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Cumulative incidence plot time to grade 3–5 CVA/TIA events. No competing events were considered. Tam tamoxifen, Let letrozole, → indicates sequence of 2 years of one agent followed by 3 years of the other agent
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Background
Compared to tamoxifen, adjuvant treatment with aromatase inhibitors improves disease outcomes of postmenopausal women with hormone receptor-positive early breast cancer. In the international, randomized, double-blind BIG 1-98 trial, 8010 women were randomized to receive tamoxifen, letrozole, or sequential use of the agents for 5 years. W...
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Citations
... Medications like tamoxifen, fulvestrant, erteberel, raloxifene, and others used for breast cancer treatment have diverse CVD effects. 74,75 Some enhance cardiovascular event risks, while others lessen them. 76 Tamoxifen reportedly both shields and harms CVDs, subject to dose, treatment duration, and other conditions. ...
Recent studies suggest that pleiotropic effects may explain the genetic architecture of cardiovascular diseases (CVDs). We conducted a comprehensive gene-centric pleiotropic association analysis for ten CVDs using genome-wide association study (GWAS) summary statistics to identify pleiotropic genes and pathways that may underlie multiple CVDs. We found shared genetic mechanisms underlying the pathophysiology of CVDs, with over two-thirds of the diseases exhibiting common genes and single-nucleotide polymorphisms (SNPs). Significant positive genetic correlations were observed in more than half of paired CVDs. Additionally, we investigated the pleiotropic genes shared between different CVDs, as well as their functional pathways and distribution in different tissues. Moreover, six hub genes, including ALDH2, XPO1, HSPA1L, ESR2, WDR12, and RAB1A, as well as 26 targeted potential drugs, were identified. Our study provides further evidence for the pleiotropic effects of genetic variants on CVDs and highlights the importance of considering pleiotropy in genetic association studies.
Purpose:
In estrogen receptor-positive (ER+) breast cancer (BC), single-nucleotide polymorphisms (SNPs) in the aromatase gene might affect aromatase inhibitors (AIs) metabolism and efficacy. Here, we assessed the impact of SNPs on prognosis and toxicity of patients receiving adjuvant letrozole.
Experimental design:
We enrolled 886 postmenopausal patients treated with 2-5 years letrozole after 2-6 years tamoxifen until the completion of 5-10 years of therapy. Germline DNA was genotyped for SNPs rs4646, rs10046, rs749292, rs727479. Log-rank test and Cox model were used for disease-free (DFS) and overall survival (OS). Cumulative incidence (CI) of BC metastasis was assessed through competing risk analysis, with contralateral BC, second malignancies non-BC death as competing events. CIs of skeletal and cardiovascular events were assessed using DFS events as competing events. Subdistribution hazard ratio (sHR) with 95% confidence intervals were calculated through Fine-Gray method.
Results:
No SNP was associated with DFS. Variants rs10046 (sHR 2.03 [1.04-2.94]), rs749292 (sHR 2.11, [1.12-3.94]), and rs727479 (sHR 2.62, [1.17-5.83]) were associated with BC metastasis. Three groups were identified based on the number of these variants (0, 1, >1). Variant-based groups were associated with BC metastasis (10-year CI 2.5%, 7.6%, 10.7%, p=0.035), and OS (10-year estimates 96.5%, 93.0%, 89.6%, p=0.030). Co-occurrence of rs10046 and rs749292 was negatively associated with 10-year CI of skeletal events (3.2% versus 10%, p=0.033). A similar association emerged between rs727479 and cardiovascular events (0.3% versus 2.1%, p=0.026).
Conclusions:
SNPs of aromatase gene predict risk of metastasis and AI-related toxicity in ER+ early BC, opening an opportunity for better treatment individualization.
Breast cancer is the most common cancer in women. Patients with breast cancer have a 4-fold increased risk of venous thromboembolism (VTE) compared to age- and sex-matched controls without cancer. VTE remains the second leading cause of death in cancer patients and an independent risk factor for mortality. In women with breast cancer, the main risk factors for developing VTE are increasing age, obesity, disease stage, central catheter placement and cancer treatments, including surgery, chemotherapy, hormonotherapy and cyclin-dependent kinase 4/6 inhibitors. In women receiving tamoxifen, the risk of VTE is particularly increased within the first 6 months after initiation of hormonotherapy, although some evidence suggests that this risk may persist through the first 2 years of treatment. The risk of VTE appears to be lower in patients receiving aromatase inhibitors. In breast cancer patients receiving cyclin-dependent kinase 4/6 inhibitors, the rate of VTE is approximately 6%. Current clinical practice guidelines for the treatment and prevention of VTE in patients with cancer suggest that thromboprophylaxis should not be used routinely in ambulatory cancer patients receiving chemotherapy or hormonotherapy. The risk-benefit ratio of thromboprophylaxis should be assessed on a case-by-case basis and be the subject of multidisciplinary discussion.
