Risk of heart disease following treatment for breast cancer – results from a population-based cohort study

Background: There is a rising concern about treatment-associated cardiotoxicities in breast cancer patients. This study aimed to determine the time- and treatment-specific incidence of arrhythmia, heart failure, and ischemic heart disease in women diagnosed with breast cancer. Methods: A register-based matched cohort study was conducted including 8015 breast cancer patients diagnosed from 2001 to 2008 in the Stockholm-Gotland region and followed up until 2017. Time-dependent risks of arrhythmia, heart failure, and ischemic heart disease in breast cancer patients were assessed using flexible parametric models as compared to matched controls from general population. Treatment-specific effects were estimated in breast cancer patients using Cox model. Results: Time-dependent analyses revealed long-term increased risks of arrhythmia and heart failure following breast cancer diagnosis. Hazard ratios (HRs) within the first year of diagnosis were 2.14 (95% CI = 1.63–2.81) for arrhythmia and 2.71 (95% CI = 1.70–4.33) for heart failure. HR more than 10 years following diagnosis was 1.42 (95% CI = 1.21–1.67) for arrhythmia and 1.28 (95% CI = 1.03–1.59) for heart failure. The risk for ischemic heart disease was significantly increased only during the first year after diagnosis (HR = 1.45, 95% CI = 1.03–2.04). Trastuzumab and anthracyclines were associated with increased risk of heart failure. Aromatase inhibitors, but not tamoxifen, were associated with risk of ischemic heart disease. No increased risk of heart disease was identified following locoregional radiotherapy. Conclusions: Administration of systemic adjuvant therapies appears to be associated with increased risks of heart disease. The risk estimates observed in this study may aid adjuvant therapy decision-making and patient counseling in oncology practices. Funding: This work was supported by the Swedish Research Council (grant no: 2018-02547); Swedish Cancer Society (grant no: CAN-19-0266); and FORTE (grant no: 2016-00081).

[1]  J. Johnston.  Aromatase inhibitors. , 2020, Critical reviews in biochemistry and molecular biology.

[2]  S. Thangaratinam,et al.  Association between the reproductive health of young women and cardiovascular disease in later life: umbrella review , 2020, BMJ.

[3]  W. Han,et al.  Effect of standard low-dose anthracycline chemotherapy on late congestive heart failure in breast cancer survivors aged between 50 and 59 at diagnosis: A nationwide study , 2020, Breast.

[4]  V. Ferrans,et al.  Cardiac Toxicity , 2020, Target Organ Toxicity.

[5]  S. Suissa,et al.  Aromatase Inhibitors and the Risk of Cardiovascular Outcomes in Women With Breast Cancer , 2020, Circulation.

[6]  L. Holmberg,et al.  Long-term risk of ischemic heart disease after adjuvant radiotherapy in breast cancer: results from a large population-based cohort , 2020, Breast Cancer Research.

[7]  M. Sarfaty,et al.  Deescalating Adjuvant Trastuzumab in HER2-Positive Early-Stage Breast Cancer: A Systemic Review and Meta-Analysis , 2019, JNCI cancer spectrum.

[8]  K. Sandelin,et al.  Validation of data quality in the Swedish National Register for Breast Cancer , 2019, BMC Public Health.

[9]  Bingshu E. Chen,et al.  Increasing the dose intensity of chemotherapy by more frequent administration or sequential scheduling: a patient-level meta-analysis of 37 298 women with early breast cancer in 26 randomised trials , 2019, The Lancet.

[10]  H. Kamel,et al.  Arterial thromboembolic events preceding the diagnosis of cancer in older persons. , 2019, Blood.

[11]  K. Bhaskaran,et al.  Long term adjuvant endocrine therapy and risk of cardiovascular disease in female breast cancer survivors: systematic review , 2018, British medical journal.

[12]  L. Holmberg,et al.  Risk of ischemic heart disease after radiotherapy for ductal carcinoma in situ , 2018, Breast Cancer Research and Treatment.

[13]  H. Kamel,et al.  Risk of Arterial Thromboembolism in Patients With Cancer. , 2017, Journal of the American College of Cardiology.

[14]  David Cameron,et al.  11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: final analysis of the HERceptin Adjuvant (HERA) trial , 2017, The Lancet.

[15]  J. Bergh,et al.  Estimating the Risks of Breast Cancer Radiotherapy: Evidence From Modern Radiation Doses to the Lungs and Heart and From Previous Randomized Trials. , 2017, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[16]  N. Rottmann,et al.  Cardiovascular co-morbidity in cancer patients: the role of psychological distress , 2016, Cardio-Oncology.

[17]  Michael Gnant,et al.  Effect of Tailored Dose-Dense Chemotherapy vs Standard 3-Weekly Adjuvant Chemotherapy on Recurrence-Free Survival Among Women With High-Risk Early Breast Cancer: A Randomized Clinical Trial. , 2016, JAMA.

