Bioavailable serum estradiol may alter radiation risk of postmenopausal breast cancer: a nested case-control study

Abstract Purpose: Ionizing radiation and high levels of circulating estradiol are known breast cancer carcinogens. We investigated the risk of first primary postmenopausal breast cancer in relation to the combined effects of whole-body ionizing radiation exposure and prediagnostic levels of postmenopausal sex hormones, particularly bioavailable estradiol (bE2). Materials and methods: A nested case-control study of 57 incident breast cancer cases matched with 110 controls among atomic bomb survivors. Joint effects of breast radiation dose and circulating levels of sex hormones were assessed using binary regression and path analysis. Results and conclusion: Radiation exposure, higher levels of bE2, testosterone and progesterone, and established reproductive risk factors were positively associated with postmenopausal breast cancer risk. A test for mediation of the effect of radiation via bE2 level suggested a small (14%) but significant mediation (p = 0.004). The estimated interaction between radiation and bE2 was large but not significant (interaction = 3.86; p = 0.32). There is accumulating evidence that ionizing radiation not only damages DNA but also alters other organ systems. While caution is needed, some portion of the radiation risk of postmenopausal breast cancer appeared to be mediated through bE2 levels, which may be evidence for cancer risks due to both direct and indirect effects of radiation.

[1]  Bryan Langholz,et al.  Case–Control Study, Nested † , 2014 .

[2]  Jennifer D. Brooks,et al.  Reproductive status at first diagnosis influences risk of radiation-induced second primary contralateral breast cancer in the WECARE study. , 2012, International journal of radiation oncology, biology, physics.

[3]  Stijn Vansteelandt,et al.  A simple unified approach for estimating natural direct and indirect effects. , 2012, American journal of epidemiology.

[4]  Yukiko Shimizu,et al.  Studies of the Mortality of Atomic Bomb Survivors.Report 12, Part I. Cancer: 1950–1990 , 2012, Radiation research.

[5]  Yukiko Shimizu,et al.  Studies of the Mortality of Atomic Bomb Survivors, Report 14, 1950–2003: An Overview of Cancer and Noncancer Diseases , 2012, Radiation research.

[6]  J. Russo,et al.  Pregnancy-Induced Changes in Breast Cancer Risk , 2011, Journal of Mammary Gland Biology and Neoplasia.

[7]  Theis Lange,et al.  Direct and Indirect Effects in a Survival Context , 2011, Epidemiology.

[8]  C. Land,et al.  Associations of Ionizing Radiation and Breast Cancer-Related Serum Hormone and Growth Factor Levels in Cancer-Free Female A-Bomb Survivors , 2011, Radiation research.

[9]  Stijn Vansteelandt,et al.  Odds ratios for mediation analysis for a dichotomous outcome. , 2010, American journal of epidemiology.

[10]  D. Preston,et al.  How Much Can We Say about Site-Specific Cancer Radiation Risks? , 2010, Radiation research.

[11]  H. Sugiyama,et al.  Timing of Menarche and First Birth in Relation to Risk of Breast Cancer in A-Bomb Survivors , 2010, Cancer Epidemiology, Biomarkers & Prevention.

[12]  H. Sugiyama,et al.  Radiation exposure and circulatory disease risk: Hiroshima and Nagasaki atomic bomb survivor data, 1950-2003 , 2010, BMJ : British Medical Journal.

[13]  J. Pearl.  Causal inference in statistics: An overview , 2009 .

[14]  E. Levin,et al.  Estrogen inhibits ATR signaling to cell cycle checkpoints and DNA repair. , 2009, Molecular biology of the cell.

[15]  Sharon Schwartz,et al.  Opening the Black Box: a motivation for the assessment of mediation. , 2009, International journal of epidemiology.

[16]  D. Preston,et al.  Breast cancer incidence following low-dose rate environmental exposure: Techa River Cohort, 1956–2004 , 2008, British Journal of Cancer.

[17]  Dale L Preston,et al.  Solid cancer incidence in atomic bomb survivors exposed in utero or as young children. , 2008, Journal of the National Cancer Institute.

[18]  Marilyn Stovall,et al.  Multiple Diagnostic X-rays for Spine Deformities and Risk of Breast Cancer , 2008, Cancer Epidemiology Biomarkers & Prevention.

[19]  D. L. Preston,et al.  Solid Cancer Incidence in Atomic Bomb Survivors: 1958–1998 , 2007, Radiation research.

[20]  L. Curtin,et al.  Limitations of follicle-stimulating hormone in assessing menopause status: findings from the National Health and Nutrition Examination Survey (NHANES 1999-2000)* , 2006, Menopause.

[21]  M. Stovall,et al.  Breast cancer risk following radiotherapy for Hodgkin lymphoma: modification by other risk factors. , 2005, Blood.

[22]  B. Grosche,et al.  Radiation Exposure due to Local Fallout from Soviet Atmospheric Nuclear Weapons Testing in Kazakhstan: Solid Cancer Mortality in the Semipalatinsk Historical Cohort, 1960–1999 , 2005, Radiation research.

[23]  F. Clavel-Chapelon,et al.  C-peptide, IGF-I, sex-steroid hormones and adiposity: a cross-sectional study in healthy women within the European Prospective Investigation into Cancer and Nutrition (EPIC) , 2005, Cancer Causes & Control.

