Abstract
Background
Antihypertensive medications are widely used among adults in the U.S. and there is some evidence that certain classes may affect the risk of adverse breast cancer outcomes, but their impact on risk of second primary contralateral breast cancer is unclear.
Methods
We used data from a population-based nested case-control study consisting of 359 women diagnosed with both a first primary breast cancer and a second primary contralateral breast cancer and 691 control women diagnosed with only a single breast cancer and individually matched to cases. Multivariate conditional logistic regression was used to estimate odds ratios and 95% confidence intervals for risks associated with ever, recency and duration of use for various antihypertensive medications.
Results
No class of antihypertensive, including calcium channel blockers, β blockers, ACE inhibitors and diuretics, was associated with risk of second primary contralateral breast cancer. These results did not change materially in a sensitivity analysis restricted to women with a history of hypertension.
Conclusion
Our findings do not support associations between use of various antihypertensives and CBC risk among women with estrogen receptor + breast cancer.
Impact
The present study adds evidence to support the safety of commonly used antihypertensive medications among breast cancer survivors with respect to risk of second primary contralateral breast cancer.
Introduction
Breast cancer survivors have a 2-to-6-fold higher risk of developing second primary contralateral breast cancer (CBC) compared to 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 U.S., 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 58–81% 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, while 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 positive (ER+) breast cancer.
Materials and Methods
We used data from a population-based nested case-control study designed to evaluate risk factors for CBC. Details regarding 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 40–79 years of age 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 prior to the reference date and former users were those whose last use was ≥6 months prior to 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 odds ratios (ORs) and 95% confidence intervals (CIs) 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.
Table 1.
Characteristics of patients with contralateral breast cancer and control patients*
| Controls | Patients with contralateral breast cancer |
|
|---|---|---|
| n=661 | n=352 | |
| n (%) | n ( %) | |
| Demographic characteristics | ||
| Age at first breast cancer diagnosis, years | ||
| 40–49 | 120 (18.2) | 69 (19.6) |
| 50–59 | 174 (26.3) | 89 (25.3) |
| 60–69 | 206 (31.2) | 108 (30.7) |
| 70–79 | 161 (24.4) | 86 (24.4) |
| Reference age, years | ||
| 40–49 | 59 ( 8.9) | 33 ( 9.4) |
| 50–59 | 129 (19.5) | 66 (18.8) |
| 60–69 | 211 (31.9) | 111 (31.5) |
| 70–79 | 199 (30.1) | 103 (29.3) |
| 80–89 | 63 ( 9.5) | 39 (11.1) |
| Year of first breast cancer diagnosis | ||
| 1990–1993 | 241 (36.5) | 131 (37.2) |
| 1994–1997 | 220 (33.3) | 115 (32.7) |
| 1998–2001 | 147 (22.2) | 79 (22.4) |
| 2002–2005 | 53 ( 8.0) | 27 ( 7.7) |
| Race/ethnicity | ||
| Non-Hispanic white | 606 (92.0) | 322 (92.0) |
| Asian/Pacific Islander | 16 ( 2.4) | 9 ( 2.6) |
| African American | 24 ( 3.6) | 11 ( 3.1) |
| Native American | 10 ( 1.5) | 5 ( 1.4) |
| Hispanic white | 3 ( 0.5) | 3 ( 0.9) |
| Missing | 2 | 2 |
| Education | ||
| High school or less | 173 (33.7) | 78 (31.5) |
| High school or some college | 169 (32.9) | 102 (41.1) |
| College graduates or higher | 172 (33.5) | 68 (27.4) |
| Missing | 147 | 104 |
| Treatments for first breast cancer | ||
| Received radiation therapy | ||
| No | 229 (34.6) | 127 (36.1) |
| Yes | 432 (65.4) | 225 (63.9) |
| Received chemotherapy | ||
| No | 488 (73.8) | 264 (75.0) |
| Yes | 173 (26.2) | 88 (25.0) |
| Received hormonal therapy, years | ||
