Background: Antihypertensive medications are widely used among adults in the United States, 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 (CBC) 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 CBC and 691 control women diagnosed with only a single breast cancer and individually matched to cases. Multivariate conditional logistic regression was used to estimate ORs 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, angiotensin-converting enzyme (ACE) inhibitors, and diuretics, was associated with risk of second primary CBC. 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–positive 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 CBC. Cancer Epidemiol Biomarkers Prev; 24(9); 1423–6. ©2015 AACR.

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.

Table 1.

Characteristics of patients with CBC and control patients

ControlsPatients with CBC
n = 661n = 352
n (%)n (%)
Demographic characteristics 
 Age at first breast cancer diagnosis, y 
  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, y 
  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 
 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, y 
  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 
 Number 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 
 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 
 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/wk 
  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 
ControlsPatients with CBC
n = 661n = 352
n (%)n (%)
Demographic characteristics 
 Age at first breast cancer diagnosis, y 
  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, y 
  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 
 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, y 
  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 
 Number 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 
 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 
 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/wk 
  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 

NOTE: 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 CBC

ControlsCases
n = 661n = 352
Use of antihypertensive medicationsn (%)n (%)OR (95% CI)
Use of calcium channel blockers 
 Never 557 (84.0) 295 (84.0) Reference 
 Ever (≥6 mo) 85 (13.0) 47 (13.4) 1.1 (0.7–1.6) 
 Unknowna NA 
Recency of use among ever usersb 
 Former 15 (2.4) 10 (3.0) 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 (3.0) 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 (81.0) 289 (82.3) Reference 
 Ever (≥6 mo) 97 (15.0) 54 (15.4) 1.0 (0.7–1.4) 
 Unknowna NA 
Recency of use among ever users 
 Former 14 (2.2) 7 (2.1) 1.2 (0.4–3.2) 
 Current 75 (12.0) 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 (2.0) 8 (2.4) 1.3 (0.5–3.3) 
 ≥3 y 43 (7.0) 24 (7.3) 0.9 (0.5–1.6) 
Use of ACE inhibitors 
 Never 522 (79.0) 271 (77.2) Reference 
 Ever (≥6 mo) 114 (17.0) 72 (20.5) 1.2 (0.9–1.8) 
 Unknowna  
Recency of use among ever users 
 Former 20 (3.2) 11 (3.3) 1.0 (0.4–2.4) 
 Current 80 (13.0) 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 (6.0) 22 (6.8) 1.1 (0.6–2.1) 
Use of diuretics 
 Never 449 (68.0) 238 (68.4) Reference 
 Ever (≥6 mo) 177 (27.0) 96 (27.6) 1.0 (0.7–1.4) 
 Unknowna  
Recency of use among ever users 
 Former 31 (5.2) 15 (4.6) 1.0 (0.5–2.1) 
 Current 119 (20.0) 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 (11.0) 32 (10.3) 1.0 (0.6–1.7) 
ControlsCases
n = 661n = 352
Use of antihypertensive medicationsn (%)n (%)OR (95% CI)
Use of calcium channel blockers 
 Never 557 (84.0) 295 (84.0) Reference 
 Ever (≥6 mo) 85 (13.0) 47 (13.4) 1.1 (0.7–1.6) 
 Unknowna NA 
Recency of use among ever usersb 
 Former 15 (2.4) 10 (3.0) 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 (3.0) 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 (81.0) 289 (82.3) Reference 
 Ever (≥6 mo) 97 (15.0) 54 (15.4) 1.0 (0.7–1.4) 
 Unknowna NA 
Recency of use among ever users 
 Former 14 (2.2) 7 (2.1) 1.2 (0.4–3.2) 
 Current 75 (12.0) 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 (2.0) 8 (2.4) 1.3 (0.5–3.3) 
 ≥3 y 43 (7.0) 24 (7.3) 0.9 (0.5–1.6) 
Use of ACE inhibitors 
 Never 522 (79.0) 271 (77.2) Reference 
 Ever (≥6 mo) 114 (17.0) 72 (20.5) 1.2 (0.9–1.8) 
 Unknowna  
Recency of use among ever users 
 Former 20 (3.2) 11 (3.3) 1.0 (0.4–2.4) 
 Current 80 (13.0) 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 (6.0) 22 (6.8) 1.1 (0.6–2.1) 
Use of diuretics 
 Never 449 (68.0) 238 (68.4) Reference 
 Ever (≥6 mo) 177 (27.0) 96 (27.6) 1.0 (0.7–1.4) 
 Unknowna  
Recency of use among ever users 
 Former 31 (5.2) 15 (4.6) 1.0 (0.5–2.1) 
 Current 119 (20.0) 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 (11.0) 32 (10.3) 1.0 (0.6–1.7) 

NOTE: 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 additionally adjusted for receipt of adjuvant hormone therapy, radiation therapy, and chemotherapy.

aTo maximize the use of data, patients who used multiple drugs of a same class and had missing duration of use for some of these drugs were classified as ever users if known duration of use was ≥6 months or unknown users if known duration of use was <6 months.

bPatients who had any incomplete information on duration of use were dropped from analyses on recency and duration.

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).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1.
Chen
Y
,
Thompson
W
,
Semenciw
R
,
Mao
Y
. 
Epidemiology of contralateral breast cancer
.
Cancer Epidemiol Biomarkers Prev
1999
;
8
:
855
61
.
2.
Early Breast Cancer Trialists' Collaborative Group
. 
Tamoxifen for early breast cancer: an overview of the randomised trials
.
Lancet
1998
;
351
:
1451
67
.
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
;
135
:
647
54
.
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
;
27
:
5312
8
.
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
;
140
:
567
75
.
6.
Barron
TI
,
Connolly
RM
,
Sharp
L
,
Bennett
K
,
Visvanathan
K
. 
Beta blockers and breast cancer mortality: a population- based study. J Clin Oncol
.
Am Soc Clin Oncol
2011
;
29
:
2635
44
.
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
;
144
:
405
16
.
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
;
69
:
6865
70
.