Endocrine therapy use and the risk of cardiovascular disease in postmenopausal breast cancer survivors: two cohort studies in the UK and US

ABSTRACTObjectiveExamine the effect of tamoxifen and aromatase inhibitors on 12 clinically relevant individual cardiovascular outcomes in postmenopausal female breast cancer survivors using large-scale datasets from the UK and US.DesignTwo prospective cohort studiesSettingPopulation-based using data from the UK Clinical Practice Datalink linked with Hospital Episode Statistics (2002-2016), and the US Surveillance, Epidemiology and End Results-Medicare database (2008-2013).Participants10005 and 22027 postmenopausal women with breast cancer in the UK and US respectively.ExposuresAromatase inhibitor compared with tamoxifen use; the US cohort additionally included a comparison with an “unexposed” group of women with oestrogen or progesterone receptor positive breast cancer but no endocrine therapy use.Outcomes12 clinically relevant individual cardiovascular outcomes (and two composite coronary and venous thromboembolic outcomes)ResultsIn both the UK and the US, there was evidence of an increased risk of coronary artery disease in aromatase inhibitor compared with tamoxifen users (UK incidence rate: 10.18 vs 6.87 per 1000 person-years, HR: 1.29, 0.94-1.76; US incidence rate: 35.26 vs 26.95 per 1000 person-years, HR: 1.29, 1.06-1.55), but the US data showed no increase in risk compared with the unexposed group (incidence rate for tamoxifen vs unexposed: 26.95 vs 38.70 per 1000 person-years, HR: 0.74, 0.60-0.92; incidence rate for aromatase inhibitors vs unexposed: 35.26 vs 28.70, HR: 0.96, 0.83-1.10). Similar patterns were seen for other cardiovascular outcomes such as arrhythmia, heart failure, and valvular heart disease. As expected, there were more venous thromboembolic events in tamoxifen users compared with both aromatase inhibitor users and those unexposed. There was a high degree of consistency between results in the two countries.ConclusionsIncreased risks of several cardiovascular diseases among aromatase inhibitor compared with tamoxifen users appeared to be driven by protective effects of tamoxifen, rather than toxic effects of aromatase inhibitors. We also confirmed the known increased risk of venous thromboembolic events in tamoxifen users.WHAT THIS PAPER ADDSWhat is already known on this topicIt is known that tamoxifen use increases venous thromboembolism risk, but evidence for other cardiovascular outcomes is less clear.Patterns of results are suggestive of a lower risk of coronary heart disease outcomes with tamoxifen compared to both aromatase inhibitor use and no tamoxifen or placebo, but cardiovascular events are often a secondary consideration and inconsistently reported in trials, and most observational studies use composite cardiovascular definitions, ignoring potentially differential effects on specific cardiovascular outcomes.What this study addsAmong postmenopausal women with breast cancer, we found an increased risk of several cardiovascular diseases in aromatase inhibitor compared with tamoxifen users across two countries, which appeared to be driven by protective effects of tamoxifen, rather than toxic effects of aromatase inhibitors. We also found the known increased venous thromboembolism risk in tamoxifen users.There was no evidence that aromatase inhibitors or tamoxifen increases cardiovascular disease risk, other than the known increased venous thromboembolism risk with tamoxifen use. However, there was an apparent protective effect of tamoxifen on other cardiovascular outcomes.

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Are previous episodes of bacterial vaginosis a predictor for vaginal symptoms in breast cancer patients treated with aromatase inhibitors?

Post Reproductive Health ◽

10.1177/2053369118757545 ◽

2018 ◽

Vol 24 (2) ◽

pp. 67-71

Author(s):

Malene R Gade ◽

Irina Goukasian ◽

Nathalie Panduro ◽

Claus Kamby ◽

Lisbeth Nilas ◽

...

