Relation between use of antihypertensive medications and risk of breast carcinoma among women ages 65–79 years

Abstract

BACKGROUND

Limited data are available regarding the incidence of breast carcinoma among users of relatively recently introduced forms of antihypertensive therapy. Although it has been suggested that women who have taken calcium channel blockers (CCBs) have an increased risk and that women who have taken angiotensin-I-converting enzyme (ACE) inhibitors have a decreased risk, currently, no conclusions can be drawn.

METHODS

A population-based case–control study of women ages 65–79 years was conducted in western Washington State. The responses of 975 women who were diagnosed with invasive breast carcinoma during 1997–1999 were compared with the responses of 1007 women in a control group. Associations between use of different types of antihypertensive medications and breast carcinoma incidence were evaluated using logistic regression.

RESULTS

Overall, women who had ever used CCBs, β-blockers, or ACE inhibitors did not have an altered risk of breast carcinoma relative to women who had never used antihypertensive medications. Although the use of immediate-release CCBs, thiazide diuretics, and potassium-sparing diuretics was associated with modestly increased risks of breast carcinoma (odds ratio [OR], 1.5; 95% confidence interval [95% CI], 1.0–2.1; OR, 1.4; 95% CI, 1.1–1.8; and OR, 1.6; 95% CI, 1.2–2.1, respectively), the absence of any trend in the size of excess risk with increasing duration or with current versus former use of these agents argues for a cautious interpretation.

CONCLUSIONS

The use of particular types of antihypertensive medications, including immediate-release CCBs and certain diuretics, may increase the risk of breast carcinoma among older women. Additional studies are warranted to clarify these potential associations. Cancer 2003;98:1504–13. © 2003 American Cancer Society.

DOI 10.1002/cncr.11663

It has been hypothesized that calcium channel blockers (CCBs) may increase cancer risk, because their blockade of calcium channels can inhibit apoptosis and, thus facilitate, the division of damaged cells with malignant potential.1 However, whereas some investigators have observed that use of CCBs is associated with an increased risk of breast carcinoma,2–4 others have not.5–11

The use of other antihypertensive medications also may be associated with an altered breast carcinoma risk. In one study, it was observed that angiotensin-I-converting enzyme (ACE) inhibitors were associated with a decrease in breast carcinoma risk,12 although other studies did not obtain the same result.2, 6, 7, 9 Diuretics that are used commonly today (including thiazide, potassium-sparing, and loop diuretics) to our knowledge were evaluated in only one study, in which it was observed that their use was associated with a modest increase in breast carcinoma risk (odds ratio [OR], 1.38; 95% confidence interval13 [95% CI], 0.83–2.29).3 A potential mechanism underlying this association is through the increased insulin resistance that results from the use of certain diuretics,14 because it has been suggested that insulin-resistant states are a risk factor for breast carcinoma.15, 16 To explore whether use of CCBs and other classes of antihypertensive medications are associated with breast carcinoma incidence, we conducted a population-based case–control study in older women.

MATERIALS AND METHODS

We conducted a population-based case–control study of women ages 65–79 years living in the three-county Seattle–Puget Sound metropolitan area. The study protocol was approved by the Fred Hutchinson Cancer Research Center Institutional Review Board, and written informed consent was obtained from all study participants.

Cases

Women ages 65–79 years with no previous history of in situ or invasive breast carcinoma who were diagnosed with invasive breast carcinoma between April 1, 1997 and May 31, 1999 were eligible for the case group. The Cancer Surveillance System, the population-based tumor registry that serves the Seattle–Puget Sound region of Washington State and participates in the Surveillance, Epidemiology, and End Results Program of the National Cancer Institute, was used to identify cases. To be eligible for the study, women' names had to appear on a list of Social Security recipients provided by the Centers for Medicare and Medicaid Services (CMS), because these records were used to identify women for the control group. Of 1210 eligible cases identified, 975 women (80.6%) were interviewed. Fourteen percent of eligible cases refused to be interviewed, 4% died before an interview could be conducted, 1% moved away from the area, and the physicians treating 1% of cases refused to allow contact with their patients.

Controls

The CMS list of Social Security recipients was used to identify women from the general population of residents of King, Pierce, and Snohomish Counties who were the same ages as the women in the case group to serve as the control group. Of the 1365 eligible women who were selected as controls, 1007 women (73.8%) were interviewed. Twenty-two percent of eligible controls refused to be interviewed, 2% died after selection but before they could be interviewed, 2% moved away from the area, and we were unable to locate 1%. Two women in the control group whose use of antihypertensive medications was unknown were excluded from all analyses.

