Publications by authors named "Amy Berrington de Gonzalez"

159 Publications

Risk of contralateral breast cancer according to first breast cancer characteristics among women in the USA, 1992-2016.

Breast Cancer Res 2021 Feb 17;23(1):24. Epub 2021 Feb 17.

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

Background: Estimates of contralateral breast cancer (CBC) risk in the modern treatment era by year of diagnosis and characteristics of the first breast cancer are needed to assess the impact of recent advances in breast cancer treatment and inform clinical decision making.

Methods: We examined CBC risk among 419,818 women (age 30-84 years) who were diagnosed with a first unilateral invasive breast cancer and survived ≥ 1 year in the US Surveillance, Epidemiology, and End Results program cancer registries from 1992 to 2015 (follow-up through 2016). CBC was defined as a second invasive breast cancer in the contralateral breast ≥ 12 months after the first breast cancer. We estimated standardized incidence ratios (SIRs) of CBC by year of diagnosis, age at diagnosis, and tumor characteristics for the first breast cancer. Cumulative incidence of CBC was calculated for women diagnosed with a first breast cancer in the recent treatment era (2004-2015, follow-up through 2016).

Results: Over a median follow-up of 8 years (range 1-25 years), 12,986 breast cancer patients developed CBC. Overall, breast cancer patients had approximately twice the risk of developing cancer in the contralateral breast when compared to that expected in the general population (SIR = 2.21, 95% CI = 2.17-2.25). SIRs for CBC declined by year of first diagnosis, irrespective of age at diagnosis and estrogen receptor (ER) status (p-trends < 0.001), but the strongest decline was after an ER-positive tumor. The 5-year cumulative incidence of CBC ranged from 1.01% (95% CI = 0.90-1.14%) in younger women (age < 50 years) with a first ER-positive tumor to 1.89% (95% CI = 1.61-2.21%) in younger women with a first ER-negative tumor.

Conclusion: Declines in CBC risk are consistent with continued advances in breast cancer treatment. The updated estimates of cumulative incidence inform breast cancer patients and clinicians on the risk of CBC and may help guide treatment decisions.
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http://dx.doi.org/10.1186/s13058-021-01400-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890613PMC
February 2021

Impact of Population Growth and Aging on Estimates of Excess U.S. Deaths During the COVID-19 Pandemic, March to August 2020.

Ann Intern Med 2020 12 15. Epub 2020 Dec 15.

National Cancer Institute, Rockville, Maryland (M.S.S., J.S.A., M.G., P.S.A., N.D.F., A.B.D.).

Background: Excess death estimates quantify the full impact of the coronavirus disease 2019 (COVID-19) pandemic. Widely reported U.S. excess death estimates have not accounted for recent population changes, especially increases in the population older than 65 years.

Objective: To estimate excess deaths in the United States in 2020, after accounting for population changes.

Design: Surveillance study.

Setting: United States, March to August 2020.

Participants: All decedents.

Measurements: Age-specific excess deaths in the United States from 1 March to 31 August 2020 compared with 2015 to 2019 were estimated, after changes in population size and age were taken into account, by using Centers for Disease Control and Prevention provisional death data and U.S. Census Bureau population estimates. Cause-specific excess deaths were estimated by month and age.

Results: From March through August 2020, 1 671 400 deaths were registered in the United States, including 173 300 COVID-19 deaths. An average of 1 370 000 deaths were reported over the same months during 2015 to 2019, for a crude excess of 301 400 deaths (128 100 non-COVID-19 deaths). However, the 2020 U.S. population includes 5.04 million more persons aged 65 years and older than the average population in 2015 to 2019 (a 10% increase). After population changes were taken into account, an estimated 217 900 excess deaths occurred from March through August 2020 (173 300 COVID-19 and 44 600 non-COVID-19 deaths). Most excess non-COVID-19 deaths occurred in April, July, and August, and 34 900 (78%) were in persons aged 25 to 64 years. Diabetes, Alzheimer disease, and heart disease caused the most non-COVID-19 excess deaths.

Limitation: Provisional death data are underestimated because of reporting delays.

Conclusion: The COVID-19 pandemic resulted in an estimated 218 000 excess deaths in the United States between March and August 2020, and 80% of those deaths had COVID-19 as the underlying cause. Accounting for population changes substantially reduced the excess non-COVID-19 death estimates, providing important information for guiding future clinical and public health interventions.

Primary Funding Source: National Cancer Institute.
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http://dx.doi.org/10.7326/M20-7385DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901655PMC
December 2020

Ct Dosimetry for The Australian Cohort Data Linkage Study.

Radiat Prot Dosimetry 2020 Nov 17. Epub 2020 Nov 17.

Melbourne School of Population and Global Health, The University of Melbourne, Parkville, Victoria, Australia.

Children undergoing computed tomography (CT) scans have an increased risk of cancer in subsequent years, but it is unclear how much of the excess risk is due to reverse causation bias or confounding, rather than to causal effects of ionising radiation. An examination of the relationship between excess cancer risk and organ dose can help to resolve these uncertainties. Accordingly, we have estimated doses to 33 different organs arising from over 900 000 CT scans between 1985 and 2005 in our previously described cohort of almost 12 million Australians aged 0-19 years. We used a multi-tiered approach, starting with Medicare billing details for government-funded scans. We reconstructed technical parameters from national surveys, clinical protocols, regulator databases and peer-reviewed literature to estimate almost 28 000 000 individual organ doses. Doses were age-dependent and tended to decrease over time due to technological improvements and optimisation.
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http://dx.doi.org/10.1093/rpd/ncaa175DOI Listing
November 2020

Subsequent Neoplasm Risk Associated With Rare Variants in DNA Damage Response and Clinical Radiation Sensitivity Syndrome Genes in the Childhood Cancer Survivor Study.

JCO Precis Oncol 2020 21;4. Epub 2020 Aug 21.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Purpose: Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown.

Patients And Methods: We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based values using a Bonferroni-corrected significance threshold of < 8.06 × 10.

Results: Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; = 4.79 × 10), most notably but nonsignificantly for (patient cases, 4.0%; matched controls, 0.6%; = 9.64 × 10). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with variants (patient cases, 1.8%; controls, 0.4%; = 3.31 × 10), another gene implicated in DNA double-strand break repair.

Conclusion: In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches.
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http://dx.doi.org/10.1200/PO.20.00141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469586PMC
August 2020

Subsequent Neoplasm Risk Associated With Rare Variants in DNA Damage Response and Clinical Radiation Sensitivity Syndrome Genes in the Childhood Cancer Survivor Study.

JCO Precis Oncol 2020 21;4. Epub 2020 Aug 21.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD.

Purpose: Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown.

Patients And Methods: We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based values using a Bonferroni-corrected significance threshold of < 8.06 × 10.

Results: Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; = 4.79 × 10), most notably but nonsignificantly for (patient cases, 4.0%; matched controls, 0.6%; = 9.64 × 10). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with variants (patient cases, 1.8%; controls, 0.4%; = 3.31 × 10), another gene implicated in DNA double-strand break repair.

Conclusion: In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches.
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http://dx.doi.org/10.1200/PO.20.00141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469586PMC
August 2020

Racial and ethnic differences in risk of second primary cancers among prostate cancer survivors.

