Use of anti-hypertensive medications and breast cancer risk among women 55–74 years of age

Abstract

Importance

Antihypertensives are the most commonly prescribed class of medications in the United States. Evidence regarding the relationship between different types of antihypertensives and breast cancer risk is sparse and inconsistent, and prior studies have lacked the capacity to assess impacts of long-term use.

Objective

To evaluate associations between use of various classes of antihypertensive medications and risks of invasive ductal and invasive lobular breast cancers among postmenopausal women.

Design

Population-based case-control study.

Setting

The three county Seattle-Puget Sound metropolitan area.

Participants

Participants were women 55–74 years of age and consisted of 880 invasive ductal breast cancer cases, 1,027 invasive lobular breast cancer cases, and 856 cancer-free controls.

Exposures

Recency and duration of use of antihypertensive medications.

Main Outcomes

Risks of invasive ductal and invasive lobular breast cancers.

Results

Current use of calcium-channel blockers for ≥10 years was associated with higher risks of ductal [odds ratio (OR)=2.4, 95% confidence interval (CI): 1.2–4.9, p for trend=0.036] and lobular breast cancers (OR=2.6, 95% CI: 1.3–5.3, p for trend=0.008). This relationship did not vary appreciably by type of calcium-channel blocker used (short-acting vs. long-acting, dihydropyridines vs. non-dihydropyridines). In contrast, use of diuretics, beta-blockers, and angiotensin II antagonists were not associated with risk.

Conclusions and Relevance

While some prior studies have suggested a positive association between calcium channel blocker use and breast cancer risk, this is the first study to observe that long-term current use of calcium channel blockers in particular are associated with breast cancer risk. Additional research is needed to confirm this finding and to evaluate potential underlying biological mechanisms.

Introduction

Considered together, the major forms of antihypertensive medications are the most commonly prescribed class of drugs in the United States. In 2010 the number of filled prescriptions for beta blockers, angiotensin-converting-enzyme (ACE) inhibitors, diuretics, calcium channel blockers, and angiotensin receptor blockers were 191.5, 168.7, 131.0, 97.9, and 83.7 million, together totaling 678.2 million filled prescriptions. Despite their widespread use, relatively few studies have characterized how use of different classes of antihypertensives are related to breast cancer risk. Of the studies that have evaluated at least one class of antihypertensive, results are somewhat inconsistent as some studies have found that use of calcium channel blockers or diuretics ^1–4 are positively associated to breast cancer risk, but most have observed no associations.^5–12 However, in these latter eight studies, few reported on more than one class of antihypertensive or on risks by duration of use. Drawing inferences across studies is challenging because of the different study designs that have been used (ranging from hospital-based studies, to cohorts of specific population, to population-based case-control and cohort studies), variations in the populations evaluated, and that the majority of these twelve studies included relatively few cases, with five having fewer than 100 cases ^1,6,9,10,12 and another three having fewer than 400 cases.^2,5,8 Further, almost all of the women in these three studies were recruited during the 1990s, and as such these analyses were limited in their abilities to assess more recently introduced forms of antihypertensives and longer durations of use.

The purpose of this study is to assess the relationships between the major classes of antihypertensives and risk of the two most common histologic types of breast cancer, invasive ductal and invasive lobular carcinomas, in a contemporary population of postmenopausal women who have experienced longer durations of antihypertensive use compared to prior studies. In the United States, an estimated 70% of all invasive breast cancers diagnosed among postmenopausal women are ductal and approximately 20% are lobular.¹³ Consideration of risk by histologic type is relevant as other risk factors, most notably use of menopausal hormone therapy,^14–16 have been shown to be differentially associated with risk of ductal compared to lobular tumors. Given that once prescribed antihypertensives are often taken for the rest of a woman’s lifetime, characterizing their potential associations with risk of developing the most common cancer affecting women, breast cancer, is of both clinical and public health importance particularly given the increasingly large number of options available to manage hypertension.