Breast cancer is the most common cancer in women. Over the past few decades, advances in cancer detection and treatment have significantly improved survival rate of breast cancer patients. However, due to the cardiovascular toxicity of cancer treatments (chemotherapy, anti-HER2 antibodies and radiotherapy), cardiovascular diseases (CVD) have become an increasingly important cause of long-term morbidity and mortality in breast cancer survivors. Endocrine therapies are prescribed to reduce the risk of recurrence and specific death in estrogen receptor-positive (ER+) early breast cancer patients, but their impact on CVD is a matter of debate. Whereas aromatase inhibitors and luteinizing hormone-releasing hormone (LHRH) analogs inhibit estrogen synthesis, tamoxifen acts as a selective estrogen receptor modulator (SERM), opposing estrogen action in the breast but mimicking their actions in other tissues, including arteries. This review aims to summarize the main clinical and experimental studies reporting the effects of tamoxifen on CVD. In addition, we will discuss how recent findings on the mechanisms of action of these therapies may contribute to a better understanding and anticipation of CVD risk in breast cancer patients.
Cardiovascular disease (CVD) is one of the most common comorbidities in breast cancer survivors. Recently, the target population and treatment period for aromatase inhibitor (AI) treatment in breast cancer patients has been expanding. However, information on adverse CVD events from the long-term use of AI is still lacking. The aim of this study was to investigate the CVD side effects of AI treatment and to evaluate the changes in lipid profile during AI treatment. A systematic search of PubMed (Medline), EMBASE, and Cochrane Library databases reporting on cardiovascular outcomes or lipid profiles change in adult female breast cancer patients (>19 years old) with AI was performed. The pooled analysis of 25 studies showed that the prevalence rate of any type of cardiovascular disease was 6.08 per 100 persons (95% CI 2.91–10.31). Angina was the most common type of heart-related cardiovascular event accounting for 3.85 per 100 persons, followed by any type of stroke (3.34) and venous thromboembolism (2.95). Ischemic stroke (OR 1.39, 95% CI 1.07–1.81) and myocardial infarction (OR 1.30, 95% CI 0.88–1.93) were more common in AI compared with tamoxifen, whereas the prevalence of venous thromboembolism (OR 0.61, 95% CI 0.37–1) was significantly lower in the AI group. In addition, treatment with AI for 6–12 months showed a decrease in HDL-cholesterol and an increase in LDL-cholesterol and total cholesterol. Various CVDs can occur when using AI, and in particular, the risk of MI and ischemic stroke increases in comparison with the adverse effect of tamoxifen. The occurrence of CVD might be related to the deterioration of the lipid profile after AI treatment. Therefore, a customized individualization strategy considering each patient’s CV risk factors is needed during AI treatment.
With the success of modern cancer therapy, breast cancer survival has steadily improved over the last decades. Treatment with aromatase inhibitors has become the preferred endocrine treatment in postmenopausal women with estrogen receptor-positive breast cancer. However, concerns have been raised over a possible cardiotoxic potential. The aim of the current paper is to review the evidence regarding cardiotoxicity with aromatase inhibitors in breast cancer.
Weighing benefits vs. risks, the improved effect of aromatase inhibitors vs. tamoxifen on breast cancer recurrence in most patients outweighs the potential risk of CV adverse events. At present it is advisable to ensure that standard measures of cardiovascular disease (CVD) management are applied to women with breast cancer, i.e., lifestyle intervention and if needed medical treatment of CVD and risk factors for CVD.
What is known and objective
Breast cancer is one of the leading causes of morbidity and mortality in women worldwide. In order to reduce the risks of its recurrence, endocrine therapies, such as tamoxifen and aromatase inhibitors are commonly administered. Despite having a similar efficacy in preventing breast cancer recurrence, these drugs differ in terms of instigating cardiovascular morbidities. Recent randomized controlled trials and cohort studies provide inconclusive evidence of the cardiovascular risks associated with the administration of these endocrine therapies. This present review and meta-analysis evaluates the comparative cardiovascular adverse event outcomes in breast cancer patients receiving tamoxifen and aromatase inhibitors. To evaluate the comparative cardiovascular adverse outcomes, such as venous thromboembolism, heart failure, angina, myocardial infarction and stroke in patients with breast cancer receiving tamoxifen and aromatase inhibitors.
