Abstract
Purpose:
Antihypertensives are commonly prescribed medications and their effect on breast cancer recurrence and mortality is not clear, particularly among specific molecular subtypes of breast cancer: luminal, triple-negative (TN), and HER2-overexpressing (H2E).
Methods:
A population-based prospective cohort study of women aged 20-69 diagnosed with a first primary invasive breast cancer between 2004-2015 was conducted in the Seattle, Washington and Albuquerque, New Mexico greater metropolitan areas. Multivariable-adjusted Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for risks of breast cancer recurrence, breast cancer-specific mortality, and all-cause mortality associated with hypertension and antihypertensives.
Results:
In this sample of 2,383 luminal, 1,559 TN, and 615 H2E breast cancer patients, overall median age was 52 (interquartile range, 44-60). Hypertension and current use of antihypertensives were associated with increased risks of all-cause mortality in each subtype. Current use of angiotensin-converting enzyme inhibitors was associated with increased risks of both recurrence and breast cancer-specific mortality among luminal patients (HR: 2.5; 95% CI: 1.5, 4.3 and HR: 1.9; 95% CI: 1.2, 3.0), respectively). Among H2E patients, current use of calcium channel blockers was associated with an increased risk of breast cancer-specific mortality (HR: 1.8; 95% CI: 0.6, 5.4).
Conclusion:
Our findings suggest that some antihypertensive medications may be associated with adverse breast cancer outcomes among women with certain molecular subtypes. Additional studies are needed to confirm these findings.
Keywords: Antihypertensives, triple-negative breast cancer, HER2-Overexpressing breast cancer, recurrence, mortality
Introduction
Hypertension is a common chronic condition impacting approximately one third of US adults [1]. Diuretics, angiotensin-converting enzyme inhibitors (ACEIs), beta blockers (BBs), and calcium channel blockers (CCBs) are medications commonly prescribed to treat hypertension. Findings on the association between common classes of antihypertensives and breast cancer outcomes have been mixed, with some studies finding an association with the use of certain antihypertensives and breast cancer outcomes [2-11], and others finding no association [11-17].
Prognosis differs by intrinsic molecular subtypes of breast cancer that are defined by hormone receptor (HR) expression (joint estrogen/progesterone receptor status) and HER2-neu expression (HER2+/−). Specifically, triple-negative (TN) (HR−/HER2−) and HER2-enriched (H2E) (ER−/HER2+) tumors are associated with a poorer prognosis than luminal (HR+) tumors. Few studies have investigated associations between hypertension or antihypertensive use and breast cancer outcomes by molecular subtype [2, 3]. Based on the results of cell-line studies, TN breast cancer cells may have a higher expression of beta-adrenergic receptors, which are targets of BBs, and HER2-overexpression is correlated with overexpression of T-type calcium channels, which are targets of CCBs [18-21]. Differences in expression of molecular targets of antihypertensives in breast cancer cells of different subtypes provides motivation for examining the association between antihypertensive medications and breast cancer outcomes separately by subtype. The present study examines the relationships between hypertension and various antihypertensive medications and risk of three breast cancer outcomes, breast cancer recurrence, breast cancer-specific mortality, and all-cause mortality, by molecular subtype.
Methods
Study Population
We conducted a population-based prospective cohort study of women diagnosed with three different molecular subtypes of breast cancer between 2004-2015. Details of this study’s design and methods have been previously published [22]. Briefly, eligible patients were women aged 20-69 years who were diagnosed with a first primary invasive breast cancer between June 1, 2004 and June 30, 2012 in the greater metropolitan area of Albuquerque, New Mexico and between June 1, 2004 and June 30, 2015 in the greater metropolitan area of Seattle, Washington. All patients were identified through the Surveillance, Epidemiology, and End Results (SEER) cancer registries serving these geographic regions. Subtypes of breast cancer were defined by joint ER/PR/HER2 status using clinical data abstracted from patient medical records. We categorized patients into the following three subtypes: luminal (ER+), H2E (ER−/HER2+), and TN (ER−/PR−/HER2−). In order to maximize enrollment of the less common subtypes, all identified TN and H2E cases were considered eligible. A random sample of luminal ER+ cases was selected that was frequency-matched on age at diagnosis, year of diagnosis, and study site to the combined set of TN and H2E cases. At the Seattle study site, 4,508 new cases were determined to be eligible for this study, of which 2,882 were enrolled, for a response rate of 63.9%. Additionally, 994 cases from prior studies at the Seattle site with overlapping eligibility criteria were enrolled. At the New Mexico study site, 681 new cases were determined to be eligible for this study, and all 681 were enrolled with medical records abstraction only. In total, 2,383 ER+, 1,559 TN, and 615 H2E cases were enrolled for a sample size of 4,557. The institutional review boards at the Fred Hutchinson Cancer Research Center and University of New Mexico approved this study.
