Use of Antihypertensive Medications Not Associated with Risk of Contralateral Breast Cancer among Women Diagnosed with Estrogen Receptor–Positive Invasive Breast Cancer

Breast cancer survivors have a 2- to 6-fold higher risk of developing second primary contralateral breast cancer (CBC) compared with the risk women in the general population have of being diagnosed with a first breast cancer (1). Use of adjuvant hormonal therapy lowers this risk by an estimated 50% (2), with some additional evidence that maintaining a healthy weight, quitting smoking, and reducing alcohol consumption may also reduce CBC risk (3, 4).

Antihypertensives, the most commonly prescribed category of medications in the United States, may also affect risks of certain adverse breast cancer outcomes. Specifically, use of β-blockers, a widely used medication to treat hypertension, heart failure, migraines, and other conditions, has been associated with 58% to 81% reductions in risk of breast cancer–specific mortality (5, 6). However, only one prior study evaluated antihypertensive use in relation to CBC risk and observed that angiotensin-converting enzyme (ACE) inhibitors was associated with a 66% higher risk of CBC, whereas other classes of antihypertensives did not impact risk (7). To further advance knowledge in this area, we examined the relationship between various antihypertensives and CBC risk among women diagnosed with estrogen receptor–positive (ER+) breast cancer.

We used data from a population-based nested case–control study designed to evaluate risk factors for CBC. Details about this study's design and data collection methods have been previously described (8). Briefly, from an underlying cohort identified through the Cancer Surveillance System (CSS, our local SEER cancer registry) of 17,628 women ages 40–79 years diagnosed in the years 1990–2005 with stage I–IIIA ER+ breast cancer, we enrolled 369 cases, defined as those diagnosed with a subsequent CBC through 2007 and 734 control women never diagnosed with a CBC individually matched 2:1 to cases on age, year of diagnosis, county, race/ethnicity, and cancer stage. Controls also had to be alive for at least the duration between their matched cases' first and CBC diagnoses.

Information on use of various antihypertensive medications between the date of the first breast cancer diagnosis (index date) and reference date (date of CBC diagnosis for cases and date of their matched case's CBC diagnosis for controls) was abstracted from medical records for 359 (97%) cases and 691 (94%) controls. Antihypertensive drugs were grouped into the following categories: calcium channel blockers, ACE inhibitors, β-blockers, and diuretics regardless of indication. Data on potential confounding variables were ascertained from a variety of sources including medical record reviews, telephone interviews conducted with study participants, and data collected by CSS.

Ever use of a given antihypertensive was defined as having used it for ≥6 months between the index and reference dates. Among ever users, current users were defined as those who had last used the medication <6 months before the reference date and former users were those whose last use was ≥6 months before reference date. A sensitivity analysis restricted to women with a history of hypertension was conducted to assess potential confounding by indication.

We used conditional logistic regression to calculate ORs and 95% confidence intervals (CI) for the associations between use of various antihypertensive medications and CBC risk. All analyses were additionally adjusted for adjuvant hormone therapy, chemotherapy, and radiation therapy; therefore, women with missing information on these treatment variables were dropped, leaving a final analytic sample of 352 cases and 661 controls. None of the variables listed in Table 1 were identified as confounders or effect modifiers of the risk estimates shown in Table 2.

Cases and controls were similar in most aspects of patients' characteristics examined (Table 1). No antihypertensive type was associated with CBC risk, and this did not vary when evaluating recency or duration of use (Table 2). These results did not change materially in a sensitivity analysis restricted to women with a history of hypertension (data not shown).

Our null results with respect to calcium channel blockers, β-blockers, and diuretics are consistent with the only previous study to evaluate their association with CBC risk (7). However, this prior study observed that ACE inhibitor use was associated with a 66% increased risk of CBC whereas we found no association. No dose–response pattern was observed in this prior study and so this may have been a chance result but warrants further investigation. Key strengths of our study include the large number of CBCs and the use of medical records review to determine medication eliminating recall bias inherent to self-reported data.

In summary, we did not find evidence that use of calcium channel blockers, β-blockers, ACE inhibitors, or diuretics is associated with CBC risk among women with ER+ breast cancer. Given the widespread use of antihypertensive medications in the United States, future efforts to confirm the safety of these and other commonly used medications will further inform breast cancer survivors and their health care providers as they consider the risk/benefit profiles of these medications.

No potential conflicts of interest were disclosed.

This article and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCI, NIH.

Conception and design: L. Chen, K.E. Malone, C.I. Li

Development of methodology: K.E. Malone, C.I. Li

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): C.I. Li

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): L. Chen, C.I. Li

Writing, review, and/or revision of the manuscript: L. Chen, K.E. Malone, C.I. Li

Study supervision: C.I. Li

This work was funded by a grant from the National Cancer Institute R01-CA097271 (C.I. Li, K.E. Malone).

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