Methods

We conducted a large population-based case-control study of the two most common histologic subtypes of breast cancer, ductal and lobular carcinomas. The overall goal of this study was to evaluate similarities and differences in the risk factor profiles of ductal and lobular breast cancers. Potentially eligible cases were all women 55 to 74 years old diagnosed with a primary invasive breast cancer between January 2000 and December 2008 in the three county greater Seattle metropolitan area with no prior history of cancer. These patients were identified through the Cancer Surveillance System (CSS), the population-based tumor registry that serves western Washington state and participates in the Surveillance, Epidemiology, and End Results program of the National Cancer Institute. We enrolled two groups of cases, those with invasive lobular cancer (ILC) and those with invasive ductal cancer (IDC). All women diagnosed with an invasive breast cancer with a lobular component, based on ICD-O codes 8520, 8522, and 8524 assigned by CSS, were potentially eligible as ILC cases. Given the greater frequency of IDC, a sample of ~25% of the total eligible IDC cases was selected for recruitment among those with an ICD-O histology code of 8500. IDC cases were frequency matched to the ILC case group by 5-year age group. The pathology reports of all cases were centrally reviewed to confirm eligibility and recategorize histology groupings as necessary. Of the 2,495 eligible cases identified, 1,984 (80%) were interviewed including 1,068 ILC and 916 IDC cases. 17% of eligible cases refused to participate and 3% died prior to interview. The case sampling strategy used, and the exclusion of breast cancers with histologies other than ductal or lobular, prohibits the assessment of risks for breast cancer overall.

We used the Mitofsky-Waksberg¹⁷ method of random digit dialing of landline telephones to identify potential controls from the general population of female residents of King, Pierce, and Snohomish counties. As such, cases without a landline telephone were excluded, but these 36 cases represented only 1.2% of our total number of potentially eligible cases. Controls were frequency matched within 5-year age groups to the ILC cases using one-step recruitment with the goal of having a 1:1:1 ratio of controls to ILC and IDC cases. Of the 1,313 eligible controls identified, 902 (69%) were interviewed and 411 (31%) declined to participate.

Data Collection

The study protocol was approved by the Fred Hutchinson Cancer Research Center Institutional Review Board, and written informed consent was obtained from all study subjects. Cases and controls were interviewed in-person primarily in women’s homes. Through a series of structured questions, detailed histories of hypertension and heart disease and all episodes of use of ACE inhibitors, angiotensin receptor blockers, beta blockers, calcium channel blockers, diuretics, and combination antihypertensive preparations regardless of indication, including beginning and ending dates, drug name, dose, route of administration, pattern of use (number of days per month), and indication, were obtained. Two primary strategies were used to enhance recall. First since these medications are typically used chronically we asked women to show the interviewer all of the bottles of prescription medications they were currently taking so that the interviewer could transcribe information directly from them. Second, for medications used in the past women were shown a photo book containing pictures of pills of commonly used antihypertensives (organized by category) along with a show card listing the brand and generic names of each of these drugs. High correlation between self-reported antihypertensive use and pharmacy record data using this approach has been previously published (cases: 92% sensitivity and 91% specificity; controls: 92% sensitivity, 93% specificity).¹⁸ All participants were additionally queried about various known or suspected breast cancer risk factors including pertinent aspects of their reproductive, medical, breast cancer screening, and family histories, as well as information about their body size, lifestyle habits, and demographic characteristics (including self-reported race and ethnicity). Our questioning was limited to exposures that occurred before each participant’s reference date. The reference date used for each woman with breast cancer was her diagnosis date. Control reference dates were assigned to reflect the expected distribution of reference dates among the cases. The mean time between reference date and interview date was 18 months for cases and 20 months for controls, and the median times were 16 months and 19 months, respectively.