| None | 183 (27.7) | 130 (36.9) |
| <1 | 100 (15.1) | 56 (15.9) |
| 1–4 | 195 (29.5) | 87 (24.7) |
| ≥5 | 183 (27.7) | 79 (22.4) |
| Tumor characteristics of first breast cancer | ||
| AJCC stage | ||
| I | 454 (68.7) | 231 (65.6) |
| II/III | 207 (31.3) | 121 (34.4) |
| Tumor size, cm | ||
| ≤1.0 | 229 (35.6) | 111 (33.0) |
| 1.1–2.0 | 282 (43.8) | 136 (40.5) |
| >2.0 | 133 (20.7) | 89 (26.5) |
| Missing | 17 | 16 |
| Established breast cancer risk factors | ||
| First-degree family history of breast cancer | ||
| No | 463 (74.3) | 227 (70.5) |
| Yes | 160 (25.7) | 95 (29.5) |
| Missing | 38 | 30 |
| No. of full-term pregnancies | ||
| Nulliparous | 98 (15.2) | 54 (15.9) |
| 1–2 | 273 (42.5) | 149 (44.0) |
| ≥3 | 272 (42.3) | 136 (40.1) |
| Missing | 18 | 13 |
| Recency of menopausal hormone use at first breast cancer diagnosis | ||
| Never | 292 (46.9) | 166 (50.9) |
| Former | 71 (11.4) | 38 (11.7) |
| Current estrogen alone user | 138 (22.2) | 70 (21.5) |
| Current estrogen + progestin user | 122 (19.6) | 52 (16.0) |
| Missing | 38 | 26 |
| Health status and lifestyle factors | ||
| Had a diagnosis of hypertension between first breast cancer and reference date | ||
| No | 330 (50.6) | 180 (51.9) |
| Yes | 322 (49.4) | 167 (48.1) |
| Missing | 9 | 5 |
| Had a diagnosis of heart disease between first breast cancer and reference date | ||
| No | 495 (76.5) | 272 (78.8) |
| Yes | 152 (23.5) | 73 (21.2) |
| Missing | 14 | 7 |
| BMI at first breast cancer diagnosis, kg/m2 | ||
| <25 | 284 (43.8) | 125 (36.5) |
| 25–29.9 | 194 (29.9) | 112 (32.7) |
| ≥30 | 170 (26.2) | 105 (30.7) |
| Missing | 13 | 10 |
| Alcohol consumption between first breast cancer and reference date, drinks/week | ||
| None | 241 (47.2) | 113 (45.2) |
| <3 | 132 (25.8) | 71 (28.4) |
| ≥3 | 138 (27.0) | 66 (26.4) |
| Missing | 150 | 102 |
| Smoking status at reference date | ||
| Never | 269 (52.2) | 120 (47.6) |
| Former | 49 ( 9.5) | 35 (13.9) |
| Current | 197 (38.3) | 97 (38.5) |
| Missing | 146 | 100 |
Cases and controls were individually matched 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.
Table 2.
Use of antihypertensive medications and risk of second primary contralateral breast cancer*
| Controls | Cases | ||||
|---|---|---|---|---|---|
| Use of antihypertensive medications |
n=661 | n=352 | |||
| n | % | n | % | OR (95% CI) | |
| Use of calcium channel blockers | |||||
| Never | 557 | 84 | 295 | 84 | Reference |
| Ever (≥ 6 mo) | 85 | 13 | 47 | 13.4 | 1.1 (0.7 ,1.6) |
| Unknown † | 0 | 1 | NA | ||
| Recency of use among ever users ‡ | |||||
| Former | 15 | 2.4 | 10 | 3 | 1.4 (0.6 ,3.5) |
| Current | 60 | 9.5 | 33 | 9.8 | 1.1 (0.7 ,1.7) |
| Duration of use among current users | |||||
| <2 y | 17 | 2.8 | 10 | 3 | 1.1 (0.5 ,2.6) |
| 2–3 y | 15 | 2.4 | 3 | 0.9 | 0.3 (0.1 ,1.6) |
| ≥3 y | 28 | 4.5 | 20 | 6.1 | 1.4 (0.7 ,2.6) |
| Use of β blockers | |||||
| Never | 535 | 81 | 289 | 82.3 | Reference |
| Ever (≥ 6 mo) | 97 | 15 | 54 | 15.4 | 1.0 (0.7 ,1.4) |
| Unknown † | 2 | 1 | NA | ||
| Recency of use among ever users | |||||
| Former | 14 | 2.2 | 7 | 2.1 | 1.2 (0.4 ,3.2) |
| Current | 75 | 12 | 41 | 12.2 | 1.0 (0.6 ,1.5) |
| Duration of use among current users | |||||
| <2 y | 20 | 3.3 | 9 | 2.7 | 0.8 (0.3 ,1.9) |
| 2–3 y | 12 | 2 | 8 | 2.4 | 1.3 (0.5 ,3.3) |
| ≥3 y | 43 | 7 | 24 | 7.3 | 0.9 (0.5 ,1.6) |
| Use of ACE inhibitors | |||||
| Never | 522 | 79 | 271 | 77.2 | Reference |
| Ever (≥ 6 mo) | 114 | 17 | 72 | 20.5 | 1.2 (0.9 ,1.8) |
| Unknown † | 1 | 1 | |||
| Recency of use among ever users | |||||
| Former | 20 | 3.2 | 11 | 3.3 | 1.0 (0.4 ,2.4) |
| Current | 80 | 13 | 54 | 16.1 | 1.3 (0.8 ,2.0) |
| Duration of use among current users | |||||
| <2 y | 31 | 5.1 | 21 | 6.5 | 1.2 (0.6 ,2.3) |
| 2–3 y | 13 | 2.2 | 11 | 3.4 | 1.7 (0.7 ,4.1) |
| ≥3 y | 36 | 6 | 22 | 6.8 | 1.1 (0.6 ,2.1) |
| Use of Diuretics | |||||
| Never | 449 | 68 | 238 | 68.4 | Reference |