Cancer Causes Control 2020 Nov 24;31(11):1011-1019. Epub 2020 Aug 24.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Purpose: Previous studies have shown an overall decreased risk of second cancers among prostate cancer survivors, but this has not been comprehensively examined by race/ethnicity. We conducted a retrospective cohort study of 716,319 one-year survivors of prostate cancer diagnosed at ages 35-84 during 2000-2015 as reported to 17 US Surveillance, Epidemiology and End Results (SEER) registries.

Methods: We estimated standardized incidence ratios (SIRs) for second primary non-prostate malignancies by race/ethnicity (non-Latino white, Black, Asian/Pacific Islander [API] and Latino), by Gleason, and by time since prostate cancer diagnosis. Poisson regression models were used to test heterogeneity between groups with the expected number as the offset.

Results: 60,707 second primary malignancies were observed. SIRs for all second cancers combined varied significantly by race/ethnicity: SIR: 0.88 (95% confidence interval: 0.87-0.89), SIR: 0.92 (0.89-0.95), SIR: 0.97 (0.95-0.99), and SIR: 1.05 (1.01-1.09) (p-heterogeneity < 0.001). SIRs for all cancers combined were higher among survivors of higher vs. lower Gleason prostate cancers irrespective of race/ethnicity. We observed significant heterogeneity by race/ethnicity in SIRs for 9 of 14 second cancer types investigated including lung, bladder, kidney, and liver.

Conclusions: Our results confirm that most prostate cancer survivors have lower risks of second cancers than expected, but the magnitude varied by race/ethnicity. Exceptionally, API men had small but significantly increased risk. Further research to understand drivers of the observed race/ethnicity heterogeneity is warranted.
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http://dx.doi.org/10.1007/s10552-020-01336-7DOI Listing
November 2020

Association of Radioactive Iodine, Antithyroid Drug, and Surgical Treatments With Solid Cancer Mortality in Patients With Hyperthyroidism.

JAMA Netw Open 2020 07 1;3(7):e209660. Epub 2020 Jul 1.

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Importance: The long-term health effects of radioactive iodine (RAI) and antithyroid drug (ATD) treatments compared with surgery for hyperthyroidism remain uncertain.

Objective: To compare solid cancer mortality rates associated with RAI and ATD treatments vs surgical management for hyperthyroidism.

Design, Setting, And Participants: This multicenter cohort study assessed patients treated for hyperthyroidism from January 1, 1946, to December 31, 1964, with follow-up through December 31, 2014. Data analysis was performed from August 1, 2019, to April 23, 2020.

Exposures: Management with RAI, ATDs, surgical intervention, or combinations of these treatments.

Main Outcomes And Measures: Comparisons of solid cancer mortality rates in each treatment group with expected rates from the general population were assessed using standardized mortality ratios (SMRs), and internal comparisons were assessed using hazard ratios (HRs) adjusted for age, sex, and underlying diagnosis (Graves disease or toxic nodular goiter).

Results: Of 31 363 patients (24 894 [79.4%] female; mean [SD] age, 46.9 [14.8] years) included in the study, 28 523 (90.9%) had Graves disease. The median follow-up time was 26.0 years (interquartile range, 12.3-41.9 years). Important differences in patient characteristics existed across treatment groups at study entry. Notably, the drug-only group (3.6% of the cohort) included a higher proportion of patients with prior cancers (7.3% vs 1.9%-4.0%), contributing to an elevated SMR for solid cancer mortality. After excluding prior cancers, solid cancer SMRs were not elevated in any of the treatment groups (SMR for surgery only, 0.82 [95% CI, 0.66-1.00]; SMR for drugs only, 0.90 [95% CI, 0.74-1.09]; SMR for drugs and surgery, 0.88 [95% CI, 0.84-0.94]; SMR for RAI only, 0.90 [95% CI, 0.84-0.96]; SMR for surgery and RAI, 0.66 [95% CI, 0.52-0.85]; SMR for drugs and RAI, 0.94 [95% CI, 0.89-1.00]; and SMR for drugs, surgery, and RAI, 0.85 [95% CI, 0.75-0.96]), and no significant HRs for solid cancer death were observed across treatment groups. Among RAI-treated patients, HRs for solid cancer mortality increased significantly across levels of total administered activity (1.08 per 370 MBq; 95% CI, 1.03-1.13 per 370 MBq); this association was stronger among patients treated with only RAI (HR, 1.19 per 370 MBq; 95% CI, 1.09-1.30 per 370 MBq).

Conclusions And Relevance: After controlling for known sources of confounding, the study found no significant differences in the risk of solid cancer mortality by treatment group. However, among RAI-treated patients, a modest positive association was observed between total administered activity and solid cancer mortality, providing further evidence in support of a dose-dependent association between RAI and solid cancer mortality.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.9660DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378755PMC
July 2020

Dose-volume effects of breast cancer radiation therapy on the risk of second oesophageal cancer.

Radiother Oncol 2020 Oct 15;151:33-39. Epub 2020 Jul 15.

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, United States.

Purpose: To investigate the relationship between oesophagus dose-volume distribution and long-term risk of oesophageal cancer after radiation therapy for breast cancer.

Materials And Methods: In a case-control study nested within a cohort of 289,748 ≥5-year survivors of female breast cancer treated in 1943-2003 in five countries, doses to the second primary cancer (D) and individual dose-volume histograms (DVH) to the entire oesophagus were reconstructed for 252 oesophageal cancer cases and 488 matched controls (median follow-up time: 13, range: 5-37 years). Using conditional logistic regression, we estimated excess odds ratios (EOR) of oesophageal cancer associated with DVH metrics. We also investigated whether DVH metrics confounded or modified D-related -risk estimates.

Results: Among the DVH metrics evaluated, median dose (D) to the entire oesophagus had the best statistical performance for estimating risk of all histological types combined (EOR/Gy = 0.071, 95% confidence interval [CI]: 0.018 to 0.206). For squamous cell carcinoma, the most common subtype, the EOR/Gy for D increased by 31% (95% CI: 3% to 205%) for each increment of 10% of V30 (p = 0.02). Adjusting for DVH metrics did not materially change the EOR/Gy for D, but there was a borderline significant positive interaction between D and V30 (p = 0.07).

Conclusion: This first study investigating the relationship between oesophagus dose-volume distribution and oesophageal cancer risk showed an increased risk per Gy for D with larger volumes irradiated at high doses. While current techniques allows better oesophagus sparing, constraints applied to D and V30 could potentially further reduce the risk of oesophageal cancer.
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http://dx.doi.org/10.1016/j.radonc.2020.07.022DOI Listing
October 2020

Outcome Assessment in Epidemiological Studies of Low-Dose Radiation Exposure and Cancer Risks: Sources, Level of Ascertainment, and Misclassification.

J Natl Cancer Inst Monogr 2020 07;2020(56):154-175

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, MD.

Background: Outcome assessment problems and errors that could lead to biased risk estimates in low-dose radiation epidemiological studies of cancer risks have not been systematically evaluated.

Methods: Incidence or mortality risks for all cancers or all solid cancers combined and for leukemia were examined in 26 studies published in 2006-2017 involving low-dose (mean dose ≤100 mGy) radiation from environmental, medical, or occupational sources. We evaluated the impact of loss to follow-up, under- or overascertainment, outcome misclassification, and changing classifications occurring similarly or differentially across radiation dose levels.