Statistical Analysis

Women who never used any type of antihypertensive medication served as the reference category. Our main analysis focused on recency of antihypertensive medication use where current users were those who ever used these medications for 6 months or longer and were currently using them within six months of their reference date. Former users were ever users of these medications for 6 months or longer who last used them more than 6 months prior to their reference date. Short-term users were women who used these medications for less than six months regardless of their recency of use. We also conducted analyses restricted only to those women who were current antihypertensive users as a means of evaluating potential confounding by indication. In these analyses current users of a particular class of antihypertensive medication were compared to women who were not using this class of antihypertensive but were current users of other classes of antihypertensives. Additionally, we assessed risks associated with different subclasses of calcium-channel blockers according to whether women used short vs. long acting calcium channel blockers and dihydropyridine vs. non-dihydropyridines. These groupings were defined as follows: short-acting: verapamil, diltiazem, nifedipine, nicardipine; long-acting: verapamil slow release (SR), diltiazem extended release (ER), amlodipine, felodipine, nifedipine SR, isradipine; dihydropyridines: amlodipine, felodipine, nifedipine SR, isradipine, nifedipine, nicardipine, and non-dihydropyridines: verapamil, diltiazem, verapamil SR, diltiazem ER.

We used polytomous logistic regression to calculate odds ratios (ORs) and their associated 95% confidence intervals (CIs) to compare IDC and ILC cases to controls.¹⁹ P-values for trend were computed across categories of duration of use (5-year categories). Given the design of this study, its frequency matched sample of IDC cases based on age, and our exclusion of other histologic subtypes of breast cancer risk, estimates for breast cancer overall could not be calculated. All analyses were conducted using Stata/SE version 11.2 (StataCorp LP, College Station, TX). All models were adjusted for age (five year categories), reference year (continuous), and county since controls were matched to cases on these factors. Several potential confounders and effect modifiers of the relationship between antihypertensive use and breast cancer risk were assessed, those included in Table 1 as well as other commonly used medications (lipid-lowering, non-steroidal anti-inflammatory, and antidepressant drugs) and common comorbid conditions (cardiovascular disease, diabetes, hyperlipidemia, and depression). Only recency of alcohol use changed our risk estimates by more than 10% when added to the model, and so only it was added as a covariate to our final statistical models. None of these factors were found to be statistically significant effect modifiers based on likelihood ratio testing (all p-values for interaction were >0.05). Excluded from all analyses were the 11 controls, 11 IDC cases, and 13 ILC cases missing data on either use of antihypertensive medications and/or recency of alcohol use leaving a final analytic sample size of 891 controls, 905 IDC cases, and 1,055 ILC cases. Lastly, we conducted analyses stratified according to estrogen receptor (ER) status in three groupings: ER+ IDC (n=735), ER− IDC (n=156), and ER+ ILC (n=996), using our controls as the common comparison group.

Table 1.