Methods
A systematic search of the academic literature was performed according to the PRISMA guidelines across five databases, including Web of Science, EMBASE, CENTRAL, Scopus, and MEDLINE. A random-effect meta-analysis was conducted to compare the cardiovascular adverse events (i.e. venous thromboembolism, heart failure, angina, myocardial infarction, stroke) in breast cancer patients treated with tamoxifen and aromatase inhibitors.
Results and discussion
From 993 studies, 20 eligible studies were identified, with 174,142 female breast cancer patients (mean age: 67.4 ± 3.8 years). A meta-analysis revealed insignificantly (p > 0.05) higher risks of venous thromboembolism (Odds ratio, 95% CI: 1.70, 0.91–3.18) in patients treated with tamoxifen as compared to aromatase inhibitors. We also observed insignificantly higher risks of stroke (0.93, 0.45–1.91), angina (0.77, 0.12–4.59), myocardial infarction (0.74, 0.30–1.79), and heart failure (0.81, 0.22–2.91) in patients receiving aromatase inhibitors as compared to tamoxifen.
What is new and conclusions
The study provides evidence regarding the comparative cardiovascular adverse outcomes between breast cancer patients consuming tamoxifen and aromatase inhibitors. The study reports an insignificant increase in the events of stroke, angina, myocardial infarction, and heart failure in breast cancer patients treated with aromatase inhibitors as compared to tamoxifen. The study also reports that tamoxifen treatment is associated with an insignificant increase in the events of venous thromboembolism as compared to treatment with aromatase inhibitors.
Background
The benefit of extending aromatase inhibitor therapy beyond 5 years in the context of previous aromatase inhibitors remains controversial. We aimed to compare extended therapy with letrozole for 5 years versus the standard duration of 2–3 years of letrozole in postmenopausal patients with breast cancer who have already received 2–3 years of tamoxifen.
Methods
This multicentre, open-label, randomised, phase 3 trial was done at 69 hospitals in Italy. Women were eligible if they were postmenopausal at the time of study entry, had stage I–III histologically proven and operable invasive hormone receptor-positive breast cancer, had received adjuvant tamoxifen therapy for at least 2 years but no longer than 3 years and 3 months, had no signs of disease recurrence, and had an Eastern Cooperative Oncology Group performance status of 2 or lower. Patients were randomly assigned (1:1) to receive 2–3 years (control group) or 5 years (extended group) of letrozole (2·5 mg orally once a day). Randomisation, with stratification by centre, with permuted blocks of size 12, was done with a centralised, interactive, internet-based system that randomly generated the treatment allocation. Participants and investigators were not masked to treatment assignment. The primary endpoint was invasive disease-free survival in the intention-to-treat population. Safety analysis was done for patients who received at least 1 month of study treatment. This trial was registered with EudraCT, 2005-001212-44, and ClinicalTrials.gov, NCT01064635.
Findings
Between Aug 1, 2005, and Oct 24, 2010, 2056 patients were enrolled and randomly assigned to receive letrozole for 2–3 years (n=1030; control group) or for 5 years (n=1026; extended group). After a median follow-up of 11·7 years (IQR 9·5–13·1), disease-free survival events occurred in 262 (25·4%) of 1030 patients in the control group and 212 (20·7%) of 1026 in the extended group. 12-year disease-free survival was 62% (95% CI 57–66) in the control group and 67% (62–71) in the extended group (hazard ratio 0·78, 95% CI 0·65–0·93; p=0·0064). The most common grade 3 and 4 adverse events were arthralgia (22 [2·2%] of 983 patients in the control group vs 29 [3·0%] of 977 in the extended group) and myalgia (seven [0·7%] vs nine [0·9%]). There were three (0·3%) serious treatment-related adverse events in the control group and eight (0·8%) in the extended group. No deaths related to toxic effects were observed.
Interpretation
In postmenopausal patients with breast cancer who received 2–3 years of tamoxifen, extended treatment with 5 years of letrozole resulted in a significant improvement in disease-free survival compared with the standard 2–3 years of letrozole. Sequential endocrine therapy with tamoxifen for 2–3 years followed by letrozole for 5 years should be considered as one of the optimal standard endocrine treatments for postmenopausal patients with hormone receptor-positive breast cancer.
Funding
Novartis and the Italian Ministry of Health.
Translation
For the Italian translation of the abstract see Supplementary Materials section.