Results: Loss to follow-up was not reported in 62% of studies, but when reported it was generally small. Only one study critically evaluated the completeness of the sources of vital status. Underascertainment of cancers ("false negatives") was a potential shortcoming for cohorts that could not be linked with high-quality population-based registries, particularly during early years of exposure in five studies, in two lacking complete residential history, and in one with substantial emigration. False positives may have occurred as a result of cancer ascertainment from self- or next-of-kin report in three studies or from enhanced medical surveillance of exposed patients that could lead to detection bias (eg, reporting precancer lesions as physician-diagnosed cancer) in one study. Most pediatric but few adult leukemia studies used expert hematopathology review or current classifications. Only a few studies recoded solid cancers to the latest International Classification of Diseases or International Classification of Diseases for Oncology codes. These outcome assessment shortcomings were generally nondifferential in relation to radiation exposure level except possibly in four studies.

Conclusion: The majority of studies lacked information to enable comprehensive evaluation of all major sources of outcome assessment errors, although reported data suggested that the outcome assessment limitations generally had little effect on risk or biased estimates towards the null except possibly in four studies.
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http://dx.doi.org/10.1093/jncimonographs/lgaa007DOI Listing
July 2020

Evaluation of Confounding and Selection Bias in Epidemiological Studies of Populations Exposed to Low-Dose, High-Energy Photon Radiation.

J Natl Cancer Inst Monogr 2020 07;2020(56):133-153

Department of Epidemiology, University of North Carolina, School of Public Health, Chapel Hill, NC, USA.

Background: Low-dose, penetrating photon radiation exposure is ubiquitous, yet our understanding of cancer risk at low doses and dose rates derives mainly from high-dose studies. Although a large number of low-dose cancer studies have been recently published, concern exists about the potential for confounding to distort findings. The aim of this study was to describe and assess the likely impact of confounding and selection bias within the context of a systematic review.

Methods: We summarized confounding control methods for 26 studies published from 2006 to 2017 by exposure setting (environmental, medical, or occupational) and identified confounders of potential concern. We used information from these and related studies to assess evidence for confounding and selection bias. For factors in which direct or indirect evidence of confounding was lacking for certain studies, we used a theoretical adjustment to determine whether uncontrolled confounding was likely to have affected the results.

Results: For medical studies of childhood cancers, confounding by indication (CBI) was the main concern. Lifestyle-related factors were of primary concern for environmental and medical studies of adult cancers and for occupational studies. For occupational studies, other workplace exposures and healthy worker survivor bias were additionally of interest. For most of these factors, however, review of the direct and indirect evidence suggested that confounding was minimal. One study showed evidence of selection bias, and three occupational studies did not adjust for lifestyle or healthy worker survivor bias correlates. Theoretical adjustment for three factors (smoking and asbestos in occupational studies and CBI in childhood cancer studies) demonstrated that these were unlikely to explain positive study findings due to the rarity of exposure (eg, CBI) or the relatively weak association with the outcome (eg, smoking or asbestos and all cancers).

Conclusion: Confounding and selection bias are unlikely to explain the findings from most low-dose radiation epidemiology studies.
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http://dx.doi.org/10.1093/jncimonographs/lgaa008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355263PMC
July 2020

Epidemiological Studies of Low-Dose Ionizing Radiation and Cancer: Rationale and Framework for the Monograph and Overview of Eligible Studies.

J Natl Cancer Inst Monogr 2020 07;2020(56):97-113

International Agency for Research on Cancer, Lyon, France.

Whether low-dose ionizing radiation can cause cancer is a critical and long-debated question in radiation protection. Since the Biological Effects of Ionizing Radiation report by the National Academies in 2006, new publications from large, well-powered epidemiological studies of low doses have reported positive dose-response relationships. It has been suggested, however, that biases could explain these findings. We conducted a systematic review of epidemiological studies with mean doses less than 100 mGy published 2006-2017. We required individualized doses and dose-response estimates with confidence intervals. We identified 26 eligible studies (eight environmental, four medical, and 14 occupational), including 91 000 solid cancers and 13 000 leukemias. Mean doses ranged from 0.1 to 82 mGy. The excess relative risk at 100 mGy was positive for 16 of 22 solid cancer studies and 17 of 20 leukemia studies. The aim of this monograph was to systematically review the potential biases in these studies (including dose uncertainty, confounding, and outcome misclassification) and to assess whether the subset of minimally biased studies provides evidence for cancer risks from low-dose radiation. Here, we describe the framework for the systematic bias review and provide an overview of the eligible studies.
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http://dx.doi.org/10.1093/jncimonographs/lgaa009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610154PMC
July 2020

Epidemiological Studies of Low-Dose Ionizing Radiation and Cancer: Summary Bias Assessment and Meta-Analysis.

J Natl Cancer Inst Monogr 2020 07;2020(56):188-200

Background: Ionizing radiation is an established carcinogen, but risks from low-dose exposures are controversial. Since the Biological Effects of Ionizing Radiation VII review of the epidemiological data in 2006, many subsequent publications have reported excess cancer risks from low-dose exposures. Our aim was to systematically review these studies to assess the magnitude of the risk and whether the positive findings could be explained by biases.

Methods: Eligible studies had mean cumulative doses of less than 100 mGy, individualized dose estimates, risk estimates, and confidence intervals (CI) for the dose-response and were published in 2006-2017. We summarized the evidence for bias (dose error, confounding, outcome ascertainment) and its likely direction for each study. We tested whether the median excess relative risk (ERR) per unit dose equals zero and assessed the impact of excluding positive studies with potential bias away from the null. We performed a meta-analysis to quantify the ERR and assess consistency across studies for all solid cancers and leukemia.

Results: Of the 26 eligible studies, 8 concerned environmental, 4 medical, and 14 occupational exposure. For solid cancers, 16 of 22 studies reported positive ERRs per unit dose, and we rejected the hypothesis that the median ERR equals zero (P = .03). After exclusion of 4 positive studies with potential positive bias, 12 of 18 studies reported positive ERRs per unit dose (P  = .12). For leukemia, 17 of 20 studies were positive, and we rejected the hypothesis that the median ERR per unit dose equals zero (P  = .001), also after exclusion of 5 positive studies with potential positive bias (P  = .02). For adulthood exposure, the meta-ERR at 100 mGy was 0.029 (95% CI = 0.011 to 0.047) for solid cancers and 0.16 (95% CI = 0.07 to 0.25) for leukemia. For childhood exposure, the meta-ERR at 100 mGy for leukemia was 2.84 (95% CI = 0.37 to 5.32); there were only two eligible studies of all solid cancers.

Conclusions: Our systematic assessments in this monograph showed that these new epidemiological studies are characterized by several limitations, but only a few positive studies were potentially biased away from the null. After exclusion of these studies, the majority of studies still reported positive risk estimates. We therefore conclude that these new epidemiological studies directly support excess cancer risks from low-dose ionizing radiation. Furthermore, the magnitude of the cancer risks from these low-dose radiation exposures was statistically compatible with the radiation dose-related cancer risks of the atomic bomb survivors.
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http://dx.doi.org/10.1093/jncimonographs/lgaa010DOI Listing
July 2020

Field Study of the Possible Effect of Parental Irradiation on the Germline of Children Born to Cleanup Workers and Evacuees of the Chornobyl Nuclear Accident.