Data Collection

Both cases and controls were interviewed in person and were asked about their use of hormone replacement therapy; menstrual, contraceptive, and reproductive histories; body size; and medical history, including cardiovascular health history and family history of cancer. Demographic data and information on smoking and alcohol use also were collected. Detailed information on history of hypertension and other cardiovascular diseases was obtained, including whether a physician had ever diagnosed them with hypertension or borderline hypertension, the date they were first diagnosed with hypertension, and the date (if any) they first started using antihypertensive medications. Women were classified as having hypertension if they reported that a physician had diagnosed them with hypertension (not just borderline hypertension and not just during pregnancy). In addition, detailed histories of all episodes of cardiovascular medication use, including the medication name, beginning and ending dates, total duration, dose, and pattern of use for each drug, were obtained. A life-events calendar and a photograph book with pictures of different types of antihypertensive medications used in the U.S. were used to enhance recall. Information on all current medication use was transcribed from the prescription labels on the medication containers provided by participants during the interview. Our questioning with regard to all of these factors was limited to exposures that occurred before each woman's reference date. The reference date used for each woman with breast carcinoma was her date of diagnosis. Control reference dates were assigned to reflect the expected distribution of reference dates among the cases.

Analysis

Antihypertensive medications were divided into four broad groupings: CCBs, β-blockers, ACE inhibitors, and diuretics. We also divided these groupings into subcategories. CCBs were divided into four groups: immediate-release (IR) nondihydropyridines (diltiazem and verapamil), IR dihydropyridines (isradipine, nifedipine, and nisoldipine), sustained-release (SR) nondihydropyridines (diltiazem SR and verapamil SR), and SR dihydropyridines (amlodipine, felodipine, and nicardipine). We distinguished between nondihydropyridines and dihydropyridines because differences between these types were assessed in a previous study of breast carcinoma3 and because these two classes of CCBs have different properties, such as affinities for different regions of the calcium channel.17 β-Blockers were divided into two groups: short-acting agents (acebutolol, metoprolol, pindolol, and timolol) and long-acting agents (atenolol, betaxolol, bisoprolol, nadolol, and propranolol). Diuretics were divided into three groups: thiazide diuretics (chlorthalidone, chlorothiazide, hydrochlorothiazide, indapamide, and metolazone), potassium-sparing diuretics (amiloride and spironolactone), and loop diuretics (bumetanide, ethacrynic acid, furosemide, and torsemide). All ACE inhibitors were grouped together and included benazepril, captopril, enalapril, and lisinopril. Users of medications containing combinations of these groups were classified as users of each of the types of antihypertensive medications included in their regimen. Women who only used other types of antihypertensive medications, including angiotensin II antagonists and antiadrenergic agents, were excluded from all analyses.

Using unconditional logistic regression, we compared all breast carcinoma cases with controls and calculated the OR as an estimate of the relative risk and the 95% CIs to assess associations between specific types of antihypertensive medications and breast carcinoma risk.18 In each analysis, never users (the referent category) were defined as women who had never used any type of antihypertensive medication. Users were defined as women who had used the specified medication for 6 months or longer, former users were ever users who had stopped taking the medication more than 6 months prior to their reference date, and current users were ever users who had used the medication within 6 months of their reference date. Users of antihypertensive medications for less than 6 months were excluded from all analyses of specific types of antihypertensive medications.

The following categorical variables, which are listed in Table 1, were evaluated as potential confounders: race, income, marital status, education, age at menarche, parity, age at first birth, type of menopause, age at menopause, duration of oral contraceptive use, ever use of hormone replacement therapy (HRT), first-degree family history of breast carcinoma, smoking status, average daily alcohol intake, and body mass index (BMI). None of these factors changed the risk estimates of the ORs of interest by more than 10% when they were included in the model. Therefore, all analyses were adjusted only for age (continuous), because controls were matched to cases on age. Age, BMI, receipt of HRT, alcohol use, smoking status, and restriction of the data to women who were white did not modify the associations observed.