Keyword(s):

Breast Cancer ◽

Bacterial Vaginosis ◽

Aromatase Inhibitor ◽

Aromatase Inhibitors ◽

University Hospital ◽

Breast Cancer Patients ◽

Vaginal Symptoms ◽

Vaginal Dryness ◽

Number Of Patients ◽

Increased Risk

Objective To estimate the prevalence of vaginal symptoms in postmenopausal women with breast cancer exposed to aromatase inhibitors, and to investigate if the risk of vaginal symptoms is associated with previous episodes of bacterial vaginosis. Methods Patients from Rigshospitalet and Herlev University Hospital, Denmark, were identified through the register of Danish Breast Cancer Cooperation Group and 78 patients participated in the study. Semiquantitave questionnaires and telephone interview were used to assess the prevalence of vaginal symptoms and previous episode(s) of bacterial vaginosis. Multivariable logistic regression models were used to assess the association between vaginal symptoms and previous episodes of bacterial vaginosis. Results Moderate to severe symptoms due to vaginal itching/irritation were experienced by 6.4% (95% CI: 2.8–14.1%), vaginal dryness by 28.4% (95% CI: 19.4–39.5%), and dyspareunia by 23.1% (95% CI: 11.0–42.1%). Patients with earlier episodes of bacterial vaginosis had an increased risk of vaginal dryness when exposed to a treatment with an aromatase inhibitor, adjusted OR 5.5 (95% CI 1.3–21.6). Conclusion A considerable number of patients exposed to aromatase inhibitor have vaginal symptoms and the risk is highest among patients with earlier episodes of bacterial vaginosis.

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Aromatase Inhibitors and the Risk of Cardiovascular Outcomes in Women With Breast Cancer

Circulation ◽

10.1161/circulationaha.119.044750 ◽

2020 ◽

Vol 141 (7) ◽

pp. 549-559 ◽

Cited By ~ 10

Author(s):

Farzin Khosrow-Khavar ◽

Kristian B. Filion ◽

Nathaniel Bouganim ◽

Samy Suissa ◽

Laurent Azoulay

Keyword(s):

Breast Cancer ◽

Myocardial Infarction ◽

Heart Failure ◽

Ischemic Stroke ◽

Incidence Rate ◽

Aromatase Inhibitors ◽

Cardiovascular Mortality ◽

Population Based ◽

Increased Risk ◽

Study Population

Background: The association between aromatase inhibitors and cardiovascular outcomes among women with breast cancer is controversial. Given the discrepant findings from randomized controlled trials and observational studies, additional studies are needed to address this safety concern. Methods: We conducted a population-based cohort study using the UK Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. The study population consisted of women newly diagnosed with breast cancer initiating hormonal therapy with aromatase inhibitors or tamoxifen between April 1, 1998, and February 29, 2016. We usedCox proportional hazards models with inverse probability of treatment and censoring weighting to estimate hazard ratios (HRs) with 95% CIs comparing new users of aromatase inhibitors with new users of tamoxifen for each of the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality). Results: The study population consisted of 23 525 patients newly diagnosed with breast cancer, of whom 17 922 initiated treatment with either an aromatase inhibitor or tamoxifen (8139 and 9783, respectively). The use of aromatase inhibitors was associated with a significantly increased risk of heart failure (incidence rate, 5.4 versus 1.8 per 1000 person-years; HR, 1.86 [95% CI, 1.14–3.03]) and cardiovascular mortality (incidence rate, 9.5 versus 4.7 per 1000 person-years; HR, 1.50 [95% CI, 1.11–2.04]) compared with the use of tamoxifen. Aromatase inhibitors were associated with elevated HRs, but with CIs including the null value, for myocardial infarction (incidence rate, 3.9 versus 1.8 per 1000 person-years; HR, 1.37 [95% CI, 0.88–2.13]) and ischemic stroke (incidence rate, 5.6 versus 3.2 per 1000 person-years; HR, 1.19 [95% CI, 0.82–1.72]). Conclusions: In this population-based study, aromatase inhibitors were associated with increased risks of heart failure and cardiovascular mortality compared with tamoxifen. There were also trends toward increased risks, although nonsignificant, of myocardial infarction and ischemic stroke. The increased risk of cardiovascular events associated with aromatase inhibitors should be balanced with their favorable clinical benefits compared with tamoxifen.

