Publications by authors named "Hazel B Nichols"

102 Publications

The Adolescent and Young Adult (AYA) Horizon Study: An AYA cancer survivorship cohort.

Cancer Epidemiol Biomarkers Prev 2021 Feb 22. Epub 2021 Feb 22.

Division of Research, Kaiser Permanente.

Background: In the United States (U.S.), >45,000 adolescent and young adult (AYA) women are diagnosed with cancer annually. Reproductive issues are critically important to AYA cancer survivors, but insufficient information is available to address their concerns. The AYA Horizon Study was initiated to contribute high-quality, contemporary evidence on reproductive outcomes for female cancer survivors in the U.S.

Methods: The study cohort includes women diagnosed with lymphoma, breast, melanoma, thyroid, or gynecologic cancer (the 5 most common cancers among women ages 15-39 years) at three study sites: the state of North Carolina and the Kaiser Permanente health systems in Northern and Southern California. Detailed information on cancer treatment, fertility procedures, and pregnancy (e.g. miscarriage, livebirth) and birth (e.g. birth weight, gestational length) outcomes are leveraged from state cancer registries, health system databases and administrative insurance claims, national data on assisted reproductive technology procedures, vital records, and survey data.

Results: We identified a cohort of 11,072 female AYA cancer survivors that includes >1,200 African American women, >1,400 Asian women, >1,600 Medicaid enrollees, and >2,500 Hispanic women using existing data sources. Active response to the survey component was low overall (N=1,679), and notably lower among minority groups compared to non-Hispanic white women.

Conclusions: Passive data collection through linkage reduces participant burden and prevents systematic cohort attrition or potential selection biases that can occur with active participation requirements.

Impact: The AYA Horizon study will inform survivorship planning as fertility and parenthood gain increasing recognition as key aspects of high-quality cancer care.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1315DOI Listing
February 2021

Risks of nonchromosomal birth defects, small-for-gestational age birthweight, and prematurity with in vitro fertilization: effect of number of embryos transferred and plurality at conception versus at birth.

J Assist Reprod Genet 2021 Feb 5. Epub 2021 Feb 5.

Epidemiology Program, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston, TX, USA.

Purpose: Excess embryos transferred (ET) (> plurality at birth) and fetal heartbeats (FHB) at 6 weeks' gestation are associated with reductions in birthweight and gestation, but prior studies have been limited by small sample sizes and limited IVF data. This analysis evaluated associations between excess ET, excess FHB, and adverse perinatal outcomes, including the risk of nonchromosomal birth defects.

Methods: Live births conceived via IVF from Massachusetts, New York, North Carolina, and Texas included 138,435 children born 2004-2013 (Texas), 2004-2016 (Massachusetts and North Carolina), and 2004-2017 (New York) were classified by ET and FHB. Major birth defects were reported by statewide registries within the first year of life. Logistic regression was used to estimate adjusted odds ratios (AORs) and 95% CIs of the risks of a major nonchromosomal birth defect, small-for-gestational age birthweight (SGA), low birthweight (LBW), and preterm birth (≤36 weeks), by excess ET, and excess ET + excess FHB, by plurality at birth (singletons and twins).

Results: In singletons with [2 ET, FHB =1] and [≥3 ET, FHB=1], risks [AOR (95% CI)] were increased, respectively, for major nonchromosomal birth defects [1.13 (1.00-1.27) and 1.18 (1.00-1.38)], SGA [1.10 (1.03-1.17) and 1.15 (1.05-1.26)], LBW [1.09 (1.02-1.13) and 1.17 (1.07-1.27)], and preterm birth [1.06 (1.00-1.12) and 1.14 (1.06-1.23)]. With excess ET + excess FHB, risks of all adverse outcomes except major nonchromosomal birth defects increased further for both singletons and twins.

Conclusion: Excess embryos transferred are associated with increased risks for nonchromosomal birth defects, reduced birthweight, and prematurity in IVF-conceived births.
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http://dx.doi.org/10.1007/s10815-021-02095-3DOI Listing
February 2021

Trends in US Cancer and Heart Disease Mortality, 1999-2018.