Table 1. Distribution of Demographic and Known or Suspected Risk Factors for Breast Cancer among 1007 Controls and 975 Breast Cancer Cases

Characteristic	Cases (n = 975)		Controls (n = 1007)
	No.	%	No.	%
Reference age
65–69 yrs	300	30.8	330	32.8
70–74 yrs	381	39.1	381	37.8
75–79 yrs	294	30.2	296	29.4
Race
White	929	95.3	925	91.9
Black	16	1.6	37	3.7
Asian/Pacific Islander	19	1.9	29	2.9
Other/unknown	11	1.1	16	1.6
Income
< $15,000	177	21.3	191	21.7
$15,000–$25,000	198	23.9	214	24.3
$25,000–$50,000	296	35.7	296	33.6
> $50,000	159	19.2	180	20.4
Missing	145	—	126	—
Marital status
Married	517	53.0	536	53.2
Widowed	301	30.9	315	31.3
Divorced/separated	125	12.8	121	12.0
Single	32	3.3	35	3.5
Education
Less than high school	126	12.9	153	15.2
High school graduate	376	38.6	395	39.3
Some college	312	32.0	286	28.4
College graduate	161	16.5	172	17.1
Missing	0	—	1	—
Age at menarche
8–11 yrs	182	18.8	173	17.2
12–13 yrs	525	54.2	520	51.7
≥ 14 yrs	261	27.0	313	31.1
Missing	7	—	1	—
Parity
Nulliparous	88	9.0	94	9.3
Parous	887	91.0	913	90.7
Age at first birth
14–19 yrs	152	17.2	187	20.5
20–24 yrs	432	48.9	435	47.7
25–29 yrs	206	23.3	205	22.5
≥ 30 yrs	93	10.5	85	9.3
Missing	92	—	95	—
Type of menopause
Natural	583	61.4	607	61.6
Induced	129	13.6	148	15.0
Hysterectomy, no bilateral oophorectomy	237	25.0	231	21.6
Missing	26	—	21	—
Age at menopause
23–39 yrs	38	6.6	64	9.9
40–44 yrs	77	13.4	99	15.3
45–49 yrs	165	28.7	172	26.6
50–54 yrs	217	37.8	222	34.3
55–68 yrs	77	13.4	90	13.9
Missing	401	—	360	—
Duration of oral contraceptive use
Never	736	76.0	752	75.4
< 5 yrs	139	14.4	159	15.9
≥ 5 yrs	93	9.6	86	8.6
Missing	7	—	10	—
Ever use of hormone replacement therapy
Never	284	29.3	339	33.8
< 5 yrs	187	19.3	230	22.9
≥ 5 yrs	499	51.4	435	43.3
Missing	5	—	3	—
First degree family history of breast cancer
No	703	77.2	771	82.9
Yes	208	22.8	159	17.1
Missing	64	—	77	—
History of hypertension
No	477	48.9	538	53.4
Yes	498	51.1	469	46.6
Cigarette smoking status
Never	450	46.2	523	51.9
Former	396	40.6	369	36.6
Current	129	13.2	115	11.4
Average grams of alcohol per day
None	461	47.5	518	51.6
< 8.2	249	25.7	248	24.7
≥ 8.2	260	26.8	238	23.7
Missing	5	—	3	—
Body mass index (kg/m^2)
≤ 23.32	209	22.3	261	27.1
23.33–26.20	240	25.6	241	25.0
26.21–30.11	245	26.1	230	23.9
≥ 30.12	245	26.1	231	24.0
Missing	36	—	44	—

To take into account the potential bias due to confounding by indication, we conducted a series of analyses that were restricted to ever users of antihypertensive medications (as defined above). For each class of antihypertensive medication, never users of the specified broad category of antihypertensive medication served as the reference group. Each of these analyses was adjusted for age (continuous).

RESULTS

A greater proportion of women in the control group were nonwhite compared with women in the case group (Table 1). Cases were somewhat more likely than controls to have an early age at menarche, to be older at the time of their first birth, to have undergone a hysterectomy without a bilateral oophorectomy, to have a first-degree family history of breast carcinoma, to be ever users of HRT, to have a history of hypertension, to be current or former smokers, to have higher levels of alcohol consumption, and to have a higher BMI. Cases and controls were similar with respect to other demographic and reproductive characteristics.

Overall, ever use of CCBs was not associated with breast carcinoma risk, and there was no evidence of a pattern related to duration of use (Table 2). Ever use of IR CCBs was associated with a 1.4-fold increased risk of breast carcinoma (95% CI, 1.0–2.1); however, once again, there was no clear pattern of increasing risk with increasing duration of use. In addition, former use of IR CCBs was associated with a heightened risk of breast carcinoma (OR, 2.0; 95% CI, 1.0–3.8), but current use was not (OR, 1.4; 95% CI, 0.9–2.1). The elevation in risk associated with ever use of IR CCBs appeared to be limited primarily to ever users of IR nondihydropyridines (OR, 1.6; 95% CI, 1.1–2.5), although few women were ever users of IR dihydropyridines (OR, 1.1; 95% CI, 0.6–2.1). Women who took SR CCBs, whether they were SR nondihyrdropyridines or SR dihyrdropyridines, had a risk of breast carcinoma similar to the risk for women who were never treated with antihypertensive agents.

