Inge M Krul1, Annemieke W J Opstal-van Winden1, Berthe M P Aleman2, Cécile P M Janus3, Anna M van Eggermond1, Marie L De Bruin4, Michael Hauptmann1, Augustinus D G Krol5, Michael Schaapveld1, Annegien Broeks6, Karen R Kooijman1, Sandra Fase1, Marnix L Lybeert7, Josée M Zijlstra8, Richard W M van der Maazen9, Ausrele Kesminiene10, Ibrahima Diallo11, Florent de Vathaire11, Nicola S Russell2, Flora E van Leeuwen12. 1. Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 2. Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 3. Department of Radiation Oncology, Erasmus University MC Cancer Institute, Rotterdam, The Netherlands. 4. Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Utrecht, The Netherlands and Copenhagen Centre for Regulatory Science, University of Copenhagen, Copenhagen, Denmark. 5. Department of Radiotherapy, Leiden University Medical Center, Leiden, The Netherlands. 6. Division of Molecular Pathology, Core Facility Molecular Pathology and Biobanking, The Netherlands Cancer Institute, Amsterdam, The Netherlands. 7. Department of Radiotherapy, Catharina Hospital, Eindhoven, The Netherlands. 8. Department of Hematology, VU University Medical Center, Amsterdam, The Netherlands. 9. Department of Radiation Oncology, Radboud University Medical Center, Nijmegen, The Netherlands. 10. Section of Environment and Radiation, International Agency for Research on Cancer, Lyon, France. 11. Cancer and Radiation Team, Centre for Research in Epidemiology and Population Health, Institut National de la Santé et de la Recherche Medicale Unit 1018, Villejuif, France. 12. Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, The Netherlands. Electronic address: f.v.leeuwen@nki.nl.
Abstract
BACKGROUND: Young women treated with chest radiation therapy (RT) for Hodgkin lymphoma (HL) experience a strongly increased risk of breast cancer (BC). It is unknown whether endogenous and exogenous gonadal hormones affect RT-associated BC risk. METHODS: We conducted a nested case-control study among female 5-year HL survivors treated before age 41. Hormone exposure and HL treatment data were collected through medical records and questionnaires for 174 BC case patients and 466 control patients. Radiation dose to breast tumor location was estimated based on RT charts, simulation films, and mammography reports. RESULTS: We observed a linear radiation dose-response curve with an adjusted excess odds ratio (EOR) of 6.1%/Gy (95% confidence interval [CI]: 2.1%-15.4%). Women with menopause <30 years (caused by high-dose procarbazine or pelvic RT) had a lower BC risk (OR, 0.13; 95% CI, 0.03-0.51) than did women with menopause ≥50 years. BC risk increased by 6.4% per additional year of post-RT intact ovarian function (P<.001). Among women with early menopause (<45 years), hormone replacement therapy (HRT) use for ≥2 years did not increase BC risk (OR, 0.86; 95% CI, 0.32-2.32), whereas this risk was nonsignificantly increased among women without early menopause (OR, 3.69; 95% CI, 0.97-14.0; P for interaction: .06). Stratification by duration of post-RT intact ovarian function or HRT use did not statistically significantly modify the radiation dose-response curve. CONCLUSIONS: BC risk in female HL survivors increases linearly with radiation dose. HRT does not appear to increase BC risk for HL survivors with therapy-induced early menopause. There are no indications that endogenous and exogenous gonadal hormones affect the radiation dose-response relationship.
BACKGROUND: Young women treated with chest radiation therapy (RT) for Hodgkin lymphoma (HL) experience a strongly increased risk of breast cancer (BC). It is unknown whether endogenous and exogenous gonadal hormones affect RT-associated BC risk. METHODS: We conducted a nested case-control study among female 5-year HL survivors treated before age 41. Hormone exposure and HL treatment data were collected through medical records and questionnaires for 174 BC case patients and 466 control patients. Radiation dose to breast tumor location was estimated based on RT charts, simulation films, and mammography reports. RESULTS: We observed a linear radiation dose-response curve with an adjusted excess odds ratio (EOR) of 6.1%/Gy (95% confidence interval [CI]: 2.1%-15.4%). Women with menopause <30 years (caused by high-dose procarbazine or pelvic RT) had a lower BC risk (OR, 0.13; 95% CI, 0.03-0.51) than did women with menopause ≥50 years. BC risk increased by 6.4% per additional year of post-RT intact ovarian function (P<.001). Among women with early menopause (<45 years), hormone replacement therapy (HRT) use for ≥2 years did not increase BC risk (OR, 0.86; 95% CI, 0.32-2.32), whereas this risk was nonsignificantly increased among women without early menopause (OR, 3.69; 95% CI, 0.97-14.0; P for interaction: .06). Stratification by duration of post-RT intact ovarian function or HRT use did not statistically significantly modify the radiation dose-response curve. CONCLUSIONS: BC risk in female HL survivors increases linearly with radiation dose. HRT does not appear to increase BC risk for HL survivors with therapy-induced early menopause. There are no indications that endogenous and exogenous gonadal hormones affect the radiation dose-response relationship.
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