Am J Epidemiol 2020 12;189(12):1451-1460

Although transgenerational effects of exposure to ionizing radiation have long been a concern, human research to date has been confined to studies of disease phenotypes in groups exposed to high doses and high dose rates, such as the Japanese atomic bomb survivors. Transgenerational effects of parental irradiation can be addressed using powerful new genomic technologies. In collaboration with the Ukrainian National Research Center for Radiation Medicine, the US National Cancer Institute, in 2014-2018, initiated a genomic alterations study among children born in selected regions of Ukraine to cleanup workers and/or evacuees exposed to low-dose-rate radiation after the 1986 Chornobyl (Chernobyl) nuclear accident. To investigate whether parental radiation exposure is associated with germline mutations and genomic alterations in the offspring, we are collecting biospecimens from father-mother-offspring constellations to study de novo mutations, minisatellite mutations, copy-number changes, structural variants, genomic insertions and deletions, methylation profiles, and telomere length. Genomic alterations are being examined in relation to parental gonadal dose, reconstructed using questionnaire and measurement data. Subjects are being recruited in exposure categories that will allow examination of parental origin, duration, and timing of exposure in relation to conception. Here we describe the study methodology and recruitment results and provide descriptive information on the first 150 families (mother-father-child(ren)) enrolled.
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http://dx.doi.org/10.1093/aje/kwaa095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822640PMC
December 2020

Risk of Second Primary Bone and Soft-Tissue Sarcomas Among Young Adulthood Cancer Survivors.

JNCI Cancer Spectr 2019 Sep 20;3(3):pkz043. Epub 2019 Jun 20.

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.

Excess sarcoma risks after childhood cancer are well established, but risks among young adulthood cancer survivors are poorly understood. Using US population-based cancer registry data, we compared bone and soft-tissue sarcoma risk vs the general population among 186 351 individuals who were diagnosed with nonsarcoma first primary malignancies at ages 20-39 years from 1975 to 2014 (follow-up through 2015) and survived at least 1 year. Bone sarcomas were rare (n = 50), but risk was statistically significantly elevated overall (2.9-fold) and greater than fivefold after Hodgkin lymphoma, non-Hodgkin lymphoma, and central nervous system tumors. Soft-tissue sarcomas were more common (n = 284) and risks were statistically significantly elevated approximately twofold overall and after melanoma and carcinomas of the breast, thyroid, and testis, and greater than fourfold after Hodgkin lymphoma and central nervous system tumors. Risks varied markedly by subtype, with the highest risks (greater than fourfold) for osteosarcoma and the soft-tissue subtypes of rhabdomyosarcoma and blood vessel and nerve sheath sarcomas. These data demonstrate elevated risk for sarcoma after a range of young adulthood cancers.
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http://dx.doi.org/10.1093/jncics/pkz043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049991PMC
September 2019

Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project.

J Hepatol 2020 Oct 11;73(4):863-872. Epub 2020 May 11.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.

Background & Aims: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear.

Methods: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study.

Results: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only.

Conclusion: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography.

Lay Summary: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.
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http://dx.doi.org/10.1016/j.jhep.2020.04.046DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901003PMC
October 2020

Trends in Alcohol-Induced Deaths in the United States, 2000-2016.

JAMA Netw Open 2020 02 5;3(2):e1921451. Epub 2020 Feb 5.

Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.

Importance: Notable increases in mortality from alcohol-induced causes over the past 2 decades in the United States have been reported. However, comprehensive assessments of trends in alcohol-induced mortality by sex, age, race/ethnicity, and social and geographic factors are lacking.

Objective: To examine trends in alcohol-induced mortality rates from 2000 to 2016, comparing results by demographic characteristics including sex, race/ethnicity, age, county-level socioeconomic status, and geographic location.

Design, Setting, And Participants: This serial cross-sectional study used US national vital statistics data for years 2000 to 2016 for all US residents older than 15 years. Data analysis was conducted from January to September 2019.

Exposures: Trends in alcohol-induced mortality by sex, race/ethnicity, age, county-level socioeconomic status (ie, median income, percentage of unemployed residents, percentage of residents with a bachelor's degree), rurality level, and US state.

Main Outcomes And Measures: Alcohol-induced mortality, ie, deaths for which alcohol holds a population-attributable fraction of 1. Deaths were expressed per 100 000 residents as absolute and age-standardized rates. Mortality trends were measured as average annual percentage changes (AAPCs) for the entire period (ie, 2000-2016) and annual percentage changes (APCs) for individual periods of change within the study period.

Results: A total of 425 045 alcohol-induced deaths were identified from 2000 to 2016 (2000: 19 627 deaths; 14 979 [76.3%] men; 2016: 34 857 deaths; 25 213 [73.3%] men). The rate of alcohol-induced deaths increased substantially among men (AAPC, 1.4%; 95% CI, 1.0% to 1.8%) and women (AAPC, 3.1%; 95% CI, 2.6% to 3.6%) and accelerated recently (men, 2012-2016: APC, 4.2%; 95% CI, 3.1% to 5.3%; women, 2013-2016: APC, 7.1%; 95% CI, 5.1% to 9.1%). The largest increases by race/ethnicity were observed among American Indian and Alaska Native men (AAPC, 3.3%; 95% CI, 2.6% to 4.0%), American Indian and Alaska Native women (AAPC, 4.2%; 95% CI, 3.8% to 4.6%), and white women (AAPC, 4.1%; 95% CI, 3.6% to 4.7%). Despite initial declines among black women, black men, and Latino men (eg, Latino men, 2000-2003: APC, -5.1%; 95% CI, -9.8% to -0.1%; 2003-2013: APC, -0.6%; 95% CI, -1.4% to 0.2%), increases occurred later in the study period (eg, Latino men, 2013-2016: APC, 4.1%; 95% CI, 0.3% to 8.1%). The rates of increase varied by age group and in turn by racial/ethnic group. Among white individuals, large absolute increases occurred in midlife (eg, men aged 55-59 years, 2000-2003: 25.5 deaths per 100 000 residents; 2013-2016: 43.3 deaths per 100 000 residents; women aged 50-54 years, 2000-2003: 7.4 deaths per 100 000 residents; 2013-2016: 16.5 deaths per 100 000 residents), although APCs were also large for ages 25 to 34 years, ranging from 4.6% to 6.9% per year among men and from 7.3% to 12.0% among women. Among American Indian and Alaska Native individuals, increases throughout the age range were observed, with the largest absolute increase occurring for ages 45 to 49 years among men (2000-2013: 113.6 deaths per 100 000 residents; 2013-2016: 193.1 deaths per 100 000 residents) and for ages 50 to 54 among women (2000-2013: from 56.1 deaths per 100 000 residents; 2013-2016: 105.1 deaths per 100 000 residents).

Conclusions And Relevance: This study found large increases in alcohol-induced death rates across age and racial/ethnic subgroups of the US population, which have accelerated over recent years. Large increases in alcohol-induced deaths among younger age groups may be associated with future increases in alcohol-related disease.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.21451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7043198PMC
February 2020

Trends in Premature Deaths Among Adults in the United States and Latin America.