Data Collection
Trained staff at the Seattle-Puget Sound and New Mexico sites conducted medical record reviews, and structured interviewer-administered questionnaires at the Seattle-Puget Sound site, to collect data on epidemiologic, demographic, and clinical factors. To ensure consistency between abstraction methods at the two study sites, a random 10% of medical record abstracts were exchanged and reviews by each site. Medical record reviews, but not questionnaires, captured detailed information on antihypertensive medications, including recency of use and class of medication.
Three breast cancer outcomes were evaluated: breast cancer recurrence, breast cancer-specific mortality (BCSM), and all-cause mortality. Data on breast cancer recurrence were obtained from patient medical records with follow-up through the last date these records were reviewed by study staff. Recurrence could not be evaluated as an outcome among our H2E cases due to the few numbers of observed recurrences within this case group. Vital status and breast cancer-specific death classification were obtained from SEER [23]. Follow-up of vital status through SEER was available through March of 2020.
The following exposures were examined: hypertension, current use of any class of antihypertensive medication, current use of diuretics, current use of CCBs, current use of BBs, and current use of ACEIs. We did not examine use of angiotensin II receptor blockers (ARBs) due to the small sample size of ARB users. Current use of antihypertensive medication was defined as use within the six months prior to one month before the date of breast cancer diagnosis.
In our recurrence analyses we excluded cases in a step-wise fashion who had been diagnosed with a second primary (n=86), a recurrence within six months of diagnosis (n=20), or with stage IV breast cancer (n=346), and those for whom a medical record review could not be conducted (n=363), or had an unknown recurrence status per medical record review (n=30) resulting in a final analytic sample of 3,713. No cases were excluded from our all-cause mortality analyses, which had a final analytic sample of 4,557. Cases missing SEER cause-specific death classification were excluded from breast cancer specific mortality analyses (n=56) for a final analytic sample of 4,501.
Statistical Analysis
Multivariable-adjusted Cox proportional hazards models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) as measures of the associations between hypertension and antihypertensive medication use and risks of recurrence, BCSM, and all-cause mortality, separately for each subtype. Multiple imputation by chained equations was used to impute missing data on 19 covariates, using the “mice” package in R, with other covariates, including the outcomes, used to inform the imputation model [24]. Outcome variables were not imputed. Variables for current use of specific classes of antihypertensives were imputed conditionally based on the imputed values of the variable for current use of any antihypertensive using post-processing. Models were fit to each of the ten imputed datasets, then estimates from each were pooled using Rubin’s rules.
Different classes of antihypertensive medications were modeled separately, with patients who were not a current user of any antihypertensive serving as the reference group, because patients could be taking more than one class of antihypertensive at the same time. A priori determined confounders adjusted for in all analyses included stage (I-IV; I-III in recurrence analyses), definitive local treatment (breast-conserving surgery and radiation, mastectomy, other), chemotherapy (yes, no), race (Non-Hispanic white, Hispanic white, African-American, Asian/Pacific Islander, Native American), age at diagnosis, body mass index (<25, 25-29, ≥30), history of adjuvant hormonal therapy (never, ever; for luminal risk estimates only), history of trastuzumab therapy (never, ever; for HER2-overexpressing risk estimates only), current use of diabetes medications, and current use of lipid-lowering medications. We also examined confounding by smoking, alcohol consumption, and diagnosis of diabetes; however, none of these variables changed risk estimates by more than 10% and thus were not included in final models. Two secondary analyses were performed to assess confounding by indication. The first used women currently taking an antihypertensive other than the one being assessed as the reference group, while the second excluded cases without a history of hypertension and used hypertensive women not currently taking an antihypertensive as the reference group. We also conducted sensitivity analyses restricted to women aged 50 or older at diagnosis, as the prevalence of hypertension and use of antihypertensives is increased in older adults. Results are not shown for cells in which less than 5 events occurred in a majority of the imputed data sets. All analyses were completed using R software.
Results
In this sample of luminal, TN, and H2E breast cancer cases, luminal cases were more likely to have had breast conservation surgery and radiation, less likely to have received chemotherapy, and slightly more likely to be nulliparous than TN and H2E cases (Table 1). Women with H2E breast cancer were more likely to be older at diagnosis, more likely to be Hispanic white, and more likely to never have used hormonal contraceptives in the five years before diagnosis than women with luminal and TN breast cancer. TN cases were more likely to be African American and have a body mass index greater than 30 kg/m2 than luminal and H2E cases.
