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 case-control 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<0.001). Among women with an early menopause (<45 years), the use of hormone replacement therapy (HRT) for ≥2 years did not increase breast cancer risk (OR 0.81, 95%CI:0.30-2.21), while this risk was non-significantly increased among women who became menopausal at ages ≥45 years (OR 1.91, 95%CI:0.70-5.20). Moreover, endogenous and exogenous hormones did not statistically significantly modify the slope of the linear radiation dose-response relationship.
Conclusion Among female survivors of HL treated with chest RT, a therapy-induced premature menopause reduces their radiation-associated breast cancer risk. However, hormone replacement therapy use did not appear to increase breast cancer risk in these women. There was no evidence for interaction between RT dose and number of years with intact ovarian function or HRT use.