JAMA Netw Open 2020 02 5;3(2):e1921085. Epub 2020 Feb 5.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland.

Importance: Premature death rates vary in the United States by race/ethnicity. Despite their socioeconomic disadvantages, US Latino populations have lower premature mortality rates than do US white populations, a phenomenon termed the "Latino or Hispanic paradox."

Objective: To investigate whether there is a broader Latin American paradox by comparing premature mortality rates in the United States according to race/ethnicity with rates in Latin America and Puerto Rico from 2001 to 2015.

Design, Setting, And Participants: This descriptive cross-sectional study used mortality data from the World Health Organization Mortality Database. All deaths occurring in individuals aged 20 to 64 years among US Latino, African American, white, and Puerto Rican and 12 other Latin American populations from January 2001 to December 2015 were selected. The data analysis began in October 2018.

Exposures: Age, sex, race/ethnicity, and country.

Main Outcomes And Measures: All-cause mortality, cause-specific mortality, age-standardized mortality rates (AMSRs), and average annual percentage change in mortality rates during 2001 to 2015.

Results: During 2001 to 2015, 22 million deaths (8 million women and 14 million men) occurred among individuals aged 20 to 64 years in the selected populations. Among women, US Latina individuals had the lowest premature mortality rates (ASMR for 2015, 144 deaths per 100 000 population) and US African American women had the highest premature mortality rate (ASMR for 2015, 340 deaths per 100 000 population) of the 16 populations studied. Rates among US white women shifted from the sixth lowest in 2001 (ASMR, 231 deaths per 100 000 population) to the 12th lowest in 2015 (ASMR, 235 deaths per 100 000 population). Among men, Peru had the lowest premature mortality rates (ASMR for 2015, 219 deaths per 100 000 population), and Belize had the highest premature mortality rates (ASMR for 2015, 702 deaths per 100 000 population). White men in the United States shifted from the fifth lowest rates in 2001 (ASMR, 396 deaths per 100 000 population) to the eighth lowest rates in 2015 (ASMR, 394 deaths per 100 000 population). Rates for both women and men decreased in all the populations studied from 2001 to 2015 (average annual percentage change range, 0.4% to 3.8% per year) except among US white populations, for which the rate plateaued (average annual percentage change, 0.02% per year [95% CI, -0.3% to 0.2% per year] for women; -0.2% per year [95% CI, -0.4% to 0.0% per year] for men) and among Nicaraguan men, for whom the rates increased (0.6% per year [95% CI, 0.2% to 1.0% per year]). The populations with the lowest mortality rates in 2015 had lower rates from all major causes, but rates were particularly lower for heart disease (21 deaths per 100 000 population) and cancer (50 deaths per 100 000 population).

Conclusions And Relevance: Premature mortality rates are lower for US Latino populations and several Latin American countries than for US white populations, suggesting that there may be a broader Latin American paradox. This analysis also highlights the high premature mortality rates among US African American populations, especially women, compared with many Latin American populations.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.21085DOI Listing
February 2020

Risk of second primary papillary thyroid cancer among adult cancer survivors in the United States, 2000-2015.

Cancer Epidemiol 2020 02 26;64:101664. Epub 2019 Dec 26.

Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Institutes of Health, National Cancer Institute, 9609 Medical Center Drive, MSC 9778 Bethesda, MD, 20892-9778, United States.

Background: While radiotherapy is a major risk factor for thyroid cancer after childhood cancer, factors contributing to increased thyroid cancer risk after adulthood cancer remain unclear.

Methods: We evaluated second primary papillary thyroid cancer (PTC) risk among 3,175,216 ≥ 1-year adult survivors of non-thyroid malignancies from US population-based cancer registries (2000-2015), using standardized incidence ratios (SIRs). Because heightened surveillance may increase detection of indolent thyroid tumors and earlier detection of advanced tumors, we examined SIRs by PTC stage and time since first cancer (latency).

Results: SIRs for second primary PTC (N = 4333) were statistically-significantly 1.2-3.5-fold elevated overall and after 23/27 first cancer types evaluated, with generally similar risks for localized and regional/distant PTC. SIRs for regional/distant PTC (N = 1501) were highest after pancreatic (SIR = 3.7; 95% confidence interval [CI] = 1.9-6.5) and soft tissue (SIR = 4.2; 95%CI = 2.8-6.2) cancers, followed by melanoma, chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), diffuse large B-cell lymphoma, and larynx, kidney, and brain/central nervous system (SIRs = 2.0-2.9) cancers. SIRs typically decreased with increasing latency but remained statistically-significantly elevated for regional/distant-PTC ≥5 years after diagnosis of cancers of the rectum, pancreas, lung/bronchus, soft tissue, female breast, uterine corpus, prostate, and kidney, and after melanoma, Hodgkin lymphoma, CLL/SLL, and follicular lymphoma. Neither total nor regional/distant PTC were clearly associated with initial course of radiotherapy or chemotherapy.

Conclusions: PTC risk was elevated after a range of first primary adult cancers but was not clearly related to treatment. Although surveillance may contribute to elevated short-term risks of PTC, longer-term elevations in regional/distant PTC may be attributable to shared risk factors.
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http://dx.doi.org/10.1016/j.canep.2019.101664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7096211PMC
February 2020

Amount and Intensity of Leisure-Time Physical Activity and Lower Cancer Risk.

J Clin Oncol 2020 03 26;38(7):686-697. Epub 2019 Dec 26.

Brigham and Women's Hospital and Harvard Medical School, Harvard T.H. Chan School of Public Health, Boston, MA.

Purpose: To determine whether recommended amounts of leisure-time physical activity (ie, 7.5-15 metabolic equivalent task [MET] hours/week) are associated with lower cancer risk, describe the shape of the dose-response relationship, and explore associations with moderate- and vigorous-intensity physical activity.

Methods: Data from 9 prospective cohorts with self-reported leisure-time physical activity and follow-up for cancer incidence were pooled. Multivariable Cox regression was used to estimate adjusted hazard ratios (HRs) and 95% CIs of the relationships between physical activity with incidence of 15 types of cancer. Dose-response relationships were modeled with restricted cubic spline functions that compared 7.5, 15.0, 22.5, and 30.0 MET hours/week to no leisure-time physical activity, and statistically significant associations were determined using tests for trend ( < .05) and 95% CIs (< 1.0).

Results: A total of 755,459 participants (median age, 62 years [range, 32-91 years]; 53% female) were followed for 10.1 years, and 50,620 incident cancers accrued. Engagement in recommended amounts of activity (7.5-15 MET hours/week) was associated with a statistically significant lower risk of 7 of the 15 cancer types studied, including colon (8%-14% lower risk in men), breast (6%-10% lower risk), endometrial (10%-18% lower risk), kidney (11%-17% lower risk), myeloma (14%-19% lower risk), liver (18%-27% lower risk), and non-Hodgkin lymphoma (11%-18% lower risk in women). The dose response was linear in shape for half of the associations and nonlinear for the others. Results for moderate- and vigorous-intensity leisure-time physical activity were mixed. Adjustment for body mass index eliminated the association with endometrial cancer but had limited effect on other cancer types.

