title: Long-term risk of cardiovascular disease in 10-year survivors of breast cancer.
abstract: BACKGROUND
  Radiotherapy for breast cancer as delivered in the 1970s has been associated with increased risk of cardiovascular disease, but recent studies of associations with modern regimens have been inconclusive. Few data on long-term cardiovascular disease risk according to specific radiation fields are available, and interaction with known cardiovascular risk factors has not been examined.
  
  
  METHODS
  We studied treatment-specific incidence of cardiovascular disease in 4414 10-year survivors of breast cancer who were treated from 1970 through 1986. Risk of cardiovascular disease in these patients was compared with general population rates and evaluated in Cox proportional hazards regression models. All statistical tests were two-sided.
  
  
  RESULTS
  After a median follow-up of 18 years, 942 cardiovascular events were observed (standardized incidence ratio = 1.30, 95% confidence interval [CI] = 1.22 to 1.38; corresponding to 62.9 excess cases per 10,000 patient-years). Breast irradiation only was not associated with increased risk of cardiovascular disease. However, radiotherapy to either the left or right side of the internal mammary chain was associated with increased cardiovascular disease risk for the treatment period 1970-1979 (for myocardial infarction, hazard ratio [HR] = 2.55, 95% CI = 1.55 to 4.19; P<.001; for congestive heart failure, HR = 1.72, 95% CI = 1.22 to 2.41; P = .002) compared with no radiotherapy. Among patients who received internal mammary chain radiotherapy after 1979, risk of myocardial infarction declined over time toward unity, whereas the risks of congestive heart failure (HR = 2.66, 95% CI = 1.27 to 5.61; P = .01) and valvular dysfunction (HR = 3.17, 95% CI = 1.90 to 5.29; P<.001) remained increased. Patients who underwent radiotherapy plus adjuvant chemotherapy (cyclophosphamide, methotrexate, and fluorouracil) after 1979 had a higher risk of congestive heart failure than patients who were treated with radiotherapy only (HR = 1.85, 95% CI = 1.25 to 2.73; P = .002). Smoking and radiotherapy together were associated with a more than additive effect on risk of myocardial infarction (HR = 3.04, 95% CI = 2.03 to 4.55; P for departure from additivity = .039).
  
  
  CONCLUSIONS
  Radiotherapy as administered from the 1980s onward is associated with an increased risk of cardiovascular disease. Irradiated breast cancer patients should be advised to refrain from smoking to reduce their risk for cardiovascular disease.
authors.affiliation: Department of Epidemiology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.
authors.forename: Maartje J
authors.initials: MJ
authors.lastname: Hooning
authors.forename: Akke
authors.initials: A
authors.lastname: Botma
authors.forename: Berthe M P
authors.initials: BM
authors.lastname: Aleman
authors.forename: Margreet H A
authors.initials: MH
authors.lastname: Baaijens
authors.forename: Harry
authors.initials: H
authors.lastname: Bartelink
authors.forename: Jan G M
authors.initials: JG
authors.lastname: Klijn
authors.forename: Carolyn W
authors.initials: CW
authors.lastname: Taylor
authors.forename: Flora E
authors.initials: FE
authors.lastname: van Leeuwen
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy*; D017024:Chemotherapy, Adjuvant / Q000009:adverse effects; D005260:Female; D005500:Follow-Up Studies; D006331:Heart Diseases / Q000453:epidemiology* / Q000209:etiology*; D006333:Heart Failure / Q000453:epidemiology / Q000209:etiology; D006349:Heart Valve Diseases / Q000453:epidemiology / Q000209:etiology; D006801:Humans; D015994:Incidence; D008875:Middle Aged; D009203:Myocardial Infarction / Q000453:epidemiology / Q000209:etiology; D009426:Netherlands / Q000453:epidemiology; D016016:Proportional Hazards Models; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects; D012107:Research Design; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects; D017741:Survivors / Q000706:statistics & numerical data*; D013997:Time Factors