Li CI, Daling JR, Tang MT, et al. Use of antihypertensive medications and breast cancer risk among women aged 55 to 74 years. JAMA Intern Med. 2013 Aug 5. [Epub ahead of print]
Population-based case-control study
Women (55–74 years old), including 880 with invasive ductal breast cancer, 1,027 with invasive lobular breast cancer, and 856 with no cancer who served as controls
Incidence of invasive ductal carcinoma and incidence of invasive lobular carcinoma
Current use of calcium channel blockers for 10 or more years was associated with higher risk of invasive ductal cancer (odds ratio [OR]: 2.4; 95% CI: 1.2–4.9; P=0.04) and lobular carcinoma 58 (OR: 2.6; 95% CI: 1.3–5.3; P=0.01 for trend). There was no difference between short- and long-acting calcium channel blockers. There was no associated risk with other antihypertensive agents.
With 1 in 3 Americans having high blood pressure,1 antihypertensive drugs are among the most frequently prescribed medicines in America. There are 11 different antihypertensive drug classes to choose from, each with its own risks and side effects. For those requiring a medication for control, this study suggests there may be an associated risk of breast cancer in postmenopausal women taking calcium channel blockers for a long duration (> 10 years).
Of course, association is not causation and this is an observational study, so we do not know if the calcium channel blockers were causative. However, this study adds to prior evidence of associated risk of cancer with this drug class. This, alongside a growing understanding of ion channel disruption as a possible culprit in cancerous processes, should give us pause.2
A nice review of ionic flux and cancer was published in 2010 in the aptly named paper, “Ion Channels and the Hallmarks of Cancer,” by Prevarskaya and colleagues.3 The review delves into the complexity of ion channels and oncogenesis, including proliferation, angiogenesis, and invasion. For example, there are 4 classes of calcium channels, and several subsets with each of them. Structurally, there are the several compartments in and around the cell, including the extracellular matrix, the cytoplasm, and the endoplasmic reticulum. The maintenance of proper growth as opposed to malignant growth is intertwined with the flux of calcium ions in concert with sodium and potassium to maintain control of the cell cycle. Each and every process involved in cellular regulation—normal and malignant—involves the flow of calcium ions.
To add to this complexity, each cancer type has its own varied expression of calcium channels, so generalizations about “cancer” should not be made based on the current abstract involving breast cancer. Human outcome data will be the only means of gauging how a drug such as the calcium channel blockers will affect risk for various cancers. To date, we do not have any prospective clinical trial evidence with breast cancer as a primary endpoint. We do have observational studies, several of which have suggested there is an associated risk of breast cancer with calcium channel blockers.
Results of a study published in 1997 are in keeping with the abstract reviewed here. The Cardiovascular Health Study was a multisite observational cohort study that began enrollment in 1989.4 In it, 3,189 women ≥65 years of age were assessed. Seventy-five incident breast cancers were identified. Use of calcium channel blockers was associated with a significantly increased risk of breast cancer (hazard ratio [HR]: 2.57; 95% CI: 1.47–4.49). No other blood pressure medications were associated with increased risk. The association increased with the use of estrogen replacement (HR: 4.48; 95% CI: 1.58–12.75). There was an alarmingly high associated risk in those taking estrogens with immediate-release calcium channel blockers (HR: 8.48; 95% CI: 2.99–24.08). The association appeared to increase with increasing dose of calcium channel blockade agent as well.
In 1996 Pahor et al published the first observational study on the associated risk of calcium channel blockers with incident cancers.5 The elderly population (≥71 years old) of 5,052 participants included 451 cancer cases and 4,601 control cases. The hazard ratio for cancer associated with calcium channel usage was 1.72 (CI: 1.27–2.34; P=0.0005). Again, effect was greater with greater dosage.