Table 1.
Distribution of patient characteristics and known breast cancer risk factors by molecular subtype.
| Variable | Luminal (N=2,383) n, % |
Triple-Negative (N=1,559) n, % |
HER2-overexpressing (N=615) n, % |
|---|---|---|---|
| Year of breast cancer diagnosis | |||
| 2004-2006 | 665 (27.9) | 436 (28.0) | 159 (25.9) |
| 2007-2008 | 512 (21.5) | 347 (22.3) | 128 (20.8) |
| 2009-2011 | 641 (26.9) | 436 (28.0) | 178 (28.9) |
| 2012-2015 | 565 (23.7) | 340 (21.8) | 150 (24.4) |
| Age at breast cancer diagnosis (years) | |||
| <40 | 351 (14.7) | 223 (14.3) | 72 (11.7) |
| 40-49 | 695 (29.2) | 433 (27.8) | 143 (23.3) |
| 50-59 | 749 (31.4) | 502 (32.2) | 233 (37.9) |
| 60-69 | 588 (24.7) | 401 (25.7) | 167 (27.2) |
| Study site | |||
| Seattle | 2,153 (90.3) | 1,252 (80.3) | 471 (76.6) |
| New Mexico | 230 (9.7) | 307 (19.7) | 144 (23.4) |
| Race/ethnicity | |||
| Non-Hispanic white | 1,923 (80.7) | 1,197 (76.8) | 474 (77.1) |
| Hispanic white | 150 (6.3) | 136 (8.7) | 61 (9.9) |
| African American | 87 (3.7) | 128 (8.2) | 28 (4.6) |
| Asian/Pacific Islander | 179 (7.5) | 65 (4.2) | 41 (6.7) |
| Native American | 44 (1.8) | 33 (2.1) | 11 (1.8) |
| Stage | |||
| I | 1,087 (45.6) | 505 (32.4) | 177 (28.8) |
| II | 859 (36.0) | 665 (42.7) | 224 (36.4) |
| III | 309 (13.0) | 248 (15.9) | 132 (21.5) |
| IV | 100 (4.2) | 78 (5.0) | 64 (10.4) |
| Missing | 28 (1.2) | 63 (4.0) | 18 (2.9) |
| First degree family history | |||
| No | 1,812 (76.0) | 1,173 (75.2) | 483 (78.5) |
| Yes | 515 (21.6) | 352 (22.6) | 120 (19.5) |
| Missing | 56 (2.4) | 34 (2.2) | 12 (2.0) |
| Number of full-term pregnancies | |||
| 0 | 582 (24.4) | 346 (22.2) | 123 (20.0) |
| 1 | 401 (16.8) | 285 (18.3) | 103 (16.7) |
| 2 | 878 (36.8) | 525 (33.7) | 226 (36.7) |
| 3+ | 507 (21.3) | 391 (25.1) | 157 (25.5) |
| Missing | 15 (0.6) | 12 (0.8) | 6 (1.0) |
| Body mass index | |||
| <25 | 964 (40.5) | 516 (33.1) | 235 (38.2) |
| 25-29 | 657 (27.6) | 460 (29.5) | 193 (31.4) |
| 30+ | 750 (31.5) | 563 (36.1) | 181 (29.4) |
| Missing | 12 (0.5) | 20 (1.3) | 6 (1.0) |
| Menopausal status | |||
| Pre-menopausal | 1,195 (50.1) | 694 (44.5) | 257 (41.8) |
| Post-menopausal | 1,182 (49.6) | 854 (54.8) | 353 (57.4) |
| Missing | 6 (0.3) | 11 (0.7) | 5 (0.8) |
| Recency of hormonal contraceptive use | |||
| Never within 5 years before diagnosis | 1,912 (80.2) | 1,231 (79.0) | 520 (84.6) |
| Former | 139 (5.8) | 110 (7.1) | 29 (4.7) |
| Current (within 6 months before diagnosis) | 260 (10.9) | 121 (7.8) | 35 (5.7) |
| Unknown recency | 16 (0.7) | 23 (1.5) | 3 (0.5) |
| Missing | 56 (2.4) | 74 (4.7) | 28 (4.6) |
| Recency of hormone replacement therapy | |||
| Never within 5 years before diagnosis | 1,971 (82.7%) | 1,240 (79.6%) | 496 (80.7%) |
| Former | 119 (5.0%) | 99 (6.4%) | 42 (6.8%) |
| Current estrogen only | 110 (4.6%) | 90 (5.8%) | 29 (4.7%) |
| Current estrogen + progestin | 119 (5.0%) | 33 (2.1%) | 10 (1.6%) |
| Missing | 64 (2.7%) | 97 (6.2%) | 38 (6.2%) |
| Surgery and radiation | |||
| Breast-conservation surgery and radiation | 1,169 (49.1) | 725 (46.5) | 189 (30.7) |
| Mastectomy (with or without radiation) | 1,090 (45.7) | 709 (45.5) | 358 (58.2) |
| Other | 121 (5.1) | 117 (7.5) | 64 (10.4) |