Table 2. Association between Use of Various Types of Antihypertensive Medications and Breast Cancer Risk

Regimen	Cases (n = 975)		Controls (n = 1007)		ORa	95% CI
	No.	%	No.	%
OR: odds ratio; 95% CI: 95% confidence interval; ACE: angiotensin-converting enzyme. a All models were adjusted for the reference age. b Never users were defined as never users of the specified antihypertensive; ever users were defined as users of the antihypertensive for ≥ 6 mos; former users were defined as ever users of the antihypertensive for ≥ 6 mos who last used the medication > 6 mos prior to the reference date; and current users were defined as ever users of the antihypertensive for ≥ 6 mos who last used the medication within 6 mos of their reference date. Also, the sum of the former users of the subcategories of calcium channel blockers, beta blockers, and diuretics do not sum to the total number of former users of any type of calcium channel blocker, β blocker, or diuretic, respectively, because some women used multiple subcategories of these medications in the past. The same is true for current users because some women were current users of medications in more than one subcategory of the same broad antihypertensive category. c P < 0.05.
Never useb	446	45.7	490	48.7	1.0	Reference
Ever use of any antihypertensive for < 6 mos	17	1.7	28	2.8	0.7	0.4–1.2
Ever use of any antihypertensive for + mos	512	52.5	489	48.6	1.1	1.0–1.4
Calcium channel blockers
Any type of calcium channel blocker
Ever useb	149	15.3	141	14.0	1.2	0.9–1.5
6 mos to 5 yrs	69	7.1	64	6.4	1.2	0.8–1.7
5–15 yrs	60	6.2	54	5.4	1.2	0.8–1.8
15 yrs	11	1.1	19	1.9	0.6	0.3–1.3
Former useb	19	1.9	10	1.0	2.1	1.0–4.5
Current useb	133	13.6	132	13.1	1.1	0.8–1.5
Immediate-release calcium channel blockers
Ever use	76	7.8	58	5.8	1.4	1.0–2.1c
6 mos to 5 yrs	35	3.6	18	1.8	2.1	1.2–3.8c
5 + yrs	39	4.0	38	3.8	1.1	0.7–1.8
Former use	25	2.6	14	1.4	2.0	1.0–3.8c
Current use	56	5.7	44	4.4	1.4	0.9–2.1
Sustained-release calcium channel blockers
Ever use	83	8.5	89	8.8	1.0	0.7–1.4
6 mos to 5 yrs	46	4.7	51	5.1	1.0	0.7–1.5
5 + yrs	34	3.5	38	3.8	1.0	0.6–1.6
Former use	10	1.0	4	0.4	2.8	0.9–8.8
Current use	78	8.0	87	8.6	1.0	0.7–1.4
Immediate-release nondihydropyridines
Ever use	61	6.3	41	4.1	1.6	1.1–2.5a
6 mos to 5 yrs	31	3.2	13	1.3	2.6	1.4–5.1c
5 + yrs	28	2.9	28	2.8	1.1	0.6–1.9
Former use	20	2.1	7	0.7	3.2	1.3–7.5c
Current use	45	4.6	35	3.5	1.4	0.9–2.2
Immediate-release dihydropyridines
