23 September, 2013

Another potential 'bomb' exploded recently, with the online publication of a study which showed that common therapies for controlling blood pressure may have an effect on the risk for breast cancer [1]. The study, which was observational and retrospective, was based on interviews with breast cancer patients and comparable healthy controls in Seattle, USA. Women were asked whether they used antihypertensive medications and, if they did, what type, when, and for how long. The cohort included 880 women with invasive ductal breast cancer, 1027 women with invasive lobular breast cancer, and 856 women with no cancer who served as controls. Results showed that those currently taking calcium-channel blockers for more than 10 years had about 2.5 times the risk for breast cancer (both ductal and lobular) compared to healthy women, whereas the use of angiotensin II antagonists was associated with a non-significant decrease in risk, and diuretics or beta-blockers were neutral in this respect. Shorter periods of use were not associated with a change in breast cancer risk.

Comment

I am certain that this news will catch the headlines, since it involves two major diseases of mid-age and beyond. However, as in many other similar scenarios, one should read the manuscript as a whole rather than only the title and abstract. There are many issues to deal with before embracing the data as they are. First, the cohort was perhaps not large enough, and the study was based on interviews/self-report, subject to people's memory. Second, some interesting questions such as doses of medications taken were not recorded and analyzed. Third, there is still no plausible explanation for this association between cancer and anti-hypertension treatment. Some researchers have hypothesized that calcium-channel blockers may inhibit apoptosis through increasing intracellular calcium levels, although evidence supporting this effect is lacking. Fourth, the Discussion section of the article brings information from previous relevant studies, which showed inconsistent results.

The California Teachers Study cohort found that diuretic use for 10 years or longer was associated with a 16% increased risk for breast cancer, while use of calcium-channel blockers and ACE inhibitors was not [2]. A case-control analysis derived from the United Kingdom-based General Practice Research Database found no disease associations with ever-use of ACE inhibitors, calcium-channel blockers, or β-blockers for 5 or more years [3]. The same Seattle research group conducted an earlier population-based case-control study (completely separate from the present study) and found that current use of thiazide and potassium-sparing diuretics was associated with 40% and 60% increases in risk of breast cancer, respectively (duration of use among current users was not assessed) [4]. All in all, of the 12 studies that have evaluated at least one class of antihypertensive agent, results are somewhat inconsistent: four studies found that use of calcium-channel blockers or diuretics is positively associated with breast cancer risk, but eight studies reported no associations. To note that these studies varied in their methodology and the parameters analyzed. Li and colleagues believe that the quality of their current data is sufficient enough to establish a reasonable conclusion that long-term use of calcium-channel blockers may increase breast cancer risk. However, the investigators say that confirmation of the study results is needed before making any clinical recommendations. An Editorial by Coogan at the same JAMA issue supports this conclusion [5]. Dr Coogan is not recommending the discontinuation of therapy at 10 years of use because the data are from an observational study, which cannot prove causality and by itself cannot make a case for change in clinical practice.

The best way to develop better human biology might be evolution-nature's trial-and-error model, where only the strongest survive, but this evolution takes millions of years. Modern medicine has changed this situation dramatically and brought longevity close to 100 years by active manipulations of human physiology. Nevertheless, the appearance of unexpected adverse effects and risks should always be expected during prolonged pharmacological treatment. Nothing in medicine is purely optimal and, therefore, the balance between the upside and the downside of therapy is what matters. Whether or not this study would have an impact on prescription habits of antihypertensive medications remains to be seen.

Amos Pines
Department of Medicine 'T', Ichilov Hospital, Tel-Aviv, Israel

References

1. 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 August 5. Epub ahead of print
http://www.ncbi.nlm.nih.gov/pubmed/23921840
2. Largent JA, Bernstein L, Horn-Ross PL, et al. Hypertension, antihypertensive medication use, and breast cancer risk in the California Teachers Study cohort. Cancer Causes Control 2010;21:1615-24.
http://www.ncbi.nlm.nih.gov/pubmed/20526803
3. Meier CR, Derby LE, Jick SS, Jick H. Angiotensin-converting enzyme inhibitors, calcium channel blockers, and breast cancer. Arch Intern Med 2000;160:349-53.
http://www.ncbi.nlm.nih.gov/pubmed/10668837
4. Li CI, Malone KE, Weiss NS, et al. Relation between use of antihypertensive medications and risk of breast carcinoma among women ages 65-79 years. Cancer 2003;98:1504-13.
http://www.ncbi.nlm.nih.gov/pubmed/14508839
5. Coogan PF. Calcium-channel blockers and breast cancer. A hypothesis revived. JAMA Intern Med 2013 August 5. Epub ahead of print.
http://www.ncbi.nlm.nih.gov/pubmed/23921818