| Missing | 3 (0.1) | 8 (0.5) | 4 (0.7) |
| Chemotherapy | |||
| No | 1,034 (43.4) | 158 (10.1) | 67 (10.9) |
| Yes | 1,343 (56.4) | 1,396 (89.5) | 544 (88.5) |
| Missing | 6 (0.3) | 5 (0.3) | 4 (0.7) |
| Hormonal treatment | |||
| Never | 207 (8.7) | 1,458 (93.5) | 580 (94.3) |
| Ever | 2,176 (91.3) | 99 (6.4) | 34 (5.5) |
| Missing | 0 | 2 (0.1) | 1 (0.2) |
| Trastuzumab treatment | |||
| Never | 2,113 (88.7) | 1,553 (99.6) | 134 (21.8) |
| Ever | 270 (11.3) | 6 (0.4) | 481 (78.2) |
| Current alcohol use at diagnosis | |||
| Not Current | 704 (29.5) | 515 (33.1) | 239 (38.9) |
| Current | 1,665 (69.9) | 1,031 (66.1) | 370 (60.2) |
| Missing | 14 (0.6) | 13 (0.8) | 6 (1.0) |
| Recency of smoking at diagnosis | |||
| Never | 1,356 (56.9) | 856 (54.9) | 351 (57.1) |
| Current | 286 (12.0) | 222 (14.2) | 89 (14.5) |
| Former | 637 (26.7) | 416 (26.7) | 150 (24.4) |
| Not Current,NOS (Never/Former) | 94 (3.9) | 55 (3.5) | 21 (3.4) |
| Missing | 10 (0.4) | 10 (0.6) | 4 (0.7) |
| Diabetes at diagnosis | |||
| No | 2,155 (90.4) | 1,301 (83.5) | 525 (85.4) |
| Yes | 161 (6.8) | 145 (9.3) | 53 (8.6) |
| Missing | 67 (2.8) | 113 (7.2) | 37 (6.0) |
| Use of diabetes medication at diagnosis | |||
| Not Current | 2,231 (93.6) | 1,363 (87.4) | 537 (87.3) |
| Current | 79 (3.3) | 83 (5.3) | 38 (6.2) |
| Missing | 73 (3.1) | 113 (7.2) | 40 (6.5) |
| Use of lipid-lowering medication at diagnosis | |||
| Not Current | 1,099 (46.1) | 770 (49.4) | 337 (54.8) |
| Current | 222 (9.3) | 160 (10.3) | 58 (9.4) |
| Missing | 1,062 (44.6) | 629 (40.3) | 220 (35.8) |
Consistent with the impact of hypertension on health status, a history of hypertension, current use of any antihypertensive, and current use of the majority of individual classes of antihypertensive were associated with increased risks of all-cause mortality across all three breast cancer subtypes, though not all confidence intervals excluded the null value of one (Table 2). Focusing on recurrence and BCSM, current use of ACEIs was associated with increased risks of both of these outcomes among luminal patients (HR: 2.5; 95% CI: 1.5, 4.3 and HR: 1.9; 95% CI: 1.2, 3.0, respectively), and to a lesser extent among TN patients (HR: 1.5; 95% CI: 0.9, 2.3 and HR: 1.4; 95% CI: 0.8, 2.2, respectively). Among H2E patients, only current use of CCBs was associated with an increased risk of BCSM (HR: 1.8; 95% CI: 0.6, 5.4); however, this estimate was based on a small number of events and thus should be interpreted with caution. We also performed analyses restricted to patients who were current users of antihypertensives to address potential confounding by indication. These same positive relationships with recurrence and BCSM were also observed in these analyses, though the associations between current ACEI use and risk of recurrence and BCSM were within the limits of chance among TN patients (Table 3). When analyses were further restricted to cases with a history of hypertension, with cases who did not use antihypertensive medications as the reference group, risk estimates for associations between antihypertensive use and ACM were attenuated among luminal and H2E cases (Table 4). Positive associations between ACEI use and recurrence and BCSM were still observed.
