes in the survey.
However, Coogan said, more research must be done before clinical practice is changed. “Given these results, should the use of CCBs be discontinued after 9.9 years? The answer is no, because these data are from an observational study, which cannot prove causality and by itself cannot make a case for clinical practice,” she wrote. “Should the results be dismissed as random noise emanating from an observational study? The answer is no, because the data make a convincing case that the hypothesis that long-term CCB use increases the risk for breast cancer is worthy of being pursued.”
For more information:
Coogan PF. JAMA Intern Med. 2013;doi:jamainternmed.2013.9069.
Li CI. JAMA Intern Med. 2013;doi:10.1001/jamainternmed.2013.9071.
Disclosure: Coogan and the researchers report no relevant financial disclosures.
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George L. Bakris , MD, FASH, FACN
This study is important because it has a larger cohort than previous studies, but like the previous studies it is observational and, hence, can only be hypothesis-generating. It proves nothing and, other than duration of follow-up and slightly higher numbers studied, it does more to cloud the situation than help it.
The study design is adequate for what was studied, but has its limitations. Moreover, mechanistically, none of the data would support the findings. Further, in the journal Medical Hypotheses, CCBs were touted to be antimetastatic agents, not procarcinogens. So again, it’s a case of epidemiology flying in the face of disease mechanisms. I agree with the findings, but with many caveats, including a study design that is hypothesis-generating.
I have not observed this link with my patients. In fact, at my institution I am the consultant for people receiving the vascular endothelial growth factor inhibitors who have metastatic cancer, as these cause hypertension in most people. CCBs have been a cornerstone of therapy, as the mechanism of hypertension from these agents appears in part to be related to endothelin. There is no evidence of reduced efficacy because of this.
These findings will not change the way I practice. It hopefully will not change practice of others either. CCBs have been shown in numerous clinical trials to reduce mortality, hence people live longer. As one of our breast cancer specialists puts it, “Women now live long enough to get breast cancer. The study does not prove causality of getting breast cancer. Breast cancer is the gift of living longer and not stroking out.”
Unfortunately in the current litigious environment — totally uncontrolled, unlike medicine — articles like this, while good for journal impact factors, also stir the pot of lawyers looking to make even more money, as the television ads attest to.
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Nancy E. Davidson, MD
Because heart disease and breast cancer are common problems in women, this population-based, case-control study about a potential linkage between antihypertensive use and breast cancer risk is of particular interest. It is a large study that studies contemporary management. It gives a somewhat perplexing result that long-term use of one type of antihypertensive — calcium-channel blockers — is associated with an elevated risk for ductal and lobular cancer, while other classes of antihypertensives are not. This is a provocative finding, and the biological underpinnings need investigation. In the interim, patients and doctors should note that CVD is quite common in women and optimal BP management is a cornerstone of risk reduction. This study should not be viewed as a reason to change management for individual patients at this time. Rather, it supports the long-term goal of developing personalized medicine strategies that will allow us to match therapeutic interventions across disease types to the individual patient.
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Franz H. Messerli, MD
There is virtually no antihypertensive drug or drug class that has not been associated with cancer at one time or another. In particular, CCBs were at the center of a heated debate in the 1990s that was ultimately resolved by the ALLHAT trial, which found no suggestion of an increased risk for cancer associated with CCBs. To the contrary, non-CV mortality was lower in the amlodipine arm compared with the other drugs.
One possible source of confusion is that hypertensive patients see physicians more often, particularly when their hypertension is more severe as to require CCB therapy. Many practicing physicians still reserve calcium blockers for more severe hypertension only. Frequent physician visits are likely to increase the odds of cancer diagnosis.
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Wajeeha Razaq, MD
Antihypertensive drugs used to lower blood pressure have made a huge impact on the lives of many, and calcium-channel blockers (CCBs) are among the most popular medications to be prescribed.
The study by Li and colleagues points toward a possible connection between long-term use of CCBs and breast cancer in women aged 55 to 74 years.
The relationship between antihypertensives and risk for breast cancer has been a topic of heated debate since the 1990s. Multiple studies have looked at this relationship with variable results. The studies were criticized, either for their methods or for the number of patients enrolled.
Few studies have positively linked CCBs and diuretics to higher risk for breast cancer, and many studies have reported no association. The ALLHAT trial — a randomized, double blind trial that included 33,357 participants with hypertension and at least one other coronary heart disease risk factor — eventually resolved the issue when it found no suggestion of increased risk for breast cancer associated with CCBs (ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. JAMA. 2002;288:2981-2997).
The study by Li and colleagues is an observational study and can’t prove the cause-and-effect relationship between the drugs and risk for cancer.
Before we throw CCBs completely out of the picture, we need to remember that these are very potent antihypertensives, and heart disease is still one of the leading causes of mortality in the world. Additionally, more studies are needed to confirm the findings of this observational study and the underlying mechanism of CCBs causing the cancer. According to Li and colleagues, one reason may be that CCBs impede apoptosis, or programmed cell death.
The investigators mentioned that all participants were queried about various known or suspected breast cancer risk factors, including pertinent aspects of their reproductive, medical, breast cancer screening and family histories, as well as information about their body size, lifestyle habits and demographic characteristics. The results showed that "both [invasive ductal carcinoma] and [invasive lobular carcinoma] patients were somewhat more likely to have a first-degree relative with breast cancer, to be current alcohol users, and to be current smokers. The proportion of current users of combined estrogen and progestin menopausal hormone therapy was highest among [invasive lobular carcinoma] patients, intermediate among [invasive ductal carcinoma] patients and lowest among controls."
These are the typical breast cancer risk factors. Hormone replacement therapy (HRT) is very strongly related to the development of breast cancer in women aged older than 50 years. In fact, it has been observed in recent years that the risk for breast cancer has somewhat declined in this population as the use of HRT has decreased. Indeed there is a question if these patients were to develop breast cancer even if they were not on CCBs, as they had many risk factors.
In short, we cannot change the clinical practice based on this observational study. This issue demands more attention, but I would not change CCBs to any other medication if the patient’s blood pressure has been stable for many years. More studies are needed to confirm the findings of this study.
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