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Survival outcome and treatment tolerability for postmenopausal females with early stage hormone receptor positive breast cancer treated with different adjuvant hormonal lines (TAM vs. AI vs. switching strategy) for 5 years

QJM ◽

10.1093/qjmed/hcab103.010 ◽

2021 ◽

Vol 114 (Supplement_1) ◽

Author(s):

Atef Youssef Riyad ◽

Dalia Abdelghany Elkhodary ◽

Wesam Reda Farag Elghamry ◽

Islam Abdelrahman Kamel Mohamed Zaki

Keyword(s):

Breast Cancer ◽

Aromatase Inhibitor ◽

Early Breast Cancer ◽

Aromatase Inhibitors ◽

Hormone Receptor ◽

Disease Free Survival ◽

Hormonal Treatment ◽

Hormone Receptor Positive ◽

Adjuvant Hormonal Treatment ◽

Her 2

Abstract Background The standard adjuvant endocrine treatment for postmenopausal female patients with hormone receptor positive early breast cancer was 5 years of tamoxifen, but recurrence and side effects restrict its usefulness. The aromatase inhibitor (anastrozole or exemestane or letrozole) was compared with tamoxifen for 5 years or started after completing 2-3 years of tamoxifen in postmenopausal female patients diagnosed with early breast cancer at "Ain Shams University Hospitals" Objective The aim of the study was to measure survival outcome and treatment tolerability for postmenopausal females with Hormone Receptor Positive early breast cancer who received adjuvant hormonal treatment with tamoxifen [TAM] only for 5 years versus those who received adjuvant hormonal treatment with tamoxifen [TAM] for 2 years switching to aromatase inhibitors [AI] in the sequential 3 years versus those who received adjuvant hormonal treatment with aromatase inhibitors [AI] solely for 5 years. Patients and methods This study included 100 postmenopausal women with early breast cancer who presented at the Clinical Oncology Department, Ain Shams University, in the interval from January 2010 until December 2015. Conclusion Similar disease free survival and overall survival were observed among the three studied groups. Switching tamoxifen to aromatase inhibitors provides better tolerability in terms of endometrial thickness when compared to 5 years of tamoxifen monotherapy. Patients who administer aromatase inhibitor included in the switching strategy experience less osteoporosis and less generalized bone pain compared to upfront aromatase inhibitor to 5 years. There was a significant improvement of disease free survival (DFS) in human epidermal growth factor receptor 2 (HER 2) negative patients receiving any adjuvant hormonal treatment line for five years in comparison to HER 2 positive patients receiving the same adjuvant hormonal treatment for five years.

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Abstract 47: Atrial Fibrillation is Associated With Increased Risk of Incident Venous Thromboembolism: The Atherosclerosis Risk in Communities Study

Circulation ◽

10.1161/circ.135.suppl_1.47 ◽

2017 ◽

Vol 135 (suppl_1) ◽

Author(s):

Pamela L Lutsey ◽

Faye L Norby ◽

Alvaro Alonso ◽

Mary Cushman ◽

Lin Y Chen ◽

...

Keyword(s):