Ever use	20	2.1	20	2.0	1.1	0.6–2.1
6 mos to 5 yrs	8	0.8	7	0.7	1.3	0.5–3.5
5 + yrs	12	1.2	11	1.1	1.2	0.5–2.8
Former use	10	1.0	8	0.8	1.4	0.5–3.5
Current use	12	1.2	11	1.1	1.2	0.5–2.8
Sustained-release nondihydropyridines
Ever use	47	4.8	49	4.9	1.1	0.7–1.6
6 mos to 5 yrs	26	2.7	26	2.6	1.1	0.6–1.9
5 + yrs	20	2.1	23	2.3	1.0	0.5–1.8
Former use	8	0.8	3	0.3	2.9	0.8–11.1
Current use	44	4.5	46	4.6	1.0	0.7–1.6
Sustained-release dihydropyridines
Ever use	42	4.3	42	4.2	1.1	0.7–1.7
6 mos to 5 yrs	25	2.6	26	2.6	1.1	0.6–1.9
5 + yrs	14	1.4	16	1.6	1.0	0.5–2.0
Former use	6	0.6	4	0.4	1.6	0.5–5.9
Current use	35	3.6	41	4.1	0.9	0.6–1.5
β-Blockers
Any type of β-blockers
Ever use	185	19.0	164	16.3	1.2	1.0–1.6
6 mos to 5 yrs	75	7.7	77	7.6	1.1	0.8–1.5
5–15 yrs	63	6.5	65	6.5	1.1	0.7–1.5
15 + yrs	40	4.1	21	2.1	2.1	1.2–3.7c
Former use	27	2.8	16	1.6	1.9	1.0–3.5
Current use	160	16.4	149	14.8	1.2	0.9–1.5
Short-acting β-blockers
Ever use	63	6.5	47	4.7	1.5	1.0–2.2
6 mos to 5 yrs	25	2.6	21	2.1	1.3	0.7–2.4
5 + yrs	38	3.9	26	2.6	1.6	1.0–2.7
Former use	34	3.5	15	1.5	2.5	1.3–4.7c
Current use	37	3.8	33	3.3	1.2	0.8–2.0
Long-acting β-blockers
Ever use	134	13.7	122	12.1	1.2	0.9–1.6
6 mos to 5 yrs	65	6.7	66	6.6	1.1	0.8–1.6
5 + yrs	69	7.1	56	5.6	1.4	0.9–2.0
Former use	14	1.4	11	1.1	1.4	0.6–3.1
Current use	124	12.7	113	11.2	1.2	0.9–1.6
ACE inhibitors
Ever use	154	15.8	152	15.1	1.1	0.9–1.4
6 mos to 5 yrs	87	8.9	85	8.4	1.1	0.8–1.6
5–15 yrs	52	5.3	47	4.7	1.2	0.8–1.8
15 + yrs	15	1.5	20	2.0	0.8	0.4–1.6
Former use	17	1.7	21	2.1	0.9	0.5–1.7
Current use	137	14.1	131	13.0	1.2	0.9–1.5
Diuretics
Any type of diuretic
Ever use	305	31.3	267	26.5	1.2	1.0–1.5c
6 mos to 5 yrs	97	9.9	90	8.9	1.2	0.9–1.6
5–15 yrs	106	10.9	87	8.6	1.3	1.0–1.8
15 + yrs	89	9.1	83	8.2	1.2	0.8–1.6
Former use	42	4.3	26	2.6	1.8	1.1–2.9c
Current use	267	27.4	244	24.2	1.2	1.0–1.5
Thiazide diuretics
Ever use	246	25.2	190	18.9	1.4	1.1–1.8c
6 mos to 5 yrs	81	8.3	58	5.8	1.5	1.1–2.2c
5 + yrs	159	16.3	130	12.9	1.3	1.0–1.7c
Former use	49	5.0	36	3.6	1.5	1.0–2.3
Current use	205	21.0	160	15.9	1.4	1.1–1.8c
Potassium-sparing diuretics
Ever use	135	13.8	95	9.4	1.6	1.2–2.1c
6 mos to 5 yrs	50	5.1	31	3.1	1.8	1.1–2.8c
5 + yrs	83	8.5	63	6.3	1.4	1.0–2.1c
Former use	31	3.2	21	2.1	1.6	0.9–2.9
Current use	113	11.6	78	7.7	1.6	1.2–2.2c
Loop diuretics
Ever use	66	6.8	83	8.2	0.9	0.6–1.2
6 mos to 5 yrs	29	3.0	43	4.3	0.7	0.5–1.2
5 + yrs	36	3.7	40	4.0	1.0	0.6–1.6
Former use	12	1.2	7	0.7	1.9	0.7–4.8
Current use	59	6.1	79	7.8	0.8	0.6–1.2