Characteristics of breast cancer cases and population-based controls

Characteristic	Controls (n=891)		Ductal cases (n=905)		Lobular cases (n=1,055)
	n	%	n	%	n	%
Age*
55–59	258	29	261	29	311	30
60–64	233	26	248	27	302	29
65–69	222	25	217	24	247	23
70–74	178	20	179	20	195	19
Race/ethnicity
Non-Hispanic white	729	89	817	90	973	92
African American	28	3	22	2	15	1
Asian/Pacific Islander	17	2	37	4	22	2
Native American	24	3	16	2	23	2
Hispanic white	30	3	13	1	22	2
Education
<High school	37	4	48	5	60	6
High school graduate	213	24	212	23	223	21
Some college/technical school	350	39	338	37	377	36
College graduate	291	33	307	34	395	37
Annual household income
<$20,000	83	11	101	13	105	11
$20,000–$34,999	140	18	137	17	172	19
$35,000–$69,999	294	38	277	35	304	33
$70,000–$89,999	89	11	101	13	136	15
≥$90,000	176	23	188	23	209	23
Missing	109		101		129
Alcohol use at reference
None	448	50	434	48	491	47
<1 drink/day	306	34	316	35	357	34
≥1 drink/day	136	15	154	17	207	20
Missing	1		1		0
Recency of alcohol use
None	322	36	311	34	364	35
Former	126	14	123	14	127	12
Current	443	50	471	52	564	54
Smoking status
Never	451	51	451	50	513	49
Former	352	40	352	39	414	39
Current	88	10	102	11	128	12
Recency of menopausal hormone therapy use
Never	254	29	322	36	266	25
Former	308	35	249	28	260	25
Current unopposed estrogen	202	23	163	18	223	21
Current estrogen and progestin	121	14	166	18	303	29
Missing	6		5		3
First-degree family history of breast cancer
No	710	82	666	77	790	77
Yes	152	18	202	23	235	23
Missing	29		37		30
Parity
Nulliparous	90	10	138	15	131	12
Parous	801	90	767	85	924	88
Age at first live birth (among parous women)
<20	176	22	167	22	181	20
20–24	382	48	330	43	411	45
25–29	171	21	189	25	213	23
30–34	53	7	64	8	87	9
≥35	19	2	17	2	31	3
Missing	0		0		1
History of hypertension
No	499	56	508	56	590	56
Yes	391	44	396	44	464	44
Missing	1		1		1
History of hypercholestorolemia
No	601	68	607	67	709	67
Yes	288	32	298	33	344	33
Missing	2		0		2
History of heart disease
No	388	44	401	45	476	45
Yes	501	56	501	56	577	55
Missing	2		3		2
Body mass index, kg/m2
<25.0	269	30	287	32	373	35
25.0–29.9	302	34	290	32	345	33
≥30.0	314	36	328	36	335	32
Missing	6		0		2
Screening mammgraphy in 2 years prior to reference date
No	106	12	99	11	93	9
Yes	783	88	805	89	962	91
Missing	2		1		0

^*Controls were matched to cases on age.

Results

Control women and IDC and ILC cases had similar distributions of age, annual household income distributions, and histories of hypertension, heart disease, and hypercholesterolemia (Table 1). Compared to control women and IDC cases, ILC cases were somewhat less likely to be African American, more likely to be college graduates, and less likely to be obese (have a body mass index ≥30.0 kg/m²). Both IDC and ILC cases were somewhat more likely to have a first-degree family history of breast cancer, to be current alcohol users, and to be current smokers. The proportion of current users of combined estrogen and progestin menopausal hormone therapy was highest among ILC cases, intermediate among IDC cases, and lowest among controls.

Overall, current, former, and short-term use of antihypertensives were not associated with risk of either IDC or ILC (Table 2). In examining duration effects for current users, an increased risk was seen only in relation to use of calcium channel blockers for 10 years or longer, and an increased risk was observed for both IDC (OR=2.4, 95% CI: 1.2–4.9, p for trend=0.036) and ILC (OR=2.6, 95% CI: 1.3–5.3, p for trend=0.008). This association with 10 years or longer of current calcium channel blocker use did not vary appreciably when results were further stratified by ER status (ER+ IDC: OR=2.3, 95% CI: 1.1–4.8; ER− IDC: OR=3.1, 95% CI: 1.1–8.8; ER+ ILC: OR=2.6, 95% CI: 1.3–5.2, data not shown). There was also some indication that current use of ACE inhibitors for 10 years or longer was associated with reduced risks of both IDC (OR=0.7, 95% CI: 0.5–1.2) and ILC (OR=0.6, 95% CI: 0.4–1.0), though the risk estimate for IDC was within the limits of chance. Again, this association did not vary according to ER status (ER+ IDC: OR=0.7, 95% CI: 0.5–1.2; ER− IDC: OR=0.5, 95% CI: 0.2–1.4; ER+ ILC: OR=0.6, 95% CI: 0.4–0.97). No statistically significant associations were seen for the other drug categories examined. With respect to diuretic use, risks associated with thiazide and non-thiazide diuretic use were also assessed separately, but neither was associated with breast cancer risk (data not shown). These same relationships were observed in analyses restricted only to current users of antihypertensives (Table 3).

Table 2.