Table 2.
Hazard ratios and 95% confidence intervals for the risk of breast cancer recurrence, breast cancer-specific mortality (BCSM), and all-cause mortality (ACM) associated with hypertension and antihypertensive use, by molecular subtype, among US women aged 21-69, 2004-2015.
| Luminal | Triple-Negative | HER2-overexpressing | ||||||
|---|---|---|---|---|---|---|---|---|
| Recurrence1 | BCSM | ACM | Recurrence1 | BCSM | ACM | BCSM | ACM | |
| Sample size | 1,982 | 2,350 | 2,383 | 1,248 | 1,540 | 1,559 | 612 | 615 |
| Number of events | 160 | 255 | 408 | 264 | 382 | 495 | 117 | 140 |
| Person-years at risk | 9,483 | 22,036 | 22,391 | 4,026 | 12,325 | 12,472 | 5,110 | 5,123 |
| HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | |
| Hypertension | ||||||||
| No | ref | ref | ref | ref | ref | ref | ref | ref |
| Yes | 1.5 (0.96, 2.4) | 1.4 (0.9, 1.9) | 1.5 (1.2, 2.0) | 1.2 (0.8, 1.7) | 1.2 (0.8, 1.6) | 1.3 (1.01, 1.8) | 0.8 (0.4, 1.4) | 1.0 (0.6, 1.7) |
| Antihypertensive medications 2 | ||||||||
| Not current antihypertensive user | ref | ref | ref | ref | ref | ref | ref | ref |
| Current – any antihypertensiveyn | 1.5 (0.96, 2.4) | 1.2 (0.8, 1.8) | 1.4 (1.04, 1.8) | 1.3 (0.9, 1.9) | 1.2 (0.9, 1.6) | 1.4 (1.1, 1.8) | 0.8 (0.4, 1.5) | 1.1 (0.6, 1.9) |
| Current – diuretics | 1.4 (0.8, 2.5) | 1.1 (0.7, 1.7) | 1.3 (0.9, 1.8) | 1.2 (0.8, 1.8) | 1.1 (0.8, 1.6) | 1.4 (1.01, 1.8) | 0.5 (0.2, 1.2) | 0.9 (0.5, 1.8) |
| Current – CCB | † | 1.8 (0.7, 4.3) | 2.1 (1.2, 3.6) | 1.4 (0.7, 2.8) | 1.4 (0.7, 2.7) | 1.9 (1.2, 3.0) | 1.8 (0.6, 5.4) | 2.5 (0.96, 6.3) |
| Current – BB | 1.3 (0.6, 2.8) | 1.3 (0.7, 2.4) | 1.7 (1.2, 2.5) | 1.3 (0.8, 2.2) | 1.3 (0.8, 2.0) | 1.8 (1.3, 2.5) | 0.8 (0.3, 2.1) | 1.0 (0.4, 2.2) |
| Current – ACEI | 2.5 (1.5, 4.3) | 1.9 (1.2, 3) | 1.6 (1.1, 2.4) | 1.5 (0.9, 2.3) | 1.4 (0.8, 2.2) | 1.5 (1.02, 2.2) | 0.9 (0.4, 2.1) | 1.3 (0.6, 2.7) |
Patients with Stage IV disease or a 2nd primary were excluded from recurrence models. Recurrence models restricted to patients with medical record review.
Current use of antihypertensive medications defined as use within the six months prior to one month before the date of diagnosis.
<5 breast cancer events occurred in this group in the majority of imputed datasets and thus HRs could not be reliably reported.
All models adjusted for stage, definitive local treatment, chemotherapy, race, body mass index, age at diagnosis, current use of diabetes medications, and current use of lipid-lowering medications. Luminal models also adjusted for history of hormonal treatment. HER2-overexpressing models also adjusted for history of trastuzumab treatment.
Abbreviations: BCSM = breast cancer-specific mortality; ACM = all-cause mortality; HR = hazard ratio; CI = confidence interval; CCB = calcium channel blocker; BB = beta blocker; ACEI = angiotensin-converting enzyme inhibitors
Table 3.