Ever use of β-blockers was associated with a 1.2-fold increased risk of breast carcinoma (95% CI, 1.0–1.6) (Table 2). The observed elevations in risk were relatively more prominent among users for ≥ 15 years (OR, 2.1; 95% CI, 1.2–3.7), former users (OR, 1.9; 95% CI, 1.0–3.5), and users of short-acting agents (OR, 1.5; 95% CI, 1.0–2.2).

Women who had taken ACE inhibitors were not at altered breast carcinoma risk, irrespective of duration or whether use was current or in the past (Table 2). Ever use of diuretics was associated with an increased risk of breast carcinoma (OR, 1.2; 95% CI, 1.0–1.5) (Table 2); in particular, ever use of thiazide (OR, 1.4; 95% CI, 1.1–1.8) and potassium-sparing diuretics (OR, 1.6; 95% CI, 1.2–2.1). The risks associated with thiazide and potassium-sparing diuretics were elevated similarly across categories of duration and whether use was current or in the past.

In analyses restricted to women who ever used antihypertensive medications, users of CCBs had the same risk of breast carcinoma as antihypertensive users who never used CCBs (Table 3). There was a suggestion that use of IR CCBs was associated with an elevation in breast carcinoma risk (OR, 1.3; 95% CI, 0.9–1.8), but this elevation was within the limits of chance, and no pattern with duration of use was observed. Use of β-blockers or ACE inhibitors also was neutral with respect to breast carcinoma risk. Whereas ever use of diuretics was not associated with breast carcinoma risk compared with use of antihypertensive medications other than diuretics, use of both thiazide and potassium-sparing diuretics was associated with modest elevations in breast carcinoma risk (OR, 1.4; 95% CI, 1.1–1.8; and OR, 1.5; 95% CI, 1.1–2.1, respectively). Again, both short and long durations of use of these types of diuretics were associated with increased risks of breast carcinoma. We also were interested in evaluating these associations among women who had not been diagnosed with hypertension, because diuretics may be prescribed for conditions other than hypertension. However, among women without a history of hypertension (46 of whom were ever users of thiazides and 28 of whom were ever users of potassium-sparing diuretics), use of neither thiazide nor potassium-sparing diuretics was associated with breast carcinoma incidence compared with women who had never taken antihypertensive agents (OR, 0.8; 95% CI, 0.5–1.5; and OR, 1.0; 95% CI, 0.5–2.0, respectively; data not shown).

Table 3. Association between the Use of Various Types of Antihypertensive Medications and Breast Cancer Risk among Ever Users of Antihypertensive Medications

Regimen	Cases (n = 512)		Controls (n = 489)		OR	95% CI
	No.	%	No.	%
OR: odds ratio; 95% CI: 95% confidence interval; CCBs: calcium channel blockers; IR: immediate release; SR: sustained release; ACE: angiotensin-converting enzyme. a P < 0.05.
Calcium channel blocker use
Never used CCBs	363	70.9	348	71.2	1.0	Reference
Ever used CCBs	149	29.1	141	28.8	1.0	0.8–1.3
6 mos to 5 yrs	69	13.5	64	13.1	1.0	0.7–1.5
5 + yrs	71	13.9	73	14.9	0.9	0.6–1.3
Ever used IR CCBs	76	14.8	58	11.9	1.3	0.9–1.8
6 mos to 5 yrs	35	6.8	18	3.7	1.9	1.0–3.4a
5 + yrs	39	7.6	38	7.8	1.0	0.6–1.6
Ever used SR CCBs	83	16.2	89	18.2	0.9	0.6–1.3
6 mos to 5 yrs	46	9.0	51	10.4	0.9	0.6–1.3
5 + yrs	34	6.6	38	7.8	0.9	0.5–1.4
Ever used IR nondihydropyridines	61	11.9	41	8.4	1.4	0.9–2.2
6 mos to 5 yrs	31	6.1	13	2.7	2.4	1.2–4.6a
5 + yrs	28	5.5	28	5.7	1.0	0.6–1.7
Ever used SR nondihydropyridines	47	9.2	49	10.0	0.9	0.6–1.4
6 mos to 5 yrs	26	5.1	26	5.3	1.0	0.5–1.7
5 + yrs	20	3.9	23	4.7	0.8	0.4–1.5
Ever used IR dihydropyridines	20	3.9	20	4.1	1.0	0.5–1.8
6 mos to 5 yrs	8	1.6	7	1.4	1.1	0.4–3.1
5 + yrs	12	2.3	11	2.2	1.0	0.5–2.4
Ever used SR dihydropyridines	42	8.2	42	8.6	0.9	0.6–1.5
6 mos to 5 yrs	25	4.9	26	5.3	0.9	0.5–1.6
5 + yrs	14	2.7	16	3.3	0.8	0.4–1.7
β-Blocker use
Never used β-blockers	327	63.9	325	66.5	1.0	Reference
Ever used β-blockers	185	36.1	164	33.5	1.1	0.9–1.5
6 mos to 5 yrs	75	14.6	77	15.7	1.0	0.7–1.4
5 + yrs	103	20.1	86	17.6	1.2	0.9–1.6
Ever used short-acting β-blockers	63	12.3	47	9.6	1.3	0.9–2.0
6 mos to 5 yrs	25	4.9	21	4.3	1.2	0.6–2.1
5 + yrs	38	7.4	26	5.3	1.5	0.9–2.5
Ever used long-acting β-blockers	134	26.2	122	24.9	1.1	0.8–1.5
6 mos to 5 yrs	65	12.7	66	13.5	1.0	0.7–1.4
5 + yrs	69	13.5	56	11.5	1.2	0.8–1.8
ACE inhibitor use
Never used ACE inhibitors	358	69.9	337	68.9	1.0	Reference
Ever used ACE inhibitors	154	30.1	152	31.1	1.0	0.7–1.3
6 mos to 5 yrs	87	17.0	85	17.4	1.0	0.7–1.4
5 + yrs	67	13.1	67	13.7	0.9	0.6–1.4
Diuretic use
Never used diuretics	207	40.4	222	45.4	1.0	Reference
Ever used diuretics	305	59.6	267	54.6	1.2	1.0–1.6
6 mos to 5 yrs	97	18.9	90	18.4	1.2	0.8–1.6
5 + yrs	195	38.1	170	34.8	1.2	0.9–1.6
Ever used thiazide diuretics	246	48.0	190	38.9	1.4	1.1–1.8a
6 mos to 5 yrs	81	15.8	58	11.9	1.5	1.0–2.2a
5 yrs	159	31.1	130	26.6	1.3	1.0–1.8
Ever used potassium sparing diuretics	135	26.4	95	19.4	1.5	1.1–2.1a
6 mos to 5 yrs	50	9.8	31	6.3	1.7	1.1–2.8a
5 + yrs	83	16.2	63	12.9	1.4	1.0–2.1
Ever used loop diuretics	66	12.9	83	17.0	0.9	0.6–1.2
6 mos to 5 yrs	29	5.7	43	8.8	0.7	0.4–1.2
5 + yrs	36	7.0	40	8.2	1.0	0.6–1.6