Recency and duration of antihypertensive medication use and risk of invasive ductal and invasive lobular breast cancer

Antihypertensive Medication Use	Controls (n=891)		Ductal cases (n=905)				Lobular cases (n=1,055)
	n	%	n	%	OR*	95% CI	n	%	OR*	95% CI
Never used antihypertensives	456	51.2	477	52.7	1.0	ref	556	52.7	1.0	ref
Short-term use (<6 months)	27	3.0	20	2.2	0.7	0.4–1.3	34	3.2	1.1	0.6–1.8
Former use of any antihypertensive	27	3.0	31	3.5	1.1	0.7–1.9	32	3.1	1.0	0.6–1.8
Current use of any antihypertensive	406	45.7	396	43.8	0.9	0.8–1.2	466	44.2	1.0	0.8–1.2
<5 years	131	14.9	126	14.2	0.9	0.7–1.2	151	14.6	1.0	0.7–1.3
5–9.9 years	90	10.3	76	8.5	0.8	0.6–1.2	104	10.0	1.0	0.7–1.4
≥10 years	174	19.8	180	20.2	1.0	0.8–1.3	193	18.6	1.0	0.8–1.3
p for trend			0.508				0.911
Current diuretic use	216	31.1	196	28.4	0.9	0.7–1.2	236	29.1	1.0	0.8–1.2
<5 years	79	11.4	77	11.2	1.0	0.7–1.4	97	12.1	1.1	0.8–1.5
5–9.9 years	48	7.0	37	5.4	0.8	0.5–1.2	48	6.0	0.9	0.6–1.3
≥10 years	84	12.2	77	11.2	0.9	0.7–1.3	81	10.1	0.9	0.6–1.3
p for trend			0.918				0.203
Current beta-blocker use	145	23.1	145	22.2	0.9	0.7–1.2	188	24.1	1.1	0.9–1.5
<5 years	66	10.6	59	9.1	0.9	0.6–1.2	78	10.1	1.0	0.7–1.4
5–9.9 years	36	5.8	33	5.1	0.9	0.5–1.4	46	6.0	1.2	0.7–1.9
≥10 years	39	6.2	48	7.4	1.1	0.7–1.8	57	7.4	1.3	0.9–2.1
p for trend			0.290				0.181
Current calcium-channel blocker use	74	13.2	94	15.7	1.3	0.9–1.8	102	14.9	1.3	0.9–1.8
<5 years	35	6.3	36	6.1	0.9	0.6–1.5	34	5.0	0.8	0.5–1.3
5–9.9 years	23	4.1	26	4.4	1.2	0.7–2.2	32	4.7	1.3	0.8–2.4
≥10 years	12	2.2	27	4.5	2.4	1.2–4.9†	31	4.6	2.6	1.3–5.3†
p for trend			0.036				0.008
Current ACE inhibitor use	135	21.7	130	20.4	0.9	0.7–1.2	158	21.2	1.0	0.8–1.3
<5 years	53	8.6	58	9.2	1.0	0.7–1.6	77	10.4	1.2	0.9–1.8
5–9.9 years	35	5.7	28	4.5	0.8	0.5–1.3	43	5.8	1.1	0.7–1.8
≥10 years	45	7.3	36	5.7	0.7	0.5–1.2	32	4.3	0.6	0.4–1.0†
p for trend			0.201				0.028
Current angiotensin II antagonist use	48	9.4	53	9.9	1.1	0.7–1.6	71	11.2	1.4	0.9–2.1
<5 years	24	4.7	30	5.6	1.2	0.7–2.2	37	5.9	1.4	0.8–2.5
5–9.9 years	9	1.8	10	1.9	1.1	0.4–2.8	17	2.7	1.8	0.8–4.3
≥10 years	13	2.6	11	2.1	0.8	0.3–1.8	13	2.1	1.0	0.4–2.2
p for trend			0.124				0.491

^*All models are adjusted for age, reference year, county, race/ethnicity, and recency of alcohol use.

^†p<0.05.

Table 3.