Conclusion: Health care providers, fitness professionals, and public health practitioners should encourage adults to adopt and maintain physical activity at recommended levels to lower risks of multiple cancers.
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http://dx.doi.org/10.1200/JCO.19.02407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7048166PMC
March 2020

Comparison of Radiation Dose Reconstruction Methods to Investigate Late Adverse Effects of Radiotherapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

Radiat Res 2020 02 3;193(2):95-106. Epub 2019 Dec 3.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.

Quantification of radiation dose to normal tissue during radiotherapy is critical for assessing risk for radiotherapy-related late effects, including subsequent neoplasms (SNs). Case-control studies of SNs typically reconstruct absorbed radiation dose to the specific SN location using individual treatment parameters. A simplified method estimates the maximum prescribed target dose to the body region in which the SN arises. We compared doses and risk estimates from these methods using data from case-control studies of subsequent brain tumors (64 cases, 244 controls) and breast cancer (94 cases, 358 controls) nested within the Childhood Cancer Survivor Study (≥5-year survivors of childhood cancer diagnosed 1970-1986). The weighted kappa statistic [95% confidence interval (CI)] evaluating agreement between categorical (>0-9.9/10-19.9/20-29.9/≥30 Gy) body-region and tumor location-specific doses was 0.95 (0.91-0.98) for brain and 0.76 (0.69-0.82) for breast. The body-region and location-specific doses were assigned to the same dose category for a smaller proportion of patients treated with fields delivering a heterogeneous dose across the tissue of interest (e.g., partial brain field = 57.1%; mantle field = 61.3%) than patients treated with fields delivering a more homogeneous dose (e.g., whole brain field = 100%). Excess odds ratios per Gy (95% CI) from conditional logistic regression were 1.25 (0.33-6.33) and 1.20 (0.31-6.14) for brain tumors and 0.21 (0.05-0.77) and 0.10 (0.02-0.44) for breast cancer, using location-specific and body-region doses, respectively. We observed that body-region doses can approximate location-specific doses when the tissue of interest is clearly in the radiation field or outside the treated body region. Agreement is lower when there is greater ambiguity of SN location relative to the treatment field.
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http://dx.doi.org/10.1667/RR15308.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7063664PMC
February 2020

Safety of the Use of Radioactive Iodine in Patients With Hyperthyroidism-Reply.

JAMA Intern Med 2019 12;179(12):1739

Hirosoft International, Eureka, California.

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http://dx.doi.org/10.1001/jamainternmed.2019.5123DOI Listing
December 2019

Involution of Breast Lobules, Mammographic Breast Density and Prognosis Among Tamoxifen-Treated Estrogen Receptor-Positive Breast Cancer Patients.

J Clin Med 2019 Nov 4;8(11). Epub 2019 Nov 4.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD 20892, USA.

Mammographic breast density (MD) reflects breast fibroglandular content. Its decline following adjuvant tamoxifen treated, estrogen receptor (ER)-positive breast cancer has been associated with improved outcomes. Breast cancers arise from structures termed lobules, and lower MD is associated with increased age-related lobule involution. We assessed whether pre-treatment involution influenced associations between MD decline and risk of breast cancer-specific death. ER-positive tamoxifen treated patients diagnosed at Kaiser Permanente Northwest (1990-2008) were defined as cases who died of breast cancer ( = 54) and matched controls (remained alive over similar follow-up; = 180). Lobule involution was assessed by examining terminal duct lobular units (TDLUs) in benign tissues surrounding cancers as TDLU count/mm, median span and acini count/TDLU. MD (%) was measured in the unaffected breast at baseline (median 6-months before) and follow-up (median 12-months after tamoxifen initiation). TDLU measures and baseline MD were positively associated among controls ( < 0.05). In multivariable regression models, MD decline (≥10%) was associated with reduced risk of breast cancer-specific death before (odds ratio (OR): 0.41, 95% CI: 0.18-0.92) and after (OR: 0.41, 95% CI: 0.18-0.94) adjustment for TDLU count/mm, TDLU span (OR: 0.34, 95% CI: 0.14-0.84), and acini count/TDLU (OR: 0.33, 95% CI: 0.13-0.81). MD decline following adjuvant tamoxifen is associated with reduced risk of breast cancer-specific death, irrespective of pre-treatment lobule involution.
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http://dx.doi.org/10.3390/jcm8111868DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6912285PMC
November 2019

Association of Breast Cancer Risk After Childhood Cancer With Radiation Dose to the Breast and Anthracycline Use: A Report From the Childhood Cancer Survivor Study.

JAMA Pediatr 2019 Oct 28. Epub 2019 Oct 28.

Radiation Epidemiology Branch, Division of Cancer Epidemiology & Genetics, National Cancer Institute, Bethesda, Maryland.

Importance: Chest irradiation for childhood cancer is associated with increases in breast cancer risk. Growing evidence suggests that anthracyclines increase this risk, but the outcome of combined anthracycline use and radiotherapy has not been studied.

Objectives: To evaluate breast cancer risk in childhood cancer survivors following radiotherapy and chemotherapy and assess whether risks varied by estrogen receptor (ER) status.

Design, Setting, And Participants: In a North American hospital-based nested case-control study, a retrospective cohort of 14 358 five-year survivors of childhood cancer, diagnosed from 1970 to 1986 and followed up through December 31, 2016, was analyzed. Cases (n = 271) were defined as women with subsequent breast cancer. Controls (n = 1044) were matched 4:1 to cases by age at first cancer and duration of follow-up (± 2 years). Data analysis was conducted from September 2017 to July 2018.

Exposures: Radiation dose to breast tumor site and ovaries and cumulative chemotherapy doses, including anthracyclines and alkylating agents.

Main Outcomes And Measures: Odds ratios (ORs) for subsequent breast cancer by ER status.

Results: A total of 271 women served as breast cancer cases (median age at first cancer diagnosis, 15 years [range, 3-20]; median age at breast cancer diagnosis, 39 years [range, 20-57]): 201 invasive (113 ER positive [ER+], 41 ER negative [ER-], and 47 unknown) and 70 in situ breast cancers. The OR for breast cancer increased with increasing radiation dose to the breast (OR per 10 Gy, 3.9; 95% CI, 2.5-6.5) and was similar for ER+ (OR per 10 Gy, 5.5; 95% CI, 2.8-12.6) and ER- (OR per 10 Gy, 4.8; 95% CI, 1.7-22.3) cancers. For women who received ovarian doses less than 1 Gy, the OR per 10 Gy to the breast was higher (OR, 6.8; 95% CI, 3.9-12.5) than for women who received ovarian doses greater than or equal to 15 Gy (OR, 1.4; 95% CI, 1.0-6.4). The OR for breast cancer increased with cumulative anthracycline dose (OR per 100 mg/m2, 1.23; 95% CI, 1.09-1.39; P < .01 for trend), and was 1.49 (95% CI, 1.21-1.83) for ER+ cancer vs 1.10 (95% CI, 0.84-1.45) for ER- cancers (P value for heterogeneity = .47). There was an additive interaction between radiotherapy and anthracycline treatment (P = .04) with the OR for the combined association between anthracycline therapy and breast radiation dose of 10 Gy or more (compared with 0 to less than 1 Gy) of 19.1 (95% CI, 7.6-48.0) vs 9.6 (95% CI, 4.4-20.7) without anthracycline use.

Conclusions And Relevance: This study provides the first evidence to date that the combination of anthracyclines and radiotherapy may increase breast cancer risks compared with use of neither treatment with a similar radiation dose response for ER+ and ER- cancers and possibly higher anthracycline risks for ER+ cancers. These results might help inform surveillance guidelines for childhood cancer survivors.
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http://dx.doi.org/10.1001/jamapediatrics.2019.3807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820042PMC
October 2019

Association of lifestyle and clinical characteristics with receipt of radiotherapy treatment among women diagnosed with DCIS in the NIH-AARP Diet and Health Study.

Breast Cancer Res Treat 2020 Jan 17;179(2):445-457. Epub 2019 Oct 17.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.

Purpose: The long-term risks and benefits of radiotherapy for ductal carcinoma in situ (DCIS) remain unclear. Recent data from the Surveillance, Epidemiology and End Results (SEER) registries showed that DCIS-associated radiotherapy treatment significantly increased risk of second non-breast cancers including lung cancer. To help understand those observations and whether breast cancer risk factors are related to radiotherapy treatment decision-making, we examined associations between lifestyle and clinical factors with DCIS radiotherapy receipt.

Methods: Among 1628 participants from the NIH-AARP Diet and Health Study, diagnosed with incident DCIS (1995-2011), we examined associations between lifestyle and clinical factors with radiotherapy receipt. Radiotherapy and clinical information were ascertained from state cancer registries. Odds ratios (ORs) and 95% confidence intervals (CIs) for radiotherapy receipt (yes/no) were estimated from multivariable logistic regression.

Results: Overall, 45% (n = 730) received radiotherapy. No relationships were observed for most lifestyle factors and radiotherapy receipt, including current smoking (OR 0.97, 95%CI 0.70, 1.34). However positive associations were observed for moderate alcohol consumption and infrequent physical activity. The strongest associations were observed for radiotherapy receipt and more recent diagnoses (2005-2011 vs. 1995-1999; OR 1.60, 95%CI 1.14, 2.25), poorly versus well-differentiated tumors (OR 1.69, 95%CI 1.16, 2.46) and endocrine therapy (OR 3.37, 95%CI 2.56, 4.44).

Conclusions: Clinical characteristics were the strongest determinants of DCIS radiotherapy. Receipt was largely unrelated to lifestyle factors suggesting that the previously observed associations in SEER were likely not confounded by these lifestyle factors. Further studies are needed to understand mechanisms driving radiotherapy-associated second malignancies following DCIS, to identify prevention opportunities for this growing population.
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http://dx.doi.org/10.1007/s10549-019-05436-0DOI Listing
January 2020

Pragmatic randomised clinical trial of proton versus photon therapy for patients with non-metastatic breast cancer: the Radiotherapy Comparative Effectiveness (RadComp) Consortium trial protocol.

BMJ Open 2019 10 15;9(10):e025556. Epub 2019 Oct 15.

Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York city, New York, USA.

Introduction: A broad range of stakeholders have called for randomised evidence on the potential clinical benefits and harms of proton therapy, a type of radiation therapy, for patients with breast cancer. Radiation therapy is an important component of curative treatment, reducing cancer recurrence and extending survival. Compared with photon therapy, the international treatment standard, proton therapy reduces incidental radiation to the heart. Our overall objective is to evaluate whether the differences between proton and photon therapy cardiac radiation dose distributions lead to meaningful reductions in cardiac morbidity and mortality after treatment for breast cancer.

Methods: We are conducting a large scale, multicentre pragmatic randomised clinical trial for patients with breast cancer who will be followed longitudinally for cardiovascular morbidity and mortality, health-related quality of life and cancer control outcomes. A total of 1278 patients with non-metastatic breast cancer will be randomly allocated to receive either photon or proton therapy. The primary outcomes are major cardiovascular events, defined as myocardial infarction, coronary revascularisation, cardiovascular death or hospitalisation for unstable angina, heart failure, valvular disease, arrhythmia or pericardial disease. Secondary endpoints are urgent or unanticipated outpatient or emergency room visits for heart failure, arrhythmia, valvular disease or pericardial disease. The Radiotherapy Comparative Effectiveness (RadComp) Clinical Events Centre will conduct centralised, blinded adjudication of primary outcome events.

Ethics And Dissemination: The RadComp trial has been approved by the institutional review boards of all participating sites. Recruitment began in February 2016. Current version of the protocol is A3, dated 08 November 2018. Dissemination plans include presentations at scientific conferences, scientific publications, stakeholder engagement efforts and presentation to the public via lay media outlets.

Trial Registration Number: NCT02603341.
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http://dx.doi.org/10.1136/bmjopen-2018-025556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797426PMC
October 2019

Association of Cardiovascular Disease With Premature Mortality in the United States.

JAMA Cardiol 2019 12;4(12):1230-1238

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland.

Importance: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in the United States. Despite substantial declines in CVD mortality rates during past decades, progress against cardiovascular deaths in midlife has stagnated, with rates increased in some US racial/ethnic groups.

Objective: To examine the trends in premature (ages 25-64 years) mortality from CVD from 2000 to 2015 by demographics and county-level factors, including education, rurality, and the prevalence of smoking, obesity, and diabetes.

Design, Setting, And Participants: This descriptive study used US national mortality data from the Surveillance, Epidemiology, and End Results data set and included all CVD deaths among individuals ages 25 to 64 years from January 2000 to December 2015. The data analysis began in February 2018.

Exposures: Age, sex, race/ethnicity, and county-level factors.

Main Outcomes And Measures: Age-standardized mortality rates and average annual percent change (AAPC) in rates by age, sex, race/ethnicity, and county-level factors (in quintiles) and relative risks of CVD mortality across quintiles of each county-level factor.

Results: In 2000 to 2015, 2.3 million CVD deaths occurred among individuals age 25 to 64 years in the United States. There were significant declines in CVD mortality for black, Latinx, and Asian and Pacific Islander individuals (AAPC: range, -1.7 to -3.2%), although black people continued to have the highest CVD mortality rates. Mortality rates were second highest for American Indian/Alaskan Native individuals and increased significantly among those aged 25 to 49 years (AAPC: women, 2.1%; men, 1.3%). For white individuals, mortality rates plateaued among women age 25 to 49 years (AAPC, 0.05%). Declines in mortality rates were observed for most major CVD subtypes except for ischemic heart disease, which was stable in white women and increased in American Indian/Alaska Native women, hypertensive heart disease, for which significant increases in rates were observed in most racial/ethnic groups, and endocarditis, for which rates increased in white individuals and American Indian/Alaska Native men. Counties with the highest prevalence of diabetes (quintile 5 vs quintile 1: relative risk range 1.6-1.8 for white individuals and 1.4-1.6 for black individuals) had the most risk of CVD mortality.

Conclusions And Relevance: There have been substantial declines in premature CVD mortality in much of the US population. However, increases in CVD mortality before age 50 years among American Indian/Alaska Native individuals, flattening rates in white people, and overall increases in deaths from hypertensive disease suggest that targeted public health interventions are needed to prevent these premature deaths.
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http://dx.doi.org/10.1001/jamacardio.2019.3891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6802055PMC
December 2019

An open invitation to join the Pediatric Proton/Photon Consortium Registry to standardize data collection in pediatric radiation oncology.