DISCUSSION

Certain limitations of the current study should be considered when interpreting the results. We were able to interview only 80.6% of all eligible cases and 73.8% of all eligible controls. Our results may be biased if the women we were unable to interview differed from those who did participate with regard to type or patterns of antihypertensive use or history of hypertension. We also relied on participants' recall of the types of cardiovascular medications they used as well as the timing and duration of use. To maximize recall, women were asked to show all of their medication bottles to their interviewer, and they also were prompted with a photograph book containing pictures of different antihypertensive medications. We have conducted a validation study on a subset of patients and found that the accuracy of self-reported use of antihypertensive medications was quite good using pharmacy records as a gold standard (unpublished results). Specifically, interclass correlation coefficients for cases and controls were 0.85 and 0.86, respectively, for any antihypertensive use within the 6-month period prior to reference date, 0.89 and 0.90 for the 2-year period prior to reference date, and 0.88 and 0.88 for the 8-year period prior to reference date. In addition, the accuracy of self-reported exposure to cardiovascular drugs appears to be consistently good in other studies.19 This study was also limited to women ages 65–79 years; thus, our results may not be applicable to younger or older women. Finally, because large numbers of comparisons were performed, some of the positive associations we observed between antihypertensive medications and breast carcinomar may have been the result of chance.20–22

An association between CCBs and breast carcinoma has been hypothesized based on the results of studies of cell lines. Those studies demonstrated that the blockade of calcium channels by CCBs can inhibit apoptosis.23–26 Because apoptosis is triggered by transmembrane influxes of calcium, these results are not surprising. Inhibition of apoptosis by CCBs may promote carcinogenesis by allowing damaged cells with malignant potential to continue to divide. However, epidemiologic evidence that bears on a possible association between use of CCBs and breast carcinoma are mixed. Whereas three early studies2–4 showed that use of CCBs was associated with an increased risk of breast carcinoma, and another study showed that use of ACE inhibitors was associated with a reduced risk,12 several studies have found no relation between broad categories of antihypertensive medications and breast carcinoma risk.5–11 However, as a whole, those studies were limited by their power and/or their methods for assessing exposures to antihypertensive medications. For example, 82–5, 9–12 of 96 cohort-based studies included ≤ 84 breast carcinoma cases. The remaining cohort study6 was quite large (852 cases), but it collected information only on broad categories of antihypertensive medications and only on use at one time point. Thus, duration of use and current versus former use in relation to risk could not be assessed, nor could that study assess the risk associated with the use of specific classes of CCBs.

