Antihypertensive drug use and breast cancer risk: a meta-analysis of observational studies

Ni, Haibo; Qin, Rui; Zhu, Xiaojue; Yu, Zhen-Quan; Gao, Rong; Liu, Huixiang

doi:10.18632/oncotarget.19117

Cited by 28 publications

(19 citation statements)

References 63 publications

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“…The site-specific cancers analysed included common cancers and subtypes that have previously been reported to be associated with blood pressure lowering treatment, comprising of breast, colorectal, lung, prostate, and skin cancers. 5 , 6 , 7 , 8 , 9 , 10 , 16 We describe the source of these outcomes for each trial, and whether or not these outcomes have been adjudicated by an endpoint committee on the basis of certain criteria, in the appendix (pp 13–17) .…”

Section: Methodsmentioning

confidence: 99%

Antihypertensive treatment and risk of cancer: an individual participant data meta-analysis

Copland¹,

Canoy²,

Nazarzadeh

et al. 2021

The Lancet Oncology

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Summary Background Some studies have suggested a link between antihypertensive medication and cancer, but the evidence is so far inconclusive. Thus, we aimed to investigate this association in a large individual patient data meta-analysis of randomised clinical trials. Methods We searched PubMed, MEDLINE, The Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov from Jan 1, 1966, to Sept 1, 2019, to identify potentially eligible randomised controlled trials. Eligible studies were randomised controlled trials comparing one blood pressure lowering drug class with a placebo, inactive control, or other blood pressure lowering drug. We also required that trials had at least 1000 participant years of follow-up in each treatment group. Trials without cancer event information were excluded. We requested individual participant data from the authors of eligible trials. We pooled individual participant-level data from eligible trials and assessed the effects of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), β blockers, calcium channel blockers, and thiazide diuretics on cancer risk in one-stage individual participant data and network meta-analyses. Cause-specific fixed-effects Cox regression models, stratified by trial, were used to calculate hazard ratios (HRs). The primary outcome was any cancer event, defined as the first occurrence of any cancer diagnosed after randomisation. This study is registered with PROSPERO (CRD42018099283). Findings 33 trials met the inclusion criteria, and included 260 447 participants with 15 012 cancer events. Median follow-up of included participants was 4·2 years (IQR 3·0–5·0). In the individual participant data meta-analysis comparing each drug class with all other comparators, no associations were identified between any antihypertensive drug class and risk of any cancer (HR 0·99 [95% CI 0·95–1·04] for ACEIs; 0·96 [0·92–1·01] for ARBs; 0·98 [0·89–1·07] for β blockers; 1·01 [0·95–1·07] for thiazides), with the exception of calcium channel blockers (1·06 [1·01–1·11]). In the network meta-analysis comparing drug classes against placebo, we found no excess cancer risk with any drug class (HR 1·00 [95% CI 0·93–1·09] for ACEIs; 0·99 [0·92–1·06] for ARBs; 0·99 [0·89–1·11] for β blockers; 1·04 [0·96–1·13] for calcium channel blockers; 1·00 [0·90–1·10] for thiazides). Interpretation We found no consistent evidence that antihypertensive medication use had any effect on cancer risk. Although such findings are reassuring, evidence for some comparisons was insufficient to entirely rule out excess risk, in particular for calcium channel blockers. Funding British Heart Foundation, National Institute for Health Research, Oxford Martin School.

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Section: Methodsmentioning

confidence: 99%

Antihypertensive treatment and risk of cancer: an individual participant data meta-analysis

Copland¹,

Canoy²,

Nazarzadeh

et al. 2021

The Lancet Oncology

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“…Thus, RAS is a potential key player in adipocyte-breast-cancer-cell interactions. RAS inhibitors such as angiotensin-converting enzyme inhibitors (ACE-I) and AT1R blockers (ARB) have recently gained interest as possible anticancer agents in both clinical and preclinical models of BC [17,18,20,21]. Some ACE-I and ARBs were found to reduce BC risk in a time-dependent manner in BC patients [21].…”

Section: Introductionmentioning

confidence: 99%

Combined Effects of Eicosapentaenoic Acid and Adipocyte Renin–Angiotensin System Inhibition on Breast Cancer Cell Inflammation and Migration