Br J Radiol 2020 Mar 1;93(1107):20190673. Epub 2019 Nov 1.

Department of Radiation Oncology, Harvard Medical School, Massachusetts General Hospital, Boston, United States.

Objective: The Pediatric Proton/Photon Consortium Registry (PPCR) is a comprehensive data registry composed of pediatric patients treated with radiation. It was established to expedite outcomes-based research. The attributes which allow the PPCR to be a successful collaboration are reviewed.

Methods And Materials: Current eligibility criteria are radiotherapy patients < 22 years treated at one of the 15 US participating institutions. Detailed health and treatment data are collected about the disease presentation and treatment exposures, and annually thereafter, in REDCap (Research Electronic Data Capture). DICOM (Digital Imaging and Communications in Medicine) imaging and radiation plans are collected through MIM/MIMcloud. An optional patient-reported quality-of-life (PedsQL) study is administered at 10 sites.

Results: Accrual started October 2012 with 2,775 participants enrolled as of 25 July 2019. Most patients, 62.0%, were treated for central nervous system (CNS) tumors, the most common of which are medulloblastoma ( = 349), ependymoma ( = 309), and glial/astrocytoma tumors ( = 279). The most common non-CNS diagnoses are rhabdomyosarcoma ( = 284), Ewing's sarcoma ( = 153), and neuroblastoma ( = 130). While the majority of participants are US residents, 18.7% come from 36 other countries. Over 685 patients participate in the PedsQL study.

Conclusions: The PPCR is a valuable research platform capable of answering countless research questions that will ultimately improve patient care. Centers outside of the USA are invited to participate directly or may engage with the PPCR to align data collection strategies to facilitate large-scale international research.

Advances In Knowledge: For investigators looking to carry out research in a large pediatric oncology cohort or interested in registry work, this paper provides an updated overview of the PPCR.
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http://dx.doi.org/10.1259/bjr.20190673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066966PMC
March 2020

Association of Radioactive Iodine Treatment With Cancer Mortality in Patients With Hyperthyroidism.

JAMA Intern Med 2019 Jul 1. Epub 2019 Jul 1.

Hirosoft International, Eureka, California.

Importance: Radioactive iodine (RAI) has been used extensively to treat hyperthyroidism since the 1940s. Although widely considered a safe and effective therapy, RAI has been associated with elevated risks of total and site-specific cancer death among patients with hypothyroidism.

Objective: To determine whether greater organ- or tissue-absorbed doses from RAI treatment are associated with overall and site-specific cancer mortality in patients with hyperthyroidism.

Design, Setting, And Participants: This cohort study is a 24-year extension of the multicenter Cooperative Thyrotoxicosis Therapy Follow-up Study, which has followed up US and UK patients diagnosed and treated for hyperthyroidism for nearly 7 decades, beginning in 1946. Patients were traced using records from the National Death Index, Social Security Administration, and other resources. After exclusions, 18 805 patients who were treated with RAI and had no history of cancer at the time of the first treatment were eligible for the current analysis. Excess relative risks (ERRs) per 100-mGy dose to the organ or tissue were calculated using multivariable-adjusted linear dose-response models and were converted to relative risks (RR = 1 + ERR). The current analyses were conducted from April 28, 2017, to January 30, 2019.

Exposures: Mean total administered activity of sodium iodide I 131 was 375 MBq for patients with Graves disease and 653 MBq for patients with toxic nodular goiter. Mean organ or tissue dose estimates ranged from 20 to 99 mGy (colon or rectum, ovary, uterus, prostate, bladder, and brain/central nervous system), to 100 to 400 mGy (pancreas, kidney, liver, stomach, female breast, lung, oral mucosa, and marrow), to 1.6 Gy (esophagus), and to 130 Gy (thyroid gland).

Main Outcomes And Measures: Site-specific and all solid-cancer mortality.

Results: A total of 18 805 patients were included in the study cohort, and the mean (SD) entry age was 49 (14) years. Most patients were women (14 671 [78.0%]), and most had a Graves disease diagnosis (17 615 [93.7%]). Statistically significant positive associations were observed for all solid cancer mortality (n = 1984; RR at 100-mGy dose to the stomach = 1.06; 95% CI, 1.02-1.10; P = .002), including female breast cancer (n = 291; RR at 100-mGy dose to the breast = 1.12; 95% CI, 1.003-1.32; P = .04) and all other solid cancers combined (n = 1693; RR at 100-mGy dose to the stomach = 1.05; 95% CI, 1.01-1.10; P = .01). The 100-mGy dose to the stomach and breast corresponded to a mean (SD) administered activity of 243 (35) MBq and 266 (58) MBq in patients with Graves disease. For every 1000 patients with hyperthyroidism receiving typical doses to the stomach (150 to 250 mGy), an estimated lifetime excess of 19 (95% CI, 3-40) to 32 (95% CI, 5-66) solid cancer deaths could occur.

Conclusions And Relevance: In RAI-treated patients with hyperthyroidism, greater organ-absorbed doses appeared to be modestly positively associated with risk of death from solid cancer, including breast cancer. Additional studies are needed of the risks and advantages of all major treatment options available to patients with hyperthyroidism.
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http://dx.doi.org/10.1001/jamainternmed.2019.0981DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604114PMC
July 2019

Trends in Mortality Due to Cancer in the United States by Age and County-Level Income, 1999-2015.

J Natl Cancer Inst 2019 08;111(8):863-866

See the Notes section for the full list of authors' affiliations.

Disparities in cancer mortality by county-level income have increased. It is unclear whether these widening disparities have affected older and younger adults equally. National death certificate data were utilized to ascertain cancer deaths during 1999-2015. Average annual percent changes in mortality rates and mortality rate ratios (RRs) were estimated by county-level income quintile and age (25-64 vs ≥65 years). Among 25- to 64-year-olds, cancer mortality rates were 30% higher (RR = 1.30, 95% confidence interval [CI] = 1.29 to 1.31) in the lowest-vs the highest-income counties in 1999-2001 and 56% higher (RR = 1.56, 95% CI = 1.55 to 1.57) in 2013-2015; the disparities among those 65 years and older were smaller but also widened over time (RR1999-2001 = 1.04, 95% CI = 1.03 to 1.05; RR2013-2015 = 1.14, 95% CI = 1.13 to 1.14). Widening disparities occurred across cancer sites. If all counties had the mortality rates of the highest-income counties, 21.5% of cancer deaths among 25- to 64-year-olds and 7.3% of cancer deaths in those 65 years and older would have been avoided in 2015. These results highlight an ongoing need for equity-focused interventions, particularly among younger adults.
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http://dx.doi.org/10.1093/jnci/djz123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6695317PMC
August 2019

Smoking, Alcohol, and Biliary Tract Cancer Risk: A Pooling Project of 26 Prospective Studies.

J Natl Cancer Inst 2019 12;111(12):1263-1278

Background: Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear.

Methods: We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided.

Results: Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend < .01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers.

Conclusions: Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract.
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http://dx.doi.org/10.1093/jnci/djz103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6910180PMC
December 2019