One previous study did report that IR CCBs had a stronger association with breast carcinoma risk compared with SR CCBs,3 and another study found that use of verapamil (an IR nondihydropyridine), but not other types of CCBs, was associated with an increase in breast carcinoma risk.8 Our study is consistent with those previous reports in finding that ever use of IR CCBs (in particular, IR nondihydropyridines) was associated with an elevated risk of breast carcinoma. IR CCBs may be expected to have a stronger association with breast carcinoma compared with SR CCBs because of differences in pharmacokinetics. Specifically, because SR agents provide a more constant dose of the CCB over time compared with IR agents, establishing a new homeostatic equilibrium between cell death and cell proliferation may occur more easily with SR preparations. Nevertheless, arguing against a casual relation are our observations that there was no pattern with respect to the duration of use of these medications (for example, our observation that ever use of IR nondihydropyridines for 6 months to 5 years was associated with an elevation in breast carcinoma risk, but that use for 5 years or longer was not, suggests that the overall association between ever use of IR nondihydropyridines and breast carcinoma risk may be spurious) and that former use had a stronger association with risk compared with current use. There also is no clear reason to expect that IR nondihydropyridine CCBs would have a stronger association with breast carcinoma risk compared with IR dihydropyridine CCBs, although nondihydropyridines and dihydropyridines have different properties and bind to different regions of the calcium channel.17 Finally, our results may have been biased because more cases than controls reported a history of hypertension. Consistent with this, when we restricted our analyses to ever users of antihypertensive medications, use of any type of CCB was not associated with breast carcinoma compared with use of any other type of antihypertensive medication. Thus, considering the available evidence, the finding of others and our own results indicating that IR CCBs may be associated with breast carcinoma incidence should be interpreted with caution.

Although one study reported that ACE inhibitors were associated with a decreased risk of breast carcinoma, consistent with other studies, we found that use of both ACE inhibitors and use of β-blockers were neutral with respect to breast carcinoma risk. There was some suggestion that short-acting β-blockers were associated with an increase in breast carcinoma risk, but this result was attenuated when the analysis was restricted to ever users of antihypertensive medications, suggesting that this association may have been confounded by indication. Given the results of our study, the other available epidemiologic evidence, and the lack of clear mechanisms through which either ACE inhibitors or β-blockers may bear on carcinogenesis, neither use of ACE inhibitors nor use of β-blockers appears to be related to breast carcinoma incidence.

A recent cohort study found that diuretic use was associated with a 1.38-fold increase risk of breast carcinoma (95% CI, 0.83–2.29); however, otherwise, information on the relation between currently used diuretics, including thiazide, potassium-sparing, and loop diuretics, is lacking. Here, we report that use of both thiazide and potassium-sparing (but not loop) diuretics, including former, current, and long-term use, are associated with elevations in breast carcinoma risk. These associations were not attenuated when the analysis was restricted to ever users of antihypertensive medications. However, because these associations were present irrespective of their duration or their current versus former use, and because they were not observed when the analysis was restricted to women without a history of hypertension, our observations must be viewed tentatively. A potential mechanism by which thiazides may alter breast carcinoma risk is through the increased insulin resistance that results from thiazide use. Specifically, it was shown that chlorthalidone (a commonly used thiazide diuretic) increased fasting blood glucose levels in a randomized controlled trial.14 Insulin resistance has been suggested as a risk factor for breast carcinoma. Although a large cohort study found no association between insulin-like growth factor-1 (IGF-1) and the risk of postmenopausal breast carcinoma,13 another recent cohort study that stratified its results by BMI reported that higher levels of glucose, insulin, and IGF-1 were associated with elevations in breast carcinoma risk among postmenopausal women with a BMI > 26 kg/m².27 In addition, it has been hypothesized that one of the mechanisms underlying the positive associations between BMI and abdominal adiposity with breast carcinoma risk is the impact these factors have on insulin resistance.15, 16 Potential mechanisms underlying the association with potassium-sparing diuretics are less clear, although it has been shown that their use increases insulin levels.28, 29

Results from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, controlled, clinical trial designed to compare the efficacies of a diuretic, a CCB, and an ACE inhibitor with respect to different cardiovascular outcomes, clearly documented that chlorthalidone, a thiazide diuretic, is as effective as other first-line treatments for hypertension.14 Furthermore, ALLHAT found that the use of neither chlortalidone, amlodipine (an SR dihydropyridine CCB), nor lisinopril (an ACE inhibitor) was associated with an elevated risk of cancer overall, although risks for specific types of cancer, including breast carcinoma, have not been reported to date. The results from our suggest that use of thiazide and potassium-sparing diuretics may be associated with modest elevations in breast carcinoma risk among women ages 65–79 years. However, we believe it would be inappropriate to alter current clinical recommendations for the treatment of hypertension based on our tentative results. Further studies evaluating these correlations, particularly among elderly women, are needed to confirm and clarify the associations documented here.