Circulation 2021 Jan 19;143(3):287-288. Epub 2021 Jan 19.

Departments of Epidemiology (C.L.A., H.B.N.), University of North Carolina at Chapel Hill.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051451DOI Listing
January 2021

Outcomes of Hormone-Receptor Positive, HER2-Negative Breast Cancers by Race and Tumor Biological Features.

JNCI Cancer Spectr 2021 Feb 23;5(1):pkaa072. Epub 2020 Sep 23.

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

Background: Black women have higher hormone receptor positive (HR+) breast cancer mortality than White women. Early recurrence rates differ by race, but little is known about genomic predictors of early recurrence among HR+ women.

Methods: Using data from the Carolina Breast Cancer Study (phase III, 2008-2013), we estimated associations between race and recurrence among nonmetastatic HR+/HER2-negative tumors, overall and by PAM50 Risk of Recurrence score, PAM50 intrinsic subtype, and tumor grade using survival curves and Cox models standardized for age and stage. Relative frequency differences (RFD) were estimated using multivariable linear regression. To assess intervention opportunities, we evaluated treatment patterns by race among patients with high-risk disease.

Results: Black women had higher recurrence risk relative to White women (crude hazard ratio = 1.81, 95% confidence interval [CI] = 1.34 to 2.46), which remained elevated after standardizing for clinical covariates (hazard ratio = 1.42, 95% CI = 1.05 to 1.93). Racial disparities were most pronounced among those with high PAM50 Risk of Recurrence score (5-year standardized recurrence risk = 18.9%, 95% CI = 8.6% to 29.1% in Black women vs 12.5%, 95% CI = 2.0% to 23.0% in White women) and high grade (5-year standardized recurrence risk = 16.6%, 95% CI = 11.7% to 21.5% in Black women vs 12.0%, 95% CI = 7.3% to 16.7% in White women). However, Black women with high-grade tumors were statistically significantly less likely to initiate endocrine therapy (RFD = -8.3%, 95% CI = -15.9% to -0.6%) and experienced treatment delay more often than White women (RFD = +9.0%, 95% CI = 0.3% to 17.8%).

Conclusions: Differences in recurrence by race appear greatest among women with aggressive tumors and may be influenced by treatment differences. Efforts to identify causes of variation in cancer treatment are critical to reducing outcome disparities.
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http://dx.doi.org/10.1093/jncics/pkaa072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7791616PMC
February 2021

The risk of birth defects with conception by ART.

Hum Reprod 2021 Jan;36(1):116-129

Division of Reproductive Endocrinology and Infertility, Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Study Question: What is the association between ART conception and treatment parameters and the risk of birth defects?

Summary Answer: Compared to naturally conceived singleton infants, the risk of a major nonchromosomal defect among ART singletons conceived with autologous oocytes and fresh embryos without use of ICSI was increased by 18%, with increases of 42% and 30% for use of ICSI with and without male factor diagnosis, respectively.

What Is Known Already: Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects but have been limited by small sample size and inadequate statistical power, failure to differentiate results by plurality, differences in birth defect definitions and methods of ascertainment, lack of information on ART treatment parameters or study periods spanning decades resulting in a substantial historical bias as ART techniques have improved.

Study Design, Size, Duration: This was a population-based cohort study linking ART cycles reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 1 January 2004 to 31 December 2015 that resulted in live births from 1 September 2004 to 31 December 2016 in Massachusetts and North Carolina and from 1 September 2004 to 31 December 2015 for Texas and New York: these were large and ethnically diverse States, with birth defect registries utilizing the same case definitions and data collected, and with high numbers of ART births annually. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Naturally conceived ART siblings were identified through the mother's information. Non-ART children were classified as being born to women who conceived with ovulation induction (OI)/IUI when there was an indication of infertility treatment on the birth certificate, but the woman did not link to the SART CORS; all others were classified as being naturally conceived.