Risk Factors ◽

Atrial Fibrillation ◽

Venous Thromboembolism ◽

Incidence Rate ◽

Case Reports ◽

Time Dependent ◽

Atherosclerosis Risk In Communities ◽

Increased Risk ◽

Atherosclerosis Risk ◽

Shared Risk

Background: It is well-established that atrial fibrillation (AF) is associated with thrombus formation in the left atrium, which can lead to ischemic stroke. Case reports, autopsies, and transesophageal echo data have indicated that clot formation also occurs in the right atrium (i.e. right-side intracardiac thrombosis) of AF patients, which could lead to pulmonary embolism (PE). However, it is unclear whether this occurrence is common. Objective: Test the hypotheses that individuals with incident AF are at elevated risk of developing venous thromboembolism (VTE), and that the association will be stronger for those presenting with PE alone versus PE and deep vein thrombosis (DVT) or DVT alone. Methods: A total of 15,205 Atherosclerosis Risk in Communities (ARIC) study participants, aged 45-64 years, were followed from baseline (1987-1989) to 2011 for incidence of AF and VTE (median follow-up 19.8 years). Incident AF and VTE events were identified via active surveillance and defined by relevant hospital discharge ICD codes. VTE events were validated by medical record review. Multivariable-adjusted Cox proportional hazards regression models were used, with AF modeled as a time-dependent covariate. We also evaluated separately risk of PE without evidence of DVT, DVT without PE, and events presenting with both PE and DVT. Results: At baseline participants were on average 54 years old, 55% female and 26% black. In the absence of AF there were 678 VTE events, for an incidence rate of 2.6 per 1000 person-years. After an AF diagnosis there were 77 events, with an incidence rate of 7.1 per 1000 person-years. In multivariable-adjusted models, having AF (versus no AF) was associated with a greater risk of incident VTE; the HR (95% CI) was 2.10 (1.65-2.68) after adjustment for demographics, 1.82 (1.42-2.32) additionally accounting for numerous AF and VTE risk factors, and 1.97 (1.53-2.53) after further adjusting for time-dependent anticoagulant use. When we restricted to PE events without evidence of DVT there were 188 events in total, of which 19 occurred following a diagnosis of AF. The HR for AF (versus no AF) was 1.53 (0.92-2.56) in fully adjusted models. For DVT alone there were 384 events in total, of which 48 occurred after AF diagnosis; the HR for AF was 2.43 (1.77-3.33). Among the 116 events presenting with both DVT and PE, 10 occurred after AF diagnosis, and the HR for AF was 1.36 (0.67-2.75). Conclusions: Diagnosis with AF was associated with a nearly 2-fold increased risk of incident VTE. The association was not stronger when isolated to those with PE without DVT, suggesting that higher risk of VTE among AF patients may be due to either the coagulation abnormalities that accompany AF, or shared risk factors that were not fully accounted for in this analysis.

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Emotional states and future risk of venous thromboembolism

Thrombosis and Haemostasis ◽

10.1160/th11-09-0667 ◽

2012 ◽

Vol 107 (03) ◽

pp. 485-493 ◽

Cited By ~ 13

Author(s):

Sigrid K. Brækkan ◽

Ida J. Hansen-Krone ◽

John-Bjarne Hansen ◽

Kristin F. Enga

Keyword(s):

Venous Thromboembolism ◽

Incidence Rate ◽

Population Based ◽

Emotional States ◽

Depressive Feelings ◽

Increased Risk ◽

Adjusted Incidence Rate ◽

Adjusted Incidence ◽

Reduced Risk

SummaryEmotional states of depression and loneliness are reported to be associated with higher risk and optimism with lower risk of arterial cardiovascular disease (CVD) and death. The relation between emotional states and risk of venous thromboembolism (VTE) has not been explored previously. We aimed to investigate the associations between self-reported emotional states and risk of incident VTE in a population-based, prospective study. The frequency of feeling depressed, lonely and happy/optimistic were registered by self-administered questionnaires, along with major co-morbidities and lifestyle habits, in 25,964 subjects aged 25–96 years, enrolled in the Tromsø Study in 1994–1995. Incident VTE-events were registered from the date of inclusion until September 1, 2007. There were 440 incident VTE-events during a median of 12.4 years of follow-up. Subjects who often felt depressed had 1.6-fold (95% CI:1.02–2.50) higher risk of VTE compared to those not depressed in analyses adjusted for other risk factors (age, sex , body mass index, oes-trogens), lifestyle (smoking, alcohol consumption, educational level) and co-morbidities (diabetes, CVD, and cancer). Often feeling lonely was not associated with VTE. However, the incidence rate of VTE in subjects who concurrently felt often lonely and depressed was higher than for depression alone (age-and sex-adjusted incidence rate: 3.27 vs. 2.21). Oppositely, subjects who often felt happy/optimistic had 40% reduced risk of VTE (HR 0.60, 95% CI: 0.41–0.87). Our findings suggest that self-reported emotional states are associated with risk of VTE. Depressive feelings were associated with increased risk, while happiness/ optimism was associated with reduced risk of VTE.

