Cardiovascular disease incidence after internal mammary chain irradiation and anthracycline-based chemotherapy for breast cancer

Boekel, Naomi B.; Jacobse, Judy N.; Schaapveld, Michael; Hooning, Maartje J.; Gietema, Jourik A.; Duane, F.; Taylor, Carolyn; Darby, Sarah C.; Hauptmann, Michael; Seynaeve, Caroline; Baaijens, Margreet H.A.; Sonke, Gabe S.; Rutgers, Emiel J.; Russell, Nicola S.; Aleman, Berthe M.P.; Leeuwen, Flora E. van

doi:10.1038/s41416-018-0159-x

Cited by 61 publications

(63 citation statements)

References 44 publications

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“…The radiotherapy results in this nested case–control study differ somewhat from those reported in our cohort study, which reported increased HF rates after radiotherapy without anthracycline treatment. For the current case–control study more detailed information was collected on HF diagnosis and recovery, and the HF definition was stricter.…”

Section: Discussioncontrasting

confidence: 99%

“…For radiotherapy there is evidence that ischaemic heart disease risk increases linearly with increasing mean heart dose (MHD) . Evidence that it can increase HF risk is, however, conflicting . This may be due to differences in HF evaluation between the different studies, e.g.…”

Section: Introductionmentioning

confidence: 99%

“…For anthracyclines there is strong evidence that HF risk increases with increasing cumulative dose . It usually occurs some years after treatment . Trastuzumab also increases HF risk but, unlike anthracycline‐related HF, it usually occurs whilst patients are still receiving trastuzumab, and it mostly resolves once treatment is stopped …”

Section: Introductionmentioning

confidence: 99%

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Heart failure after treatment for breast cancer

Boekel

Duane

Jacobse

et al. 2019

European J of Heart Fail

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Background We aimed to develop dose–response relationships for heart failure (HF) following radiation and anthracyclines in breast cancer treatment, and to assess HF associations with trastuzumab and endocrine therapies. Methods and results A case–control study was performed within a cohort of breast cancer survivors treated during 1980–2009. Cases (n = 102) had HF as first cardiovascular diagnosis and were matched 1:3 on age and date of diagnosis. Individual cardiac radiation doses were estimated, and anthracycline doses and use of trastuzumab and endocrine therapy were abstracted from oncology notes. For HF cases who received radiotherapy, the estimated median mean heart dose (MHD) was 6.8 Gy [interquartile range (IQR) 0.9–13.7]. MHD was not associated with HF risk overall [excess rate ratio (ERR) = 1%/Gy, 95% confidence interval (CI) −2 to 10]. In patients treated with anthracyclines, exposure of ≥20% of the heart to ≥20 Gy was associated with a rate ratio of 5.7 (95% CI 1.7–21.7) compared to <10% exposed to ≥20 Gy. For cases who received radiotherapy, median cumulative anthracycline dose was 247 mg/m2 (IQR 240–319). A dose‐dependent increase was observed after anthracycline without trastuzumab (ERR = 1.5% per mg/m2, 95% CI 0.5–4.1). After anthracycline and trastuzumab, the rate ratio was 34.9 (95% CI 11.1–110.1) compared to no chemotherapy. Conclusions In absence of anthracyclines, breast cancer radiotherapy was not associated with increased HF risk. Strongly elevated HF risks were observed after treatment with anthracyclines and also after treatment with trastuzumab. The benefits of these systemic treatments usually exceed the risks of HF, but our results emphasize the need to support ongoing efforts to evaluate preventative strategies.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Heart failure after treatment for breast cancer

Boekel

Duane

Jacobse

et al. 2019

European J of Heart Fail

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“…Finally, our study was cross‐sectional and patients who developed cardiovascular disease prior to study invitation might have been over‐ or under‐represented. However, the study was embedded within established BC cohorts and for the NKI‐AVL cohort we have information on cardiovascular disease incidence and mortality, enabling us to explore selection bias. We found no evidence for patient selection by comparing cardiovascular disease incidence rates of responders and non‐responders, and since only seven patients died of cardiovascular disease before study initiation, we believe that survival bias is negligible.…”

Section: Discussionmentioning

confidence: 99%

“…We conducted a cross‐sectional study within two established hospital‐based cohorts of BC survivors for which we have previously collected information on cardiovascular disease incidence through general practitioners and cardiologists . Eligible women were treated for invasive BC (TNM stage I–III) or ductal carcinoma in situ (DCIS) at ages 40–50 years in the Netherlands Cancer Institute – Antoni van Leeuwenhoek (NKI‐AVL) or University Medical Center Groningen (UMCG), and were either 5–7 or 10–12 years after initial treatment.…”

Section: Methodsmentioning

confidence: 99%

Myocardial dysfunction in long‐term breast cancer survivors treated at ages 40–50 years