Participants/materials, Setting, Methods: The study population included 135 051 ART children (78 362 singletons and 56 689 twins), 23 647 naturally conceived ART siblings (22 301 singletons and 1346 twins) and 9396 children born to women treated with OI/IUI (6597 singletons and 2799 twins) and 1 067 922 naturally conceived children (1 037 757 singletons and 30 165 twins). All study children were linked to their respective State birth defect registries to identify major defects diagnosed within the first year of life. We classified children with major defects as either chromosomal (i.e. presence of a chromosomal defect with or without any other major defect) or nonchromosomal (i.e. presence of a major defect but having no chromosomal defect), or all major defects (chromosomal and nonchromosomal). Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CI to evaluate the risk of birth defects due to conception with ART (using autologous oocytes and fresh embryos), and with and without the use of ICSI in the absence or presence of male factor infertility, with naturally conceived children as the reference. Analyses within the ART group were stratified by combinations of oocyte source (autologous, donor) and embryo state (fresh, thawed), with births from autologous oocytes and fresh embryos as the reference. Analyses limited to fresh embryos were stratified by oocyte source (autologous, donor) and the use of ICSI. Triplets and higher-order multiples were excluded.

Main Results And The Role Of Chance: A total of 21 998 singleton children (1.9%) and 3037 twin children (3.3%) had a major birth defect. Compared to naturally conceived children, ART singletons (conceived from autologous oocytes, fresh embryos without the use of ICSI) had increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% 1.05, 1.32), cardiovascular defects (AOR 1.20, 95% CI 1.03, 1.40), and any birth defect (AOR 1.18, 95% CI 1.09, 1.27). Compared to naturally conceived children, ART singletons conceived (from autologous oocytes, fresh embryos) with the use of ICSI, the risks were increased for a major nonchromosomal birth defect (AOR 1.30, 95% CI 1.16, 1.45 without male factor diagnosis; AOR 1.42, 95% CI 1.28, 1.57 with male factor diagnosis); blastogenesis defects (AOR 1.49, 95% CI 1.08, 2.05 without male factor; AOR 1.56, 95% CI 1.17, 2.08 with male factor); cardiovascular defects (AOR 1.28, 95% CI 1.10,1.48 without male factor; AOR 1.45, 95% CI 1.27, 1.66 with male factor); in addition, the risk for musculoskeletal defects was increased (AOR 1.34, 95% CI 1.01, 1.78 without male factor) and the risk for genitourinary defects in male infants was increased (AOR 1.33, 95% CI 1.08, 1.65 with male factor). Comparisons within ART singleton births conceived from autologous oocytes and fresh embryos indicated that the use of ICSI was associated with increased risks of a major nonchromosomal birth defect (AOR 1.18, 95% CI 1.03, 1.35), blastogenesis defects (AOR 1.65, 95% CI 1.08, 2.51), gastrointestinal defects (AOR 2.21, 95% CI 1.28, 3.82) and any defect (AOR 1.11, 95% CI 1.01, 1.22). Compared to naturally conceived children, ART singleton siblings had increased risks of musculoskeletal defects (AOR 1.32, 95% CI 1.04, 1.67) and any defect (AOR 1.15, 95% CI 1.08, 1.23). ART twins (conceived with autologous oocytes, fresh embryos, without ICSI) were at increased risk of chromosomal defects (AOR 1.89, 95% CI 1.10, 3.24) and ART twin siblings were at increased risk of any defect (AOR 1.26, 95% CI 1.01, 1.57). The 18% increased risk of a major nonchromosomal birth defect in singleton infants conceived with ART without ICSI (∼36% of ART births), the 30% increased risk with ICSI without male factor (∼33% of ART births), and the 42% increased risk with ICSI and male factor (∼31% of ART births) translates into an estimated excess of 386 major birth defects among the 68 908 singleton children born by ART in 2017.

Limitations, Reasons For Caution: In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing vs vitrification), and data on ICSI was only available in the fresh embryo ART group. In the OI/IUI group, it was not possible to differentiate type of non-ART treatment utilized, and in both the ART and OI/IUