Outline. 1 RBE of Low Energy Radiations 2 WECARE -- Genetic Interaction 3 Second Cancers 4 Million Radiation Worker Study

Transcription

1 Outline 1 RBE of Low Energy Radiations 2 WECARE -- Genetic Interaction 3 Second Cancers 4 Million Radiation Worker Study John Boice, Vanderbilt University, NCRP November 17, 2014 National Academy of Sciences Nuclear and Radiations Studies Board

2 1 BIOLOGICAL EFFECTIVENESS OF LOW ENERGY RADIATIONS Steve Simon, Chairman REB, NCI Dudley Goodhead SC 1-20 is evaluating the risk of cancer from exposure to photons and beta particles that addresses dependence of relative biological effectiveness (RBE) on energy Coming Soon Simon et al. Biological effectiveness of photons and electrons as a function of energy. H Phys (in press)

3 Progress : RBE at Low Energies Epidemiology: Does not provide definitive evidence Challenge: To combine diverse threads of evidence: microdosimetry, DNA damage, radiobiology of cells and animals, and epidemiology. Approach: Assess biological effectiveness as subjective probability density functions (PDFs) for selected discrete energies. COMBINING EVIDENCE FROM RESEARCH THREADS STAY TUNED MUCH MORE TO COME Slide composite from Steve Simon, NCI 2014 SLIDES and PODCAST AVAILABLE courtesy of Colorado State University on NCRP Website and at: enters/maperc/training/trainingprograms/pages/ncrp-meeting.aspx

4 2 Genes and Radiation: Does Genetic Predisposition Matter in Radiation- Induced Breast Cancer? CRH Symposium 60 th Annual Meeting of the Radiation Research Society September 23, 2014 Las Vegas Jonine L. Bernstein, PhD Daniel Stram PhD John Boice Jr, ScD Roy Shore, PhD, ScD Abstract Available at Slide courtesy of Jonine Bernstein The Women's Environment Cancer and Radiation Epidemiology (WECARE) Study

5 Genetic Susceptibility Second Breast Cancer Genes Radiation Exposure RR 95% CI BRCA1 mutation BRCA2 mutation Gy (age <40 y) Gy (age >45 y) Bernstein J et al. BRCA1_Eur J Ca 2013 Bernstein J et al. ATM_JNCI 102, 2010 Concannon et al. Cancer Res 68, 2008 Stovall, IJROBP 72, 2008 Begg et al, JAMA Genes Predispose to Breast Cancer BRAC1/2, PALB2 2 Radiation Risk When Exposures Occur Early, < 40 y 3 Some Women may be Particularly Sensitive by Virtue of their Genetic Backdrop

6 Slide template courtesy of Dr. William Gerald Courtesy of Lois Travis, Roswell Park Medical Center If Rembrandt were alive Today The Genomics Anatomy Lesson Methods have focused on candidate genes, pathways and across the genome.

7 Courtesy of Jonine Bernstein Manhattan Plot for Interaction with Dose, WECARE I and II, iselect, All Races, Adjusted for Confounders

8 Courtesy of Jonine Bernstein, MSKCC Genomic Risk Score (GRS) = the Sum of 14 Known GWAS Hits (SNPs) that Replicated in WECARE Risk of 2 nd Breast Cancer by Quartiles of the GRS Quartile Cases Controls OR LCL UCL Q Ref Q2 vs Q Q3 vs Q Q4 vs Q

9 Summary: GWAS Analysis of Interaction Effects with Radiation Dose A Genomic Risk Score (GRS) predicted the development of second breast cancer. Radiation-induced 2 nd breast cancer may be influenced by genetic factors (both rare and common variants), and exposure at a young age. STAY TUNED MUCH MORE TO COME Risk was highest in the highest dose category among women who carried the most risky alleles.

10 Travis et al. Health Phys 106:220, 2014

11 Chapters NCRP Report No Introduction 3. Radiobiology and Cancer Biology 4. Epidemiologic Methods 5. Modern Radiation Therapy Conformal, IMRT, Protons, C-14, Neutrons 6. Dosimetry Relevant to 2 nd Cancers 7. Genetic Susceptibility 8. 2 nd Cancer Risks 9. 2 nd Cancer Dose Response 10. Cardiovascular Disease 11. Recommendations Protons

12 Childhood Cancer Survivor Study and WECARE Study Cumulative Breast Cancer Risk Cumulative Risk By age 50 HL: 35% SEER: 4% BRCA1: 31% Hodgkin lymphoma (HL) Chest XRT BRCA1 Carrier* Other childhood cancer Chest XRT.1 SEER Benchmark Age, years * Population-based estimate Courtesy of Greg Armstrong, St Jude Moskowitz et al, J Clin Oncol, 2014

13 Genome-Wide Association Study of Subsequent Neoplasms Among Childhood Cancer Survivors CHILDHOOD CANCER SURVIVOR STUDY (CCSS) and NATIONAL CANCER INSTITUTE Research Hypothesis: Inherited genetic variation may alter the biological response of normal cells to DNA damage and immunosuppression from ionizing radiation and/or chemotherapeutic agents and thereby alter cancer susceptibility. CRH Symposium Radiation Research Society, September 2014 Genotyping was conducted for 5324 childhood cancer survivors using the lllumina Human0mni5Exome microarray, with over 4.1 million loci. STAY TUNED MUCH MORE TO COME

14 One Million U.S. Radiation Workers and Veterans 4 Robert Oppenheimer, General Leslie Groves, Enrico Fermi, Hans Bethe, Theodore Hall Manhattan Project 360,000 Atomic Veterans 115,000 Nuclear Utility Workers 150,000 Industrial Radiographers 130,000 Medical & other >250,000 OAK (HARDTACK I), Enewetak, 8.9 MT, 28 Jun 1958 Bouville et al. Dose Reconstruction for the Million-Worker Epidemiologic Study. H Phys (in press)

15 Studying One Million U.S. Radiation Workers and Veterans Why? We know much about the effects of radiation when received all at once (instantaneously), but the gap in knowledge is when it s received over years (protracted).

16 Manhattan Project and other Workers (Selected U.S. Nuclear Facilities) Atomics International / Rocketdyne (1948) Mound Laboratory (1947) Mallinckrodt (1942) Los Alamos National Laboratory (1942) Hanford Reservation (1943) Savannah River Site (1950) Oak Ridge Reservation K-25, X-10 and Y-12 (1942) Sandia National Laboratories (1945) Rocky Flats Environmental Technology Site (1951) Paducah Gaseous Diffusion Plant (1953) Fernald Environmental Management Project (1953) 16

17 Rocketdyne Updated Mortality Analysis Larger combined studies of early workers in the United States using similar methodologies are warranted to refine and clarify radiation risks after protracted exposures.

18 Mound (Polonium)

19 Combined Heart Analyses (Mound + Rocketdyne) 45K cases of heart disease in these few studies compared with 14K among A- Bomb Survivors (Shimizu BMJ 2009) mgy STAY TUNED MUCH MORE TO COME Zhang J, Stram DO, Cohen SS, Pawel D, Sesso H, Boice J. Radiation Research Society Annual Meeting September 2014

20 SC 6-9: U.S. Radiation Workers and Nuclear Weapons Test Participants Radiation Dose Assessment A Bouville Chairman R Toohey Co-Chairman H Beck T Brock L Dauer K Eckerman D Hagemeyer R Leggett B Napier K Pryor M Rosenstein J Thompson D Schauer S Sherbini D Miller D Stram J Till C Yoder C Zeitlin

21 Study of Atomic Veterans The Eight Series Study

22 Male Breast Cancer Among Atomic Veterans 1 Preliminary Dose (mgy) Total Breast cancer cases Cohort 16,177 58,456 18,822 10,248 10, ,270 Relative risk % confidence interval Adjusted for test site, rank (enlisted/officer), year of birth, and year of first participation at a weapons test and sampling fraction. The subcohort is an ~1% random sample of all participants in the Eight Series Study. Use a 10 y dose lag. 2 Referent category.

23 Testes Cancer Among Atomic Veterans 1 Preliminary Dose (mgy) Total Breast cancer cases Cohort 59,023 18,261 17,322 10,575 9, ,270 Relative risk % confidence interval Adjusted for test site, rank (enlisted/officer), year of birth, and year of first participation at a weapons test and sampling fraction. The subcohort is an ~1% random sample of all participants in the Eight Series Study. Use a 10 y dose lag. 2 Referent category.

24 Leukemia (Other Than CLL) Among Atomic Veterans 1 - Preliminary Dose (mgy) Total Leukemia cases Full cohort 58,888 19,045 17,067 11,310 7, ,270 Relative risk % confidence interval Adjusted for test site, service, rank (enlisted/officer), year of birth, and year of first participation at a weapons test and sampling fraction. 2 y dose lag. 2 Referent category.

25 Myelodysplastic Syndrome Among Atomic Veterans 1 Preliminary Dose (mgy) Total Breast cancer cases Full cohort 58,793 19,031 17,068 11,327 8, ,270 Relative risk % confidence interval Adjusted for test site, rank (enlisted/officer), year of birth, and year of first participation at a weapons test and sampling fraction. Use a 10 y dose lag. 2 Referent category.

26 Ischemic Heart Disease Among Atomic Veterans 1 Preliminary Dose (mgy) Total IHD cases 9,072 2,672 2,390 1,561 1, ,786 Full cohort 59,676 18,472 16,781 11,148 7, ,270 Relative risk % confidence interval Adjusted for test site, rank (enlisted/officer), year of birth, and year of first participation at a weapons test and sampling fraction. Use a 10 y dose lag. 2 Referent category. STAY TUNED MUCH MORE TO COME

27 Nuclear Power Plant Workers U.S. Early Nuclear Utility Workers 150,000 Hired Before 1985 Large numbers Good dosimetry At the time allowable doses could be up to 30 msv per quarter considering 50 x (Age 18) msv Some cumulative doses were as high as 1000 msv Hall EJ et al. DOE Workshop. Rad Res 2009

28 Laying the groundwork for a Registry of Radiation Workers Vincent T. DeVita, Jr., M.D.

29 1991 NRC - Radiation Exposure Information and Reporting System (REIRS) Designed with health studies in mind Slide, courtesy of Terry Brock, modified 29

30 316 Leukemias; 40 >100 mgy. A-Bomb 312 total; 129 >100 mgy. STAY TUNED MUCH MORE TO COME

31 Comparison with Atomic Bomb Survivor Study External Dose (msv) Million Worker Study Total to Date Atomic Bomb Survivor Study (Ozasa 2012) < 5 msv 6,507,275 38, ,652 29, ,211 5, ,456 6, ,120 3, ,007 1,763 > 2000 msv TOTAL 7,553,932* 86,611 > 100 msv 83,005 18,141 STAY TUNED VERY MUCH MORE TO COME *3000 rolls of microfilm to come 4x more High Dose Subjects As of Oct 2013

32 Sponsors A National Effort 32

33 Comment on Timing for BEIR VIII