Breast cancer after Hodgkin lymphoma: Influence of endogenous and exogenous gonadal hormones on the radiation dose-response relationship

Background. After chest radiotherapy (RT) for Hodgkin lymphoma (HL), women experience a dose-dependent increase of breast cancer risk. It is unknown whether endogenous and exogenous gonadal hormones affect the radiation dose-response relationship. Methods. We conducted a casecontrol study nested within a cohort of female 5-year HL survivors treated before age 41 years between 1965 and 2000. Detailed data on HL treatment, reproductive factors and hormone use were collected through medical records and questionnaires for 174 breast cancer cases and 466 matched HL controls who did not develop breast cancer. RT charts, simulation films and mammography reports were used to estimate the radiation dose to the location of the breast tumor (and similar location for matched controls). Results. The median interval between HL diagnosis and breast cancer diagnosis was 21.9 years. Ninety-eight percent of the cases received supradiaphragmatic RT and 3% pelvic RT (without successful oophoropexy) compared with 92% and 9% of the controls respectively. We observed a linear radiation dose-response relationship for risk of breast cancer with an adjusted excess odds ratio (EOR) of 5.4%/Gray (95%CI:1.8%-13.3%). Women who reached menopause before age 30 years (caused by high dose of procarbazine or pelvic RT) had a lower risk (OR 0.13; 95%CI:0.03-0.54) than women who reached menopause at age ≥50 years when adjusted for RT dose. Breast cancer risk increased by 7.4% for each additional year of intact ovarian function after RT (P