Hazard ratios and 95% confidence intervals for the risk of breast cancer recurrence, breast cancer-specific mortality (BCSM), and all-cause mortality (ACM) associated with antihypertensive use by molecular subtype with patients currently using other antihypertensives serving as the reference group, among US women aged 21-69, 2004-2015.
| Luminal | Triple-Negative | HER2-overexpressing | ||||||
|---|---|---|---|---|---|---|---|---|
| Recurrence1 | BCSM | ACM | Recurrence1 | BCSM | ACM | BCSM | ACM | |
| Sample size | 350 | 378 | 381 | 255 | 291 | 292 | 93 | 94 |
| Number of events | 30 | 47 | 98 | 60 | 83 | 127 | 23 | 34 |
| Person-years at risk | 1,602 | 3,325 | 3,354 | 790 | 2,069 | 2,082 | 718 | 720 |
| HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | |
| Diuretics 2 | ||||||||
| Not current | ref | ref | ref | ref | ref | ref | ref | ref |
| Current | 0.8 (0.4, 2.0) | 0.7 (0.3, 1.3) | 0.8 (0.5, 1.3) | 0.8 (0.5, 1.4) | 0.9 (0.6, 1.4) | 1.0 (0.7, 1.4) | 0.4 (0.05, 3.1) | 0.9 (0.3, 2.9) |
| CCB | ||||||||
| Not current | ref | ref | ref | ref | ref | ref | ref | ref |
| Current | † | 1.5 (0.5, 4.1) | 1.6 (0.9, 2.7) | 1.1 (0.5, 2.3) | 1.3 (0.6, 2.6) | 1.5 (0.9, 2.3) | † | 1.8 (0.5, 6.5) |
| BB | ||||||||
| Not current | ref | ref | ref | ref | ref | ref | ref | ref |
| Current | 0.8 (0.3, 2.1) | 1.1 (0.5, 2.3) | 1.5 (0.9, 2.4) | 1.1 (0.6, 2.0) | 1.1 (0.7, 1.9) | 1.4 (0.9, 2.2) | 0.8 (0.1, 5.0) | 0.7 (0.2, 2.2) |
| ACEI | ||||||||
| Not current | ref | ref | ref | ref | ref | ref | ref | ref |
| Current | 2.8 (1.1, 6.7) | 2.3 (1.2, 4.3) | 1.3 (0.8, 2.0) | 1.2 (0.7, 2.2) | 1.4 (0.8, 2.3) | 1.1 (0.7, 1.6) | 1.0 (0.1, 8.0) | 1.2 (0.3, 4.7) |
Patients with Stage IV disease or a 2nd primary were excluded from recurrence models. Recurrence models restricted to patients with medical record review.
Current use of antihypertensive medications defined as use within the six months prior to one month before the date of diagnosis.
<5 breast cancer events occurred in this group in the majority of imputed datasets and thus HRs could not be reliably reported.
All models adjusted for stage, definitive local treatment, chemotherapy, race, body mass index, current use of diabetes medications, current use of lipid-lowering medications, and age at diagnosis. Luminal models also adjusted for history of hormonal treatment. HER2-overexpressing models also adjusted for history of trastuzumab treatment.
Abbreviations: BCSM = breast cancer-specific mortality; ACM = all-cause mortality; HR = hazard ratio; CI = confidence interval; CCB = calcium channel blocker; BB = beta blocker; ACEI = angiotensin-converting enzyme inhibitors
Table 4.
Hazard ratios and 95% confidence intervals for the risk of breast cancer recurrence, breast cancer-specific mortality (BCSM), and all-cause mortality (ACM) associated with antihypertensive use by molecular subtype with patients with a history of hypertension but not taking antihypertensives serving as the reference group, restricted to participants with a history of hypertension, among US women aged 21-69, 2004-2015.