| Ever (≥ 6 mo) | 177 | 27 | 96 | 27.6 | 1.0 (0.7 ,1.4) |
| Unknown † | 4 | 4 | |||
| Recency of use among ever users | |||||
| Former | 31 | 5.2 | 15 | 4.6 | 1.0 (0.5 ,2.1) |
| Current | 119 | 20 | 72 | 22.2 | 1.2 (0.8 ,1.7) |
| Duration of use among current users | |||||
| <2 y | 35 | 6.2 | 29 | 9.4 | 1.6 (0.9 ,2.8) |
| 2–3 y | 20 | 3.5 | 11 | 3.5 | 1.2 (0.5 ,3.0) |
| ≥3 y | 64 | 11 | 32 | 10.3 | 1.0 (0.6 ,1.7) |
ORs and 95% Cis were estimated using conditional logistic regression to account for matching factors (age, year of first breast cancer diagnosis, stage of risk breast cancer, county of residence and race/ethnicity). All models were additional adjusted for receipt of adjuvant hormone therapy, radiation therapy and chemotherapy. CI= confidence interval; OR=odds ratio.
To maximize the utility of data, patients who used multiple drugs of a same class and had missing duration of use for some of these drugs would be classified as ever users if known duration of use was ≥ 6 mo, or unknown users if known duration of use was < 6 mo.
Patients had any incomplete information on duration of use were dropped from analyses on recency and duration.
Results
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).
Discussion
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 while 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 includes 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 U.S., 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.
Acknowledgments
Grant support:
This work was funded by a grant from the National Cancer Institute R01-CA097271 (C.I. Li, K.E. Malone).
Footnotes
Disclosure of Potential Conflicts of Interest:
No potential conflicts of interest were disclosed.
Disclaimer:
This article and its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NCI, NIH.
References
- 1.Chen Y, Thompson W, Semenciw R, Mao Y. Epidemiology of contralateral breast cancer. Cancer Epidemiol Biomarkers Prev. 1999 Oct;8(10):855–861. [PubMed] [Google Scholar]
- 2.Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet. 1998 May 16;351(9114):1451–1467. [PubMed] [Google Scholar]
- 3.Druesne-Pecollo N, Touvier M, Barrandon E, Chan DSM, Norat T, Zelek L, et al. Excess body weight and second primary cancer risk after breast cancer: a systematic review and meta-analysis of prospective studies. Breast Cancer Res Treat. 2012 Oct;135(3):647–654. doi: 10.1007/s10549-012-2187-1. [DOI] [PubMed] [Google Scholar]
- 4.Li CI, Daling JR, Porter PL, Tang M-TC, Malone KE. Relationship between potentially modifiable lifestyle factors and risk of second primary contralateral breast cancer among women diagnosed with estrogen receptor-positive invasive breast cancer. J Clin Oncol. 2009 Nov 10;27(32):5312–5318. doi: 10.1200/JCO.2009.23.1597. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Botteri E, Munzone E, Rotmensz N, Cipolla C, De Giorgi V, Santillo B, et al. Therapeutic effect of β-blockers in triple-negative breast cancer postmenopausal women. Breast Cancer Res Treat. 2013 Aug;140(3):567–575. doi: 10.1007/s10549-013-2654-3. [DOI] [PubMed] [Google Scholar]
- 6.Barron TI, Connolly RM, Sharp L, Bennett K, Visvanathan K. Beta blockers and breast cancer mortality: a population- based study. J Clin Oncol. Amer Soc Clinical Oncology. 2011 Jul 1;29(19):2635–2644. doi: 10.1200/JCO.2010.33.5422. [DOI] [PubMed] [Google Scholar]
- 7.Boudreau DM, Yu O, Chubak J, Wirtz HS, Bowles EJA, Fujii M, et al. Comparative safety of cardiovascular medication use and breast cancer outcomes among women with early stage breast cancer. Breast Cancer Res Treat. 2014 Feb 21; doi: 10.1007/s10549-014-2870-5. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Li CI, Daling JR, Porter PL, Tang M-TC, Malone KE. Adjuvant hormonal therapy for breast cancer and risk of hormone receptor-specific subtypes of contralateral breast cancer. Cancer Res. 2009 Sep 1;69(17):6865–6870. doi: 10.1158/0008-5472.CAN-09-1355. [DOI] [PMC free article] [PubMed] [Google Scholar]