Rasha

Kahathuduwa

Ramalingam

et al. 2020

Cancers

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Obesity is a major risk factor for breast cancer (BC). Obesity-related metabolic alterations such as inflammation and overactivation of the adipose renin–angiotensin system (RAS) may contribute to the progression of BC. Clinically used antihypertensive drugs such as angiotensin-converting enzyme inhibitors (ACE-I) and dietary bioactive components such as eicosapentaenoic acid (EPA) are known for their anti-inflammatory and adipose RAS blocking properties. However, whether EPA enhances the protective effects of ACE-I in lessening adipocyte inflammation on BC cells has not been studied. We hypothesized that combined EPA and ACE-I would attenuate BC cell inflammation and migration possibly via adipose RAS inhibition. To test our hypothesis, we examined the (i) direct effects of an ACE-I (captopril (CAP)) or EPA, individually and combined, on MCF-7 and MDA-MB-231 human BC cells, and the (ii) effects of conditioned medium (CM) from human adipocytes pretreated with the abovementioned agents on BC cells. We demonstrated that CM from adipocytes pretreated with EPA with or without captopril (but not direct treatments of BC cells) significantly reduced proinflammatory cytokines expression in both BC cell lines. Additionally, cell migration was reduced in MDA-MB-231 cells in response to both direct and CM-mediated CAP and/or EPA treatments. In summary, our study provides a significant insight into added benefits of combining anti-inflammatory EPA and antihypertensive ACE-I to attenuate the effects of adipocytes on breast cancer cell migration and inflammation.

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“…In previous studies, CCBs have been shown to inhibit apoptosis by interfering with calcium-triggered signals, suggesting the possibility of promoting cancer [28]. Accordingly, numerous studies have been conducted on the risk of developing breast cancer by CCBs [29, 30]. A recent meta-analysis of observational studies has reported that there is no correlation between CCBs and carcinogenesis in breast cancer (risk ratio: 1.07, 95% CI: 0.99–1.16) [29].…”

Section: Discussionmentioning

confidence: 99%

“…Accordingly, numerous studies have been conducted on the risk of developing breast cancer by CCBs [29, 30]. A recent meta-analysis of observational studies has reported that there is no correlation between CCBs and carcinogenesis in breast cancer (risk ratio: 1.07, 95% CI: 0.99–1.16) [29]. In contrast, some reports have shown that CCBs suppress the activity of T cells by inhibiting interleukin-2, which is required for the differentiation of T cells [6, 8, 9, 31].…”

Section: Discussionmentioning

confidence: 99%

Verification of the effects of calcium channel blockers on the immune microenvironment of breast cancer

et al. 2019

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Background A higher density of tumor-infiltrating lymphocytes (TILs) can lead to greater therapeutic effects and improved prognoses in cancer treatment. Similar results have been observed in breast cancer, particularly in triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2-enriched breast cancer. Calcium channel blockers (CCBs) are antihypertensive drugs (AHTs) that have also been reported to suppress the functions of T cells and macrophages. In this study, we evaluated TILs before pre-operative chemotherapy (POC) in breast cancer and retrospectively analyzed the correlation between CCBs and TILs or prognosis. Methods Of the patients treated with POC, 338 who had evaluable TILs were enrolled in this study. The correlations among TILs were evaluated according to standard methods, and CCB use and prognosis were investigated retrospectively. Results Before POC, 65 patients (19.2%) took AHTs (CCBs: 41/338, 12.1%). The TIL density was significantly lower among patients administered CCBs for the group of all patients and for patients with TNBC ( p = 0.040, p = 0.009, respectively). Additionally, patients with TNBC who were administered CCBs showed significantly lower response rates for POC ( p = 0.040). In all patients receiving POC, no significant differences in disease-free survival (DFS) or overall survival (OS) were observed in patients administered CCBs ( p = 0.712, p = 0.478, log-rank tests, respectively). Furthermore, no significant differences were found, even in patients with TNBC (DFS: p = 0.441, OS: p = 0.727, log-rank tests, respectively). Conclusions In patients with TNBC undergoing treatment for hypertension with CCBs, TILs in the needle biopsy specimens before treatment were significantly lower, and the response rate of POC was not sufficient. Thus, the immunosuppressive effects of CCBs may also affect the immune microenvironment. Electronic supplementary material The online version of this article (10.1186/s12885-019-5828-5) contains supplementary material, which is available to authorized users.

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Antihypertensive drug use and breast cancer risk: a meta-analysis of observational studies

Cited by 28 publications

References 63 publications

Antihypertensive treatment and risk of cancer: an individual participant data meta-analysis

Antihypertensive treatment and risk of cancer: an individual participant data meta-analysis

Combined Effects of Eicosapentaenoic Acid and Adipocyte Renin–Angiotensin System Inhibition on Breast Cancer Cell Inflammation and Migration

Verification of the effects of calcium channel blockers on the immune microenvironment of breast cancer

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