title: Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin's disease.
abstract: BACKGROUND
  Female survivors of Hodgkin's disease (HD) have a strongly elevated risk of breast cancer, but factors responsible for the increased risk are not well known.
  
  
  METHODS
  We investigated the effects of radiation dose, chemotherapy (CT), and reproductive factors on breast cancer risk in a nested case-control study in The Netherlands in a cohort of 770 female patients who had been diagnosed with HD before age 41. Detailed treatment information and data on reproductive factors were collected for 48 case patients who developed breast cancer 5 or more years after diagnosis of HD and 175 matched control subjects. The radiation dose was estimated to the area of the breast where the case patient's tumor had developed and to a comparable location in matched control subjects. Relative risks (RRs) of breast cancer were calculated by conditional logistic regression. Statistical tests were two-sided.
  
  
  RESULTS
  The risk of breast cancer increased statistically significantly with radiation dose (P(trend) =.01); patients who received 38.5 Gy or more had an RR of 4.5 (95% confidence interval [CI] = 1.3 to 16) times that of patients who received less than 4 Gy. Patients who received both CT and radiotherapy (RT) had a statistically significantly lower risk than those treated with RT alone (RR = 0.45, 95% CI = 0.22 to 0.91). Breast cancer risk increased with increasing radiation dose among patients who received RT only (RR = 12.7, 95% CI = 1.8 to 86, for patients receiving > or =38.5 Gy) but not among patients treated with CT and RT. Sixty-nine percent of control subjects treated with RT and more than six cycles of CT, but only 9% of those who received RT alone, reached menopause before age 41. Reaching menopause before age 36 was associated with a strongly reduced risk of breast cancer (RR = 0.06, 95% CI = 0.01 to 0.45).
  
  
  CONCLUSIONS
  Breast cancer risk increases with increasing radiation dose up to at least 40 Gy. The substantial risk reduction associated with CT may reflect its effect on menopausal age, suggesting that ovarian hormones promote tumorigenesis after radiation has produced an initiating event.
authors.affiliation: Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, The Netherlands. f.v.leeuwen@nki.nl
authors.forename: Flora E
authors.initials: FE
authors.lastname: van Leeuwen
authors.forename: Willem J
authors.initials: WJ
authors.lastname: Klokman
authors.forename: Marilyn
authors.initials: M
authors.lastname: Stovall
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Dahler
authors.forename: Mars B
authors.initials: MB
authors.lastname: van't Veer
authors.forename: Evert M
authors.initials: EM
authors.lastname: Noordijk
authors.forename: Mariad A
authors.initials: MA
authors.lastname: Crommelin
authors.forename: Berthe M P
authors.initials: BM
authors.lastname: Aleman
authors.forename: Annegien
authors.initials: A
authors.lastname: Broeks
authors.forename: Mary
authors.initials: M
authors.lastname: Gospodarowicz
authors.forename: Lois B
authors.initials: LB
authors.lastname: Travis
authors.forename: Nicola S
authors.initials: NS
authors.lastname: Russell
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000009:adverse effects*; D001943:Breast Neoplasms / Q000209:etiology* / Q000378:metabolism; D016022:Case-Control Studies; D017024:Chemotherapy, Adjuvant; D016001:Confidence Intervals; D004307:Dose-Response Relationship, Radiation; D005260:Female; D006689:Hodgkin Disease / Q000188:drug therapy* / Q000378:metabolism / Q000532:radiotherapy*; D006728:Hormones / Q000378:metabolism*; D006801:Humans; D008875:Middle Aged; D016609:Neoplasms, Second Primary / Q000209:etiology* / Q000378:metabolism; D016017:Odds Ratio; D011879:Radiotherapy Dosage; D018714:Radiotherapy, Adjuvant / Q000009:adverse effects; D012306:Risk
chemical_list: D006728:Hormones