Recency and duration of antihypertensive medication use and risk of ductal and lobular breast cancer among women with hypertension who were currently using antihypertensive medication

Current Antihypertensive Medication Use	Controls (n=360)		Ductal cases (n=353)				Lobular cases (n=416)
	n	%	n	%	OR*	95% CI	n	%	OR*	95% CI
Not currently using a diuretic	168	46.7	178	50.4	1.0	ref	195	47.0	1.0	ref
Current diuretic use	192	53.3	175	49.6	0.9	0.7–1.2	220	53.0	1.1	0.8–1.4
<5 years	68	19.2	70	20.1	1.0	0.7–1.5	94	23.2	1.3	0.9–1.9
5–9.9 years	44	12.4	32	9.2	0.7	0.4–1.1	40	9.9	0.8	0.5–1.3
≥10 years	75	21.1	68	19.5	0.9	0.6–1.4	76	18.8	0.9	0.6–1.4
p for trend			0.753				0.110
Not currently using a beta-blocker	234	65.0	222	62.9	1.0	ref	253	61.0	1.0	ref
Current beta-blocker use	126	35	131	37.1	1.1	0.8–1.5	162	39.0	1.2	0.9–1.6
<5 years	55	15.4	53	15.2	1.0	0.7–1.6	63	15.4	1.0	0.7–1.5
5–9.9 years	33	9.3	27	7.8	0.9	0.5–1.5	42	10.3	1.2	0.7–2.0
≥10 years	34	9.6	46	13.2	1.4	0.9–2.3	50	12.3	1.4	0.9–2.2
p for trend			0.355				0.213
Not currently using a calcium-channel blocker	290	80.6	268	75.9	1.0	ref	325	78.1	1.0	ref
Current calcium-channel blocker use	70	19.4	85	24.1	1.4	0.9–2.0	91	21.9	1.2	0.8–1.6
<5 years	33	9.3	32	9.2	1.0	0.6–1.8	31	7.5	0.8	0.5–1.4
5–9.9 years	22	6.2	23	6.6	1.2	0.7–2.3	29	7.1	1.2	0.7–2.1
≥10 years	11	3.1	25	7.2	2.6	1.2–5.4†	26	6.3	2.2	1.0–4.5†
p for trend			0.032				0.011
Not currently using an ACE inhibitor	232	64.4	225	63.7	1.0	ref	261	62.9	1.0	ref
Current ACE inhibitor use	128	35.6	128	36.3	1.0	0.7–1.4	154	37.1	1.0	0.8–1.4
<5 years	48	13.4	57	16.5	1.2	0.8–1.9	74	18.1	1.3	0.9–2.0
5–9.9 years	34	9.5	28	8.1	0.8	0.5–1.4	42	10.3	1.1	0.7–1.8
≥10 years	44	12.3	35	10.1	0.7	0.5–1.2	32	7.8	0.6	0.4–0.98†
p for trend			0.097				0.016
Not currently using an angiotensin II antagonist	314	87.2	303	86.1	1.0	ref	347	83.6	1.0	ref
Current angiotensin II antagonist use	46	12.8	49	13.9	1.1	0.7–1.7	68	16.4	1.4	0.9–2.1
<5 years	22	6.1	28	8.0	1.3	0.7–2.4	35	8.5	1.4	0.8–2.5
5–9.9 years	9	2.5	9	2.6	1.1	0.4–2.8	17	4.1	1.9	0.8–4.4
≥10 years	13	3.6	11	3.1	0.9	0.4–2.0	13	3.2	1.0	0.4–2.2
p for trend			0.111				0.495

^*All models are adjusted for age, reference year, county, race/ethnicity, and recency of alcohol use.

^†p<0.05.

