Originally published as JCO Early Release 10.1200/JCO.2008.20.7738 on July 20 2009

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Radiation Dose and Breast Cancer Risk in the Childhood Cancer Survivor Study

From the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN; Department of Radiation Physics, The University of Texas M. D. Anderson Cancer Center, Houston, TX; Department of Pathology, Nationwide Children's Hospital, Ohio State University School of Medicine, Columbus, OH; Department of Pediatrics, Emory University, Atlanta, GA; Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA; Department of Pediatric Oncology, Dana-Farber Cancer Institute; Department of Medicine, Children's Hospital, Boston, MA; Department of Radiation Oncology, Stanford University Medical Center, Stanford, CA; Department of Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, PA; and Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN.

Corresponding author: Peter D. Inskip, ScD, Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, 6120 Executive Blvd, Rm 7052, Bethesda, MD 20892-7238; e-mail: inskippe{at}mail.nih.gov.

Purpose The purpose of this study was to quantify the risk of breast cancer in relation to radiation dose and chemotherapy among survivors of childhood cancer.

Methods We conducted a case-control study of breast cancer in a cohort of 6,647 women who were 5-year survivors of childhood cancer and who were treated during 1970 through 1986. One hundred twenty patients with histologically confirmed breast cancer were identified and were individually matched to four selected controls on age at initial cancer and time since initial cancer. Medical physicists estimated radiation dose to the breast tumor site and ovaries on the basis of medical records.

Results The odds ratio for breast cancer increased linearly with radiation dose, and it reached 11-fold for local breast doses of approximately 40 Gy relative to no radiation (P for trend < .0001). Risk associated with breast irradiation was sharply reduced among women who received 5 Gy or more to the ovaries (P = .002). The excess odds ratio per Gy was 0.36 for those who received ovarian doses less than 5 Gy and was 0.06 for those who received higher doses. Radiation-related risk did not vary significantly by age at exposure. Borderline significantly elevated risks were seen for doxorubicin, dactinomycin, dacarbazine, and carmustine.

Conclusion Results confirm the radiation sensitivity of the breast in girls age 10 to 20 years but do not demonstrate a strong effect of age at exposure within this range. Irradiation of the ovaries at doses greater than 5 Gy seems to lessen the carcinogenic effects of breast irradiation, most likely by reducing exposure of radiation-damaged breast cells to stimulating effects of ovarian hormones.

The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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