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Postscript: starting oral contraceptives (25 May, page 41)

Drug and Therapeutics Bulletin ◽

10.1136/dtb.30.14.56 ◽

1992 ◽

Vol 30 (14) ◽

pp. 56.1-56

Keyword(s):

Breast Cancer ◽

Oral Contraceptives ◽

Contraceptive Use ◽

Causal Relation ◽

Case Control ◽

Term Pregnancy ◽

Oral Contraceptive Use ◽

Increased Risk ◽

The Uk

In our article on oral contraceptives (OCs) we state that ‘oral contraceptives increase the risk of breast cancer with long-term use but reduce the risk of endometrial and ovarian cancer’. Some commentators have questioned the breast cancer risk. The UK National Case-Control (UKNCC) study, which looked at oral contraceptive use in women with breast cancer diagnosed before age 36, found a trend for increased risk associated with duration of use.1 ‘The simplest and most plausible explanation’, say the authors of the study, ‘must be that there is a substantial causal relation between prolonged use and breast cancer in young women.’ The increased risk seems to be associated particularly with OC use before the first full-term pregnancy.2 Several studies found no excess risk in OC users aged 45 or over, few of whom had taken the pill before their first pregnancy.3–5 In the UKNCC study the relative risk of breast cancer was 1.43 after 4–8 years’ use and 1.74 after more than 8 years’ use. In broad terms this means that three women in 1000 who use oral contraceptives for 4 or more years might be expected to be under treatment for breast cancer by age 36, compared with two per 1000 non-users.

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Real-world starting dose and outcomes of palbociclib plus an aromatase inhibitor for metastatic breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e13021 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e13021-e13021

Author(s):

Debra A. Patt ◽

Xianchen Liu ◽

Benjamin Li ◽

Lynn McRoy ◽

Rachel M. Layman ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Aromatase Inhibitor ◽

Real World ◽

Metastatic Breast ◽

Routine Practice ◽

First Line ◽

Starting Dose ◽

The Us

e13021 Background: Palbociclib (PA) has been approved for HR+/HER2–advanced/metastatic breast cancer (mBC) in combination with an aromatase inhibitor (AI) or fulvestrant for more than 6 years. Regardless of the labeled recommended starting dose of 125mg/day, some patients initiate palbociclib at lower doses in routine practice. This study described real-world starting dose, patient characteristics, and effectiveness outcomes of first line PA+ AI for mBC in the US clinical setting. Methods: We conducted a retrospective analysis of Flatiron Health’s nationwide longitudinal electronic health records, which came from over 280 cancer clinics representing more than 2.2 million actively treated cancer patients in the US. Between February 2015 and September 2018, 813 HR+/HER2– mBC women initiated PA+AI as first-line therapy and had ≥ 3 months of potential follow-up. Patients were followed from start of PA+AI to December 2018, death, or last visit, whichever came first. Real-world progression-free survival (rwPFS) was defined as the time from the start of PA+AI to death or disease progression. Real-world tumor response (rwTR) was assessed based on the treating clinician’s assessment of radiologic evidence for change in burden of disease over the course of treatment. Multivariate analyses were performed to adjust for demographic and clinical characteristics. Results: Of 813 eligible patients, 68.3% were white, median age was 65.0 years, and 42.9% had visceral disease (lung and/or liver). Median duration of follow-up was 21.0 months. 805 patients had records of PA starting dose, with 125mg and 75/100mg/day being 86.5% and 13.5%, respectively. Patients who started at 75/100mg/day were more likely to be ≥75 years than those who started at 125mg/day (38.5% vs 17.1%). Other baseline and disease characteristics were generally evenly distributed. Patients who started at 125mg/day had longer median rwPFS (27.8 vs 18.6 months, adjusted HR=0.74, 95%CI=0.52-1.05) and higher rwTR (54.0% vs. 40.4%) than those patients who started 100/75mg/day (adjusted OR=1.76, 95%CI=1.13-2.74). Table presents results in detail. Conclusions: Most patients in this study initiated palbociclib at 125mg/day and dose adjustment was similar regardless of starting dose. These real-world findings may support initiation of palbociclib at a dose of 125mg/day in combination with AI for the first-line treatment of HR+/HER2- mBC. [Table: see text]

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