In evaluating risks according to calcium-channel blocker subclass, there was some indication that risks may be higher among current users of short-acting formulations (Table 4). Current users of short-acting calcium channel blockers had a 3.7-fold (95% CI: 1.2–11.8) increased risk of IDC and a similar 3.6-fold (95% CI: 1.2–11.4) increased risk of ILC. However, because of the infrequency of use of short-acting preparations the effect of duration of use could not be assessed. Overall, current use of long-acting calcium channel blockers was not related to risk of IDC or ILC, but again current users for 10 years or longer did have elevated risks (IDC: OR=2.7, 95% CI: 1.2–5.7; ILC: OR=2.5, 95% CI: 1.2–5.5). Current use of non-dihydropyridines for any duration was associated with a 60% increased risk of both IDC and ILC (though the risk estimate for IDC was within the limits of change), but only current use of dihyrdropyridines for 10 years or longer was associated with elevated risks of IDC and ILC (IDC: OR=3.0, 95% CI: 1.0–8.9; ILC: OR=3.4, 95% CI: 1.1–9.9).

Table 4.

Recency and duration of use of different classes of calcium channel blocker and risk of ductal and lobular breast cancer

Type of Calcium-channel blocker use	Controls (n=891)		Ductal cases (n=905)				Lobular cases (n=1,055)
	n	%	n	%	OR*	95% CI	n	%	OR*	95% CI
Never used antihypertensives	456	51.2	477	52.7	1.0	ref	556	52.7	1.0	ref
Short-acting calcium-channel blockers
Former use	19	4.0	26	5.0	1.3	0.7–2.4	23	3.9	1.1	0.6–2.1
Current use	4	0.8	14	2.7	3.7	1.2–11.8†	14	2.4	3.6	1.2–11.4†
Long-acting calcium-channel blockers
Former use	20	3.7	17	3.0	0.9	0.4–1.7	14	2.1	0.6	0.3–1.2
Current use	71	13.0	80	13.9	1.1	0.8–1.6	89	13.5	1.1	0.8–1.6
<5 years	35	6.5	32	5.6	0.8	0.5–1.4	32	4.9	0.8	0.5–1.3
5–9.9 years	21	3.9	20	3.5	1.0	0.5–1.9	26	4.0	1.2	0.6–2.2
≥10 years	10	1.8	25	4.4	2.7	1.2–5.7†	26	4.0	2.5	1.2–5.5†
p for trend			0.010				0.007
Dihydropyridine calcium-channel blockers
Former use	19	3.6	22	4.0	1.1	0.6–2.2	17	2.7	0.8	0.4–1.6
Current use	48	9.2	51	9.3	1.1	0.7–1.7	54	8.6	1.1	0.7–1.7
<5 years	27	5.2	27	4.9	0.9	0.5–1.6	23	3.7	0.7	0.4–1.3
5–9.9 years	14	2.7	11	2.0	0.9	0.4–2.0	16	2.6	1.2	0.5–2.5
≥10 years	5	1.0	12	2.2	3.0	0.99–8.9	14	2.2	3.4	1.1–9.9†
p for trend			0.128				0.006
Non-dihydropyridine calcium-channel blockers
Former use	21	4.2	18	3.3	0.9	0.4–1.7	22	3.5	0.9	0.5–1.7
Current use	27	5.4	44	8.2	1.6	1.0–2.7	50	8.0	1.6	1.0–2.7†
<5 years	10	2.0	14	2.6	1.3	0.6–3.0	15	2.4	1.2	0.5–2.7
5–9.9 years	9	1.8	14	2.6	1.6	0.7–3.8	16	2.6	1.7	0.7–3.9
≥10 years	6	1.2	14	2.6	2.4	0.9–6.3	16	2.6	2.5	1.0–6.6
p for trend			0.081				0.114

^*All models are adjusted for age, reference year, county, race/ethnicity, and recency of alcohol use.

^†p<0.05.