[24]  Jose Russo,et al.  The protective role of pregnancy in breast cancer , 2005, Breast Cancer Research.

[25]  Siva Sivaganesan,et al.  Statistical assessment of mediational effects for logistic mediational models , 2004, Statistics in medicine.

[26]  J. Cologne,et al.  Uncertainty in estimating probability of causation in a cross-sectional study: joint effects of radiation and hepatitis-C virus on chronic liver disease , 2004, Journal of radiological protection : official journal of the Society for Radiological Protection.

[27]  C. Land,et al.  Improving the efficiency of nested case-control studies of interaction by selecting controls using counter matching on exposure. , 2004, International journal of epidemiology.

[28]  M. Akahoshi,et al.  Noncancer Disease Incidence in Atomic Bomb Survivors, 1958–1998 , 2004, Radiation research.

[29]  A. Hida,et al.  Effects of radiation on fatty liver and metabolic coronary risk factors among atomic bomb survivors in Nagasaki. , 2003, Hypertension research : official journal of the Japanese Society of Hypertension.

[30]  M. Hauptmann,et al.  Cancer incidence in the U.S. radiologic technologists health study, 1983–1998 , 2003 .

[31]  J. Dixon,et al.  Breast cancer risk among the survivors of atomic bomb and patients exposed to therapeutic ionising radiation. , 2003, European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology.

[32]  M. Hauptmann,et al.  Cancer incidence in the US radiologic technologists health study, 1983-1998. , 2002, Cancer.

[33]  A. Mattsson,et al.  Excess breast cancer risk and the role of parity, age at first childbirth and exposure to radiation in infancy , 2001, British Journal of Cancer.

[34]  C. Land,et al.  A prospective study of estradiol and breast cancer in Japanese women. , 2000, Cancer Epidemiology, Biomarkers and Prevention.

[35]  K. Kodama,et al.  Effects of radiation on the longitudinal trends of total serum cholesterol levels in the atomic bomb survivors. , 1999, Radiation research.

[36]  P. Good.  Resampling Methods , 1999, Birkhäuser Boston.

[37]  G R Howe,et al.  Breast cancer mortality between 1950 and 1987 after exposure to fractionated moderate-dose-rate ionizing radiation in the Canadian fluoroscopy cohort study and a comparison with breast cancer mortality in the atomic bomb survivors study. , 1995, Radiation research.

[38]  Bryan Langholz,et al.  Counter-matching: A stratified nested case-control sampling method , 1995 .

[39]  C. Land,et al.  Incidence of female breast cancer among atomic bomb survivors, 1950-1985. , 1994, Radiation research.

[40]  M. Pike,et al.  A case-control interview study of breast cancer among Japanese A-bomb survivors. I. Main effects , 1994, Cancer Causes & Control.

[41]  M. Pike,et al.  A case-control interview study of breast cancer among Japanese A-bomb survivors. II. Interactions with radiation dose , 1994, Cancer Causes & Control.

[42]  D. Preston,et al.  Cancer incidence in atomic bomb survivors. Part IV: Comparison of cancer incidence and mortality. , 1994, Radiation research.

[43]  D. Preston,et al.  Cancer incidence in atomic bomb survivors. Part II: Solid tumors, 1958-1987. , 1994, Radiation research.

[44]  D. Preston,et al.  Cancer incidence in atomic bomb survivors. Part I: Use of the tumor registries in Hiroshima and Nagasaki for incidence studies. , 1994, Radiation research.

[45]  D. Preston,et al.  Frequent chest X-ray fluoroscopy and breast cancer incidence among tuberculosis patients in Massachusetts. , 1991, Radiation research.

[46]  D. Pierce,et al.  Allowing for random errors in radiation dose estimates for the atomic bomb survivor data. , 1990, Radiation research.

[47]  C. Land,et al.  Incidence of female breast cancer among atomic bomb survivors, Hiroshima and Nagasaki, 1950-1990. , 1987, Radiation research.

[48]  S Greenland,et al.  Tests for interaction in epidemiologic studies: a review and a study of power. , 1983, Statistics in medicine.

[49]  W. S. Maxfield,et al.  The synergism between radiation and estrogen in the production of mammary cancer in the rat. , 1971, Cancer research.

[50]  K. Kodama,et al.  DS02R1: Improvements to Atomic Bomb Survivors’ Input Data and Implementation of Dosimetry System 2002 (DS02) and Resulting Changes in Estimated Doses , 2017, Health physics.

[51]  R Core Team,et al.  R: A language and environment for statistical computing. , 2014 .

[52]  K. Nakachi,et al.  Long-term effects of radiation dose on inflammatory markers in atomic bomb survivors. , 2005, The American journal of medicine.

[53]  George D. Kerr,et al.  Reassessment of the atomic bomb radiation dosimetry for Hiroshima and Nagasaki : dosimetry system 2002 : report of the joint US-Japan working group , 2005 .

[54]  J. J. Broerse,et al.  Effects of X-irradiation, ovariohysterectomy and estradiol-17 beta on incidence, benign/malignant ratio and multiplicity of rat mammary neoplasms--a preliminary report. , 1986, Leukemia research.