| Luminal | Triple-Negative | HER2-overexpressing | ||||||
|---|---|---|---|---|---|---|---|---|
| Recurrence1 | BCSM | ACM | Recurrence1 | BCSM | ACM | BCSM | ACM | |
| Sample size | 397 | 477 | 481 | 295 | 361 | 364 | 120 | 121 |
| Number of events | 34 | 62 | 126 | 61 | 89 | 135 | 24 | 37 |
| Person-years at risk | 1,823 | 4,177 | 4,212 | 922 | 2,686 | 2,717 | 958 | 959 |
| HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | HR (95% CI) | |
| History of hypertension, but not current antihypertensive user | ref | ref | ref | ref | ref | ref | ref | ref |
| Current – any antihypertensive2 | 1.3 (0.4, 3.7) | 0.8 (0.4, 1.6) | 0.9 (0.6, 1.5) | 1.6 (0.8, 3.2) | 1.5 (0.7, 3.0) | 1.4 (0.8, 2.5) | 0.5 (0.1, 3.4) | 0.9 (0.2, 3.6) |
| Current – diuretics | 1.1 (0.4, 3.4) | 0.7 (0.3, 1.4) | 0.8 (0.5, 1.4) | 1.4 (0.7, 3.0) | 1.4 (0.7, 2.9) | 1.4 (0.8, 2.5) | 0.3 (0.04, 3.0) | 0.9 (0.2, 4.0) |
| Current – CCB | † | 1.2 (0.4, 3.4) | 1.3 (0.7, 2.7) | 1.5 (0.6, 4.0) | 1.6 (0.6, 4.4) | 1.8 (0.9, 3.7) | 1.1 (0.1, 13.7) | 1.8 (0.3, 9.7) |
| Current – BB | 1.2 (0.4, 4.3) | 1.0 (0.4, 2.4) | 1.2 (0.7, 2.2) | 1.5 (0.6, 3.6) | 1.5 (0.7, 3.3) | 1.7 (0.9, 3.3) | 0.4 (0.03, 5.8) | 0.6 (0.1, 3.7) |
| Current – ACEI | 2.0 (0.7, 5.9) | 1.2 (0.6, 2.5) | 1.1 (0.6, 1.8) | 1.8 (0.8, 3.9) | 1.7 (0.8, 3.7) | 1.5 (0.8, 2.8) | 0.6 (0.1, 3.8) | 1.1 (0.3, 4.5) |
Patients with Stage IV disease or a 2nd primary were excluded from recurrence models. Recurrence models restricted to patients with medical record review.
Current use of antihypertensive medications defined as use within the six months prior to one month before the date of diagnosis.
<5 breast cancer events occurred in this group in the majority of imputed datasets and thus HRs could not be reliably reported.
All models adjusted for stage, definitive local treatment, chemotherapy, race, body mass index, current use of diabetes medications, current use of lipid-lowering medications, and age at diagnosis. Luminal models also adjusted for history of hormonal treatment. HER2-overexpressing models also adjusted for history of trastuzumab treatment.
Abbreviations: BCSM = breast cancer-specific mortality; ACM = all-cause mortality; HR = hazard ratio; CI = confidence interval; CCB = calcium channel blocker; BB = beta blocker; ACEI = angiotensin-converting enzyme inhibitors
Discussion
In this prospective analysis of luminal, TN, and H2E breast cancer we observed that certain classes of antihypertensive medications were associated with risks of recurrence and BCSM. Specifically, we found evidence that current ACEI use was positively associated with risks of recurrence and BCSM among luminal patients and, to a lesser extent, among TN patients. This is supported by results from our analyses restricted to current antihypertensive users. Also of note was that among antihypertensive users, ACEI use was associated with risks of the two breast cancer specific outcomes of interest, but it was not associated with risk of all-cause mortality suggesting that it may promote breast cancer growth/spread. Prior studies evaluating these relationships have not stratified breast cancer patients by molecular subtype, and this could contribute to the mixed results that have been reported. Somewhat consistent with our results, an observational study observed that ACEI use was associated with an increased risk of recurrence, but not increased risks of either BCSM or all-cause mortality. However, this study did not collect data on HER2 status [9]. A retrospective cohort study of female members in an integrated health plan found a higher risk of a second primary breast cancer associated with ACEI use but did not find an association with risk of recurrence [5]. Seven additional studies did not find an association between ACEI use and increased risk of breast cancer events [4, 6, 7, 10, 12, 14, 17]. Again, though, ours is the first study to divide patients by molecular subtype defined by joint ER/PR/HER2 status making direct comparisons to the published literature difficult to interpret. The mechanism by which ACEIs alter the renin-angiotensin system to lower blood pressure may also contribute to changes in the tumor microenvironment [25]. Specifically, increased inflammation and angiogenesis in the tumor microenvironment resulting from the effects of ACEIs on the renin-angiotensin system could be responsible for the observed relationship between ACEI use and breast cancer-specific outcomes [26]. It is also of note that patients with certain cardiovascular indications, such as heart failure, coronary heart disease, or secondary stroke prevention, tend to be prescribed ACEIs over other antihypertensive medications. While we were not able to adjust for these indications due to lack of data on them, there is little existing evidence to suggest that they are related to risk of breast cancer outcomes [17,27,28].