Jacobse

Steggink

Sonke

et al. 2019

European J of Heart Fail

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Aims Anthracyclines increase heart failure (HF) risk, but the long‐term prevalence of myocardial dysfunction in young breast cancer (BC) survivors is unknown. Early measures of left ventricular myocardial dysfunction are needed to identify BC patients at risk of symptomatic HF. Methods and results Within an established cohort, we studied markers for myocardial dysfunction among 569 women, who were 5–7 years (n = 277) or 10–12 years (n = 292) after BC treatment at ages 40–50 years. Left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) were assessed by echocardiography. N‐terminal pro‐brain natriuretic peptide (NT‐proBNP) was measured in serum. Associations between patient‐related and treatment‐related risk factors and myocardial dysfunction were evaluated using linear and logistic regression. Median ages at BC diagnosis and cardiac assessment were 46.7 and 55.5 years, respectively. Anthracycline‐treated patients (n = 313), compared to the no‐anthracycline group (n = 256), more often had decreased LVEF (10% vs. 4%), impaired GLS (34% vs. 27%) and elevated NT‐proBNP (23% vs. 8%). GLS and LVEF declined in a linear fashion with increasing cumulative anthracycline dose (GLS: +0.23 and LVEF: −0.40 per cycle of 60 mg/m2; P < 0.001) and GLS was worse for patients with left breast irradiation. The risk of NT‐proBNP >125 ng/L was highest for patients who received 241–300 mg/m2 anthracycline dose compared to the no‐anthracycline group (odds ratio: 3.30, 95% confidence interval: 1.83–5.96). Conclusion Impaired GLS and increased NT‐proBNP levels are present in a substantial proportion of young BC survivors treated with anthracyclines. Whether this will lead to future cardiac disease needs to be evaluated by longitudinal assessment.

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Identification of Risk of Cardiovascular Disease by Automatic Quantification of Coronary Artery Calcifications on Radiotherapy Planning CT Scans in Patients With Breast Cancer

et al. 2021

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IMPORTANCE Cardiovascular disease (CVD) is common in patients treated for breast cancer, especially in patients treated with systemic treatment and radiotherapy and in those with preexisting CVD risk factors. Coronary artery calcium (CAC), a strong independent CVD risk factor, can be automatically quantified on radiotherapy planning computed tomography (CT) scans and may help identify patients at increased CVD risk.OBJECTIVE To evaluate the association of CAC with CVD and coronary artery disease (CAD) in patients with breast cancer. DESIGN, SETTING, AND PARTICIPANTSIn this multicenter cohort study of 15 915 patients with breast cancer receiving radiotherapy between 2005 and 2016 who were followed until December 31, 2018, age, calendar year, and treatment-adjusted Cox proportional hazard models were used to evaluate the association of CAC with CVD and CAD.EXPOSURES Overall CAC scores were automatically extracted from planning CT scans using a deep learning algorithm. Patients were classified into Agatston risk categories (0, 1-10, 11-100, 101-399, >400 units). MAIN OUTCOMES AND MEASURESOccurrence of fatal and nonfatal CVD and CAD were obtained from national registries. RESULTSOf the 15 915 participants included in this study, the mean (SD) age at CT scan was 59.0 (11.2; range, 22-95) years, and 15 879 (99.8%) were women. Seventy percent (n = 11 179) had no CAC. Coronary artery calcium scores of 1 to 10, 11 to 100, 101 to 400, and greater than 400 were present in 10.0% (n = 1584), 11.5% (n = 1825), 5.2% (n = 830), and 3.1% (n = 497) respectively. After a median follow-up of 51.2 months, CVD risks increased from 5.2% in patients with no CAC to 28.2% in patients with CAC scores higher than 400. After adjustment, CVD risk increased with higher CAC score (hazard ratio [HR] CAC = 1-10 = 1.1; 95% CI, 0.9-1.4; HR CAC = 11-100 = 1.8; 95% CI, 1.5-2.1; HR CAC = 101-400 = 2.1; 95% CI, 1.7-2.6; and HR CAC>400 = 3.4; 95% CI, 2.8-4.2). Coronary artery calcium was particularly strongly associated with CAD (HR CAC>400 = 7.8; 95% CI, 5.5-11.2). The association between CAC and CVD was strongest in patients treated with anthracyclines (HR CAC>400 = 5.8; 95% CI, 3.0-11.4) and patients who received a radiation boost (HR CAC>400 = 6.1; 95% CI, 3.8-9.7).CONCLUSIONS AND RELEVANCE This cohort study found that coronary artery calcium on breast cancer radiotherapy planning CT scan results was associated with CVD, especially CAD. Automated CAC scoring on radiotherapy planning CT scans may be used as a fast and low-cost tool to identify patients with breast cancer at increased risk of CVD, allowing implementing CVD risk-mitigating strategies with the aim to reduce the risk of CVD burden after breast cancer.

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Cardiovascular disease incidence after internal mammary chain irradiation and anthracycline-based chemotherapy for breast cancer

Abstract: Women treated with anthracycline-based chemotherapy and IMC irradiation (in an older era) with considerable mean heart dose exposure have substantially increased incidence of several CVDs. Screening may be appropriate for some BC patient groups.

Cited by 61 publications

References 44 publications

Heart failure after treatment for breast cancer

Heart failure after treatment for breast cancer

Myocardial dysfunction in long‐term breast cancer survivors treated at ages 40–50 years

Identification of Risk of Cardiovascular Disease by Automatic Quantification of Coronary Artery Calcifications on Radiotherapy Planning CT Scans in Patients With Breast Cancer

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