[18]  P. Austin,et al.  The risk of myocardial infarction with aromatase inhibitors relative to tamoxifen in post-menopausal women with early stage breast cancer. , 2016, European journal of cancer.

[19]  P. Austin,et al.  BREAST CANCER THERAPY-RELATED CARDIAC DYSFUNCTION IN ADULT WOMEN TREATED IN ROUTINE CLINICAL PRACTICE A POPULATION BASED COHORT STUDY , 2016 .

[20]  P. Austin,et al.  Breast Cancer Therapy-Related Cardiac Dysfunction in Adult Women Treated in Routine Clinical Practice: A Population-Based Cohort Study. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[21]  Jingmei Li,et al.  Associations of Breast Cancer Risk Prediction Tools With Tumor Characteristics and Metastasis. , 2016, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[22]  C. Taylor,et al.  Cardiac Side-effects From Breast Cancer Radiotherapy. , 2015, Clinics in oncology.

[23]  J. Forbes,et al.  Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials , 2015, The Lancet.

[24]  E. Rutgers,et al.  Cardiovascular Morbidity and Mortality After Treatment for Ductal Carcinoma In Situ of the Breast , 2014, Journal of the National Cancer Institute.

[25]  G. Hortobagyi,et al.  Trastuzumab-related cardiotoxicity among older patients with breast cancer. , 2013, Journal of Clinical Oncology.

[26]  P. Hall,et al.  Risk of ischemic heart disease in women after radiotherapy for breast cancer. , 2013, The New England journal of medicine.

[27]  P. Malmström,et al.  Effects of adjuvant tamoxifen therapy on cardiac disease: results from a randomized trial with long-term follow-up , 2013, Breast Cancer Research and Treatment.

[28]  Michel G Khouri,et al.  Contemporary Reviews in Cardiovascular Medicine Cancer Therapy – Induced Cardiac Toxicity in Early Breast Cancer Addressing the Unresolved Issues , 2012 .

[29]  Heather Eliassen,et al.  Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies , 2012, The Lancet. Oncology.

[30]  L. Allen,et al.  Risk of Heart Failure in Breast Cancer Patients After Anthracycline and Trastuzumab Treatment: A Retrospective Cohort Study , 2012, Journal of the National Cancer Institute.

[31]  Mats Lambe,et al.  Adherence and discontinuation of adjuvant hormonal therapy in breast cancer patients: a population-based study , 2012, Breast Cancer Research and Treatment.

[32]  K. Czene,et al.  Prognosis of patients with breast cancer: causes of death and effects of time since diagnosis, age, and tumor characteristics. , 2011, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  J. Ludvigsson,et al.  External review and validation of the Swedish national inpatient register , 2011, BMC public health.

[34]  Juxiang Chen,et al.  Risk of cardiac dysfunction with trastuzumab in breast cancer patients: a meta-analysis. , 2011, Cancer treatment reviews.

[35]  Xianglin L. Du,et al.  Cardiac toxicity associated with anthracycline‐containing chemotherapy in older women with breast cancer , 2009, Cancer.

[36]  E. Yeh,et al.  Cardiovascular complications of cancer therapy: incidence, pathogenesis, diagnosis, and management. , 2009, Journal of the American College of Cardiology.

[37]  S. Swain,et al.  Cardiac Toxicity in Breast Cancer Survivors: Review of Potential Cardiac Problems , 2008, Clinical Cancer Research.

[38]  Chao-Po Lin,et al.  Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. , 2007, Cancer research.

[39]  J. Goodwin,et al.  Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[40]  H. Bartelink,et al.  Long-term risk of cardiovascular disease in 10-year survivors of breast cancer. , 2007, Journal of the National Cancer Institute.

[41]  Wei-Ting Hwang,et al.  Late cardiac mortality and morbidity in early-stage breast cancer patients after breast-conservation treatment. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[42]  A. Neugut,et al.  Chemotherapy and cardiotoxicity in older breast cancer patients: a population-based study. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  R. Hajjar,et al.  Inhibition of ErbB2 causes mitochondrial dysfunction in cardiomyocytes: implications for herceptin-induced cardiomyopathy. , 2004, Journal of the American College of Cardiology.

[44]  M Rosén,et al.  A national record linkage to study acute myocardial infarction incidence and case fatality in Sweden. , 2001, International journal of epidemiology.

[45]  C. Earle,et al.  The Temporal Risk of Heart Failure Associated With Adjuvant Trastuzumab in Breast Cancer Patients: A Population Study. , 2016, Journal of the National Cancer Institute.

[46]  N. M. González Senac.  [Suicide and cardiovascular death after a cancer diagnosis]. , 2012, Revista clinica espanola.

[47]  Per Hall,et al.  Cardiac doses from Swedish breast cancer radiotherapy since the 1950s. , 2009, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[48]  C. Mackenzie,et al.  A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. , 1987, Journal of chronic diseases.

[49]  O. Beahrs.  The American Joint Committee on Cancer. , 1984, Bulletin of the American College of Surgeons.