We also observed that current CCB use was associated with risk of BCSM only among H2E patients; however, the confidence interval surrounding this estimate was wide due to a small sample size. Four prior studies did not find an association between CCB use and breast cancer events [4, 5, 15, 29], and a recent case-control study from Taiwan reported a decreased risk of breast cancer recurrence associated with CCB use, but information on breast cancer subtype was not reported in any of these studies [30]. CCBs may have a role in promoting breast cancer growth [31], but the scientific evidence is unclear, and few studies have focused specifically on H2E breast cancer. This relationship may be impacted by the cardiovascular effects of trastuzumab treatment; however, our small numbers of CCB users with H2E breast cancer prevented us from analyzing separately cases who did and did not receive trastuzumab. CCBs reduce the amount of calcium in cells with long-acting voltage-gated calcium channels in order to lower blood pressure [32,33]. HER2-overexpressing cell lines have been shown to also overexpress certain types of calcium channels, which are targeted by CCBs [19-21]. CCBs could potentially interact with the overexpression of calcium channels associated with H2E breast cancer to reduce calcium levels inside tumor cells and thus increase evasion of apoptosis and tumor progression [34].
Consistent with our results, six other studies also did not find an association between BB use and breast cancer events [4, 5, 7, 9, 13, 17]. Although some previous studies have identified a protective effect of BBs on breast cancer outcomes [2, 3, 8, 10, 11], it has been noted that more commonly prescribed beta-1 antagonists (i.e. atenolol) does not have the same inhibiting effects on tumor progression as beta-2 and beta-3 antagonists [35,36]. If there were a greater proportion of beta-1 antagonist users in our study population, this may explain the lack of association found with BBs and breast cancer outcomes.
The main strength of this prospective study compared to other similar studies was the relatively large sample of TN and H2E breast cancer cases that were included compared to previous studies. We also used medical records to obtain information on medication use and breast cancer recurrence, which eliminated biases present in studies that rely solely on patient recall. The current analysis is not without limitations, however. Our assessment of antihypertensive use was limited to the time just prior to breast cancer diagnosis and so changes in regimens post diagnosis were not captured. However, given the chronic nature of antihypertensive use a cancer diagnosis typically does not trigger changing existing regimens that are effective and well-tolerated by patients limiting the potential impact of this limitation [37,38]. As discussed previously, we relied on medical records for exposure and outcome ascertainment, which could have resulted in some degree of misclassification if the medical record was not accurate. Additionally, the limited number of outcome events prevented us from further analyzing antihypertensive medication use by duration of use or by subclass of medication. Another potential source of bias in observational studies involving medication use is confounding by indication, where the indication for being prescribed the medication causes both the use of the medication and contributes to the outcome of interest. We explored the potential effect of confounding by indication by conducting an analysis restricted to current users of antihypertensives and comparing current use of one class of antihypertensives to current use of other classes of antihypertensives. The recapitulation of our main results with respect to ACEI and CCB use and risks of recurrence and BCSM suggest that these findings are not the consequence of confounding by indication. We also further restricted analyses to women with a history of hypertension and compared antihypertensive medication users to women who did not use an antihypertensive. Risk estimates for ACM were attenuated, and associations between ACEI use and recurrence were still evident. However, even though we adjusted for relevant variables, and restricted to current hypertensive users to avoid confounding by indication, some unmeasured characteristic of hypertensive users may still have contributed to these results.
In conclusion, our findings suggest that some antihypertensive medications may be associated with adverse breast cancer outcomes among women with certain molecular subtypes of breast cancer. As this is the first study to evaluate these relationships by subtype, future studies are needed to confirm these results. If confirmed, alterations to antihypertensive regimens for hypertensive breast cancer survivors could be an additional strategy to reduce risks of recurrence and breast cancer specific mortality among these patients.
Funding:
This project was supported by the National Cancer Institute (grant numbers: T32CA09168 (N.C. Lorona), 261201000029C (to C.I. Li), P50 CA148143 (to L.S.Cook, D.A. Hill, C.I. Li), 261201000033C (to C.L. Wiggins), Cancer Center Support Grant 2 P30 CA118100-11 (to L.S. Cook, D.A. Hill, C.L. Wiggins), Contract HHSN261201800014I, Task Order HHSN26100001 (to C.L. Wiggins), and 3R01CA189184-04S1 (to C.I. Li)) and the Department of Defense Breast Cancer Research Program (grant number: BC112721 (to C.I. Li)). The funders of this study had no role in the study design, data collection, data analysis, manuscript preparation, or the decision to publish this manuscript.
Footnotes
Conflicts of interest: The authors have no conflicts of interest to report.
Ethics approval: The institutional review boards at the Fred Hutchinson Cancer Research Center and University of New Mexico approved this study.
Availability of data and code: The datasets analyzed and code used during the current study are available from the corresponding author on reasonable request.
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