Discussion

This contemporary study of postmenopausal breast cancer adds to evidence that most commonly used forms of antihypertensives are not related to breast cancer risk even if used for long durations. However, our results do suggest that long-term current use of calcium-channel blockers is associated with an increased risk of both IDC and ILC, and that these associations do not vary according to ER status. Confounding by indication is unlikely to explain these relationships in as findings were similar in analyses limited only to women with hypertension who were currently using antihypertensive medications. Direct comparisons of these results to other studies is challenging given differences in study design and exposure characteristics. In particular, most prior studies had substantially smaller sample sizes and limited ability to assess risks according to duration of recent use. Focusing on the three larger studies, our prior Seattle-Puget Sound population-based case-control study (which is completely separate from this current study) found that current use of thiazide and potassium sparing diuretics were each associated with 40% and 60% increases in risk of breast cancer, respectively (duration of use among current users was not assessed);⁴ an analysis of the California Teachers Study (CTS) cohort found that diuretic use for 10 years or longer was associated with a 16% increased risk while use of calcium channel blockers and ACE inhibitors were not (recency of use in the full cohort could not be assessed);³ and 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 beta blockers for five or more years (results specific to current users were not presented).⁷ So there is considerable variability in findings across these studies. With respect to diuretics, we did not observe an increased risk of breast cancer associated with diuretic use, though the elevations in observed in two of these prior studies were quite modest and lie within the 95% confidence intervals of our risk estimates. However, none of these three studies found that calcium channel blockers were associated with an increased risk, though both our prior study and the UK study were limited to only evaluating use for 5 years or longer and here we observed an increase in risk only among users for 10 years or longer. Of note though, in our prior study we did find that ever use of short-acting calcium channel blockers was associated with a 40% increased risk of breast cancer that was statistically significant. With respect to CTS, while it collected data on different durations of diuretic use, it did not collect duration information for other forms of antihypertensives, including calcium channel blockers, limiting comparisons to our results.

Biological mechanisms through which calcium-channel blockers could influence breast cancer risk are unknown. These medications have a broad spectrum of physiologic effects, and with respect to calcium-channel blockers some have hypothesized that they may inhibit apoptosis through increasing intracellular calcium levels,^1,10,20 though evidence supporting this effect is lacking.²¹ The suggestion that risk may be higher with short-acting calcium-channel blockers, and that an increased risk associated with long-acting formulations is only observed among long-term users, may help inform studies aimed at elucidating potential biological mechanisms. However, these results require confirmation as this is the first study to report the impact of long-term use of calcium-channel blockers on breast cancer risk.

Here we also reserved a reduction in breast cancer risk associated with long-term use of ACE inhibitors. As described above, no prior studies evaluating ACE inihibitors have observed this relationship. Consequently this observation needs to be interpreted cautiously, and it requires replication in studies with sufficient numbers of long-term ACE inhibitor users.

Recall bias is a potential limitation of this case-controls study. However, misclassification of exposure was reduced by focusing analyses on current use, and using a protocol where study interviewers reviewed the prescription bottles of study participants and recorded detailed data directly from them.¹⁸ Further, the differences seen according to class of antihypertensive medication are very unlikely to be affected by recall bias. Such bias would require one to assume that breast cancer patients recalled exposures only to calcium channel blockers and ACE inhibitors, but not of other types of antihypertensives, differently than did control women. Two factors enhance the generalizability of this study, one is its population-based design and the second is its high overall response rates from both cases and controls. There is some potential for selection bias given the somewhat lower response rate among controls compared to cases. However, in order for this to impact our results this would require controls who were users of calcium-channel blockers, but not users of other types of antihypertensives, to have selectively refused study participation, which is unlikely. Other major strengths of this study are its substantial sample size and that it was conducted in a population and during a more recent time period such that long-term antihypertensive use was common. Specifically, 45% of our population-based controls were current antihypertensive users and 20% were current users for 10 years or longer.

In summary, this study provides evidence that long-term recent use of calcium-channel blockers may be associated with an increased risk of breast cancer. Further efforts to confirm this association are needed and are of public health importance, given that antihypertensives are the most commonly prescribed class of medication in the United States. Quantification of the potential relationships between use of these medications and breast cancer risk has the potential to add to clinical decision making regarding selection of antihypertensive agents for hypertensive patients as the benefits and risks of potential medications are weighed.