Not all studies have suggested an association. A 1997 JAMA publication assessed cancer incidence in 9,513 participants (40–69 years old) in a case-control drug surveillance study that took place from 1983–1996.6 Overall cancers, as well as breast cancer specifically, were not associated with any increased incidence. A much more recent (2012) review of studies on antihypertensive agents and cancer also concluded there is not enough evidence to assert causation for any of the drugs.7
It should come as little surprise that calcium channel blockers may influence carcinogenic processes in breast tissue.
In a 2013 follow up publication of the Cardiovascular Health Study, the association of increased breast cancer incidence was only apparent in those taking immediate-release forms of calcium channel blockers, versus sustained-release forms.8 Those who had taken immediate-release calcium channel blockers within the past 2 years had a 1.6-fold increased risk (CI 95%: 1.0–2.5). Those who used calcium channel blockers most recently had a 2.4-fold increase in risk of breast cancer (95% CI: 1.3–4.5). They found no association with other antihypertensives used. This is in contrast to the current abstract, which found an associated risk with long-term use of extended-release as well as immediate-release forms.
It should come as little surprise that calcium channel blockers may influence carcinogenic processes in breast tissue. The mammary gland, by virtue of concentrating calcium for milk production during lactation, has unique calcium homeostatic mechanisms. Disruption of calcium channels/transporters and/or binding proteins has implications for breast cancer pathophysiology.9 The role of ionic channels in general is gaining in interest as a means of thwarting the growth and aggressiveness of various cancers.10 Indeed, in vitro evidence suggests that calcium channel blockage reduces growth of an aggressive breast cancer cell line (MDA-MB-231) by affecting sodium ion transport. This is a reminder of the complexity of intracellular ionic flux, as well as the dangers of extrapolating any data from in vitro findings to clinical use.
Heart disease is still the No. 1 cause of death in America. Hypertension should be controlled with foundational measures such as diet, normalizing body weight, stress reduction, select nutrients (eg, repletion of potassium and magnesium), and perhaps select herbal medicines. When natural means of control are insufficient, medications may be necessary. Given the current information on calcium channel blocking agents and increased breast cancer incidence, beginning with other classes of drugs makes sense—especially in patients who have other risk factors for breast cancer or have a heightened anxiety of developing breast cancer. The data are preliminary, but avoiding calcium channel blockers may provide peace of mind for patient and practitioner alike.
For more research involving integrative oncology, click here.
- Centers for Disease Control: Blood Pressure Facts. http://www.cdc.gov/bloodpressure/facts.htm. Updated March 20, 2013. Accessed September 2, 2013.
- Fiske J, Fomin V, Brown M, Duncan R, Sikes R. Voltage-sensitive ion channels and cancer. Cancer Metastasis Rev. 2006;25:493-500.
- Prevarskaya N, Skryma R, Shuba Y. Ion channels and the hallmarks of cancer. Trends Mol Med. 2010;16:107-121.
- Fitzpatrick AL, Daling JR, Furberg CD, Kronmal RA, Weissfeld JL. Use of calcium channel blockers and breast carcinoma risk in postmenopausal women. Cancer. 1997;80:1438-1447.
- Pahor M, Guralnik JM, Ferrucci L, et al. Calcium-channel blockade and incidence of cancer in aged populations. Lancet. 1996;348:493-497.
- Rosenberg L, Rao R, Palmer JR, et al. Calcium channel blockers and the risk of cancer. JAMA. 1998;279:1000-1004.
- Singh A, Bangalore S. Which, if any, antihypertensive agents cause cancer? Curr Opin Cardiol. 2012;27:374-380.
- Saltzman B, Weiss N, Sieh W, et al. Use of antihypertensive medications and breast cancer risk. Cancer Causes Control. 2013;24:365-371.
- Lee WJ, Monteith GR, Roberts-Thomson SJ. Calcium transport and signaling in the mammary gland: Targets for breast cancer. Biochim Biophys Acta. 2006;1765:235-255.
- Roger S, Potier M, Vandier C, Besson P, Le Guennec J-Y. Voltage-gated sodium channels: new targets in cancer therapy? Curr Pharm Des. 2006;12:3681-3695.