Cardiotoxicity of aromatase inhibitors and tamoxifen in postmenopausal women with breast cancer: a systematic review and meta-analysis of randomized controlled trials

Khosrow‐Khavar, Farzin; Filion, Kristian B.; Alqurashi, Suhad; Torabi, Nazi; Bouganim, Nathaniel; Suissa, Samy; Azoulay, Laurent

doi:10.1093/annonc/mdw673

Cited by 152 publications

(124 citation statements)

References 62 publications

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“…Another population-based observational study of a heterogeneous population of 74 women with early breast cancer who received adjuvant hormonal therapy and subsequently underwent cardiac angiography concluded that aromatase inhibitors significantly increased the hazard for CAD compared to tamoxifen [ 111 ]. These studies, however, are in direct conflict with recent genome-wide association studies that attribute this finding to the cardioprotective effects of tamoxifen versus the detrimental effects of aromatase inhibitors [ 112 ].…”

Section: Aromatase and The Cardiovascular Systemmentioning

confidence: 91%

The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy

et al. 2017

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Epidemiologic studies have previously suggested that premenopausal females have reduced incidence of cardiovascular disease (CVD) when compared to age-matched males, and the incidence and severity of CVD increases postmenopause. The lower incidence of cardiovascular disease in women during reproductive age is attributed at least in part to estrogen (E2). E2 binds to the traditional E2 receptors (ERs), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ), as well as the more recently identified G-protein-coupled ER (GPR30), and can exert both genomic and non-genomic actions. This review summarizes the protective role of E2 and its receptors in the cardiovascular system and discusses its underlying mechanisms with an emphasis on oxidative stress, fibrosis, angiogenesis, and vascular function. This review also presents the sexual dimorphic role of ERs in modulating E2 action in cardiovascular disease. The controversies surrounding the clinical use of exogenous E2 as a therapeutic agent for cardiovascular disease in women due to the possible risks of thrombotic events, cancers, and arrhythmia are also discussed. Endogenous local E2 biosynthesis from the conversion of testosterone to E2 via aromatase enzyme offers a novel therapeutic paradigm. Targeting specific ERs in the cardiovascular system may result in novel and possibly safer therapeutic options for cardiovascular protection.

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Section: Aromatase and The Cardiovascular Systemmentioning

confidence: 91%

The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy

et al. 2017

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“…Many women with BC receive endocrine therapy and chemotherapy in addition to RT. Studies have shown a higher risk of cardiovascular disease in patients treated with aromatase inhibitors (AI) compared to tamoxifen, though this elevation in risk may be explained by a cardioprotective effect of tamoxifen [12,13]. Cytotoxic agents, especially regimens including anthracyclines, are associated with an increased risk of congestive heart failure [14,15].…”

Section: Introductionmentioning

confidence: 99%

Long-term risk of ischemic heart disease after adjuvant radiotherapy in breast cancer: results from a large population-based cohort

et al. 2020

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Background: Adjuvant radiotherapy (RT) for breast cancer (BC) has been associated with an increased risk of ischemic heart disease (IHD). We examined the incidence of IHD in a large population-based cohort of women with BC. Methods: The Breast Cancer DataBase Sweden (BCBaSe) includes all women diagnosed with BC from 1992 to 2012 (n = 60,217) and age-matched women without a history of BC (n = 300,791) in three Swedish health care regions. Information on comorbidity, educational level, and incidence of IHD was obtained through linkage with populationbased registries. The risk of IHD was estimated by Cox proportional hazard regression analyses and cumulative incidence by the Kaplan-Meier method. Results: Women with BC had a lower risk of IHD compared to women without BC with a hazard ratio (HR) of 0.91 (95% CI 0.88-0.95). When women with left-sided BC were compared to right-sided BC, an increased HR for IHD of 1.09 (95% CI 1.01-1.17) was seen. In women receiving RT, a HR of 1.18 (95% CI 1.06-1.31) was seen in left-sided compared to right-sided BC, and the HRs increased with more extensive lymph node involvement and with the addition of systemic therapy. The cumulative IHD incidence was increased in women receiving left-sided RT compared to right-sided RT, starting from the first years after RT and sustained with longer follow-up. Conclusions: Women given RT for left-sided BC during 1992 to 2012 had an increased risk of IHD compared to women treated for right-sided BC. These women were treated in the era of three-dimensional conformal RT (3DCRT), and the results emphasize the importance of further developing and implementing RT techniques that lower the cardiac doses, without compromising the beneficial effects of RT.

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“…Tamoxifen has demonstrated favourable cardiovascular effects such as a reduction in total and low-density lipoprotein cholesterol (LDL-C) levels, an increase in high-density lipoprotein cholesterol levels, and a decrease in fibrinogen level [16][17][18] . A meta-analysis comparing tamoxifen with AIs showed that AIs were associated with a 19% increase in cardiovascular events, which may be due to the cardio-protective effect of tamoxifen 4 . However, whether tamoxifen increases the thromboembolism risk remains inconclusive 5 .…”

Section: Discussionmentioning

confidence: 99%

Major Adverse Cardiovascular Events after Treatment in Early-stage Breast Cancer Patients Receiving Hormone Therapy

Chou

Huang

Kornelius

et al. 2020

Sci Rep

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This nationwide population-based study investigated the differences in the risks of major adverse cardiovascular events (MAces) among patients with hormone receptor-positive early-stage breast cancer undergoing different combinations of adjuvant treatments in Taiwan. Data from the National Health Insurance Research Database (NHIRD) and Taiwan Cancer Registry (TCR) along with the national mortality data were used. Patients who underwent surgery as the first mode of treatment were divided into four groups based on the subsequent adjuvant therapy received: hormone therapy (H), hormone therapy + chemotherapy (CH), hormone therapy + radiotherapy (RH), and hormone therapy + radiotherapy + chemotherapy (CRH) groups. The risks of fatal and nonfatal MACE among the groups were examined using the inverse probability of treatment weighted hazard ratio (IPTW-HR). Adjuvant treatment, age, tumour size, and comorbidities significantly affected the risks of MACEs among the 19,007 patients analysed. For nonfatal MACEs, the IPTW-HR was significantly lower in the CH group compare to the H group (0.704, 95% confidence interval [CI]: 0.516-0.961). No significant differences in the risks for fatal MACE were observed among the four groups. The IPTW-HRs for haemorrhagic stroke in the CH group was 0.424 (95% CI: 0.188-0.957), for congestive heart failure (CHF) in the RH group was 0.260 (95% CI: 0.088-0.762), and for ischaemic heart disease in the CRH group was 0.544 (95% CI: 0.317-0.934). Increase in the adjuvant modality does not necessarily increase the nonfatal or fatal MACE risks. Cardiac health should be monitored even in patients receiving hormone therapy alone.

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Cardiotoxicity of aromatase inhibitors and tamoxifen in postmenopausal women with breast cancer: a systematic review and meta-analysis of randomized controlled trials

Abstract: The increased risk of cardiovascular events with AIs relative to tamoxifen is likely the result of cardioprotective effects of the latter. This new evidence should be considered when assessing the benefits and risks of AIs in the treatment of breast cancer.

Cited by 152 publications

References 62 publications

The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy

The protective role of estrogen and estrogen receptors in cardiovascular disease and the controversial use of estrogen therapy

Long-term risk of ischemic heart disease after adjuvant radiotherapy in breast cancer: results from a large population-based cohort

Major Adverse Cardiovascular Events after Treatment in Early-stage Breast Cancer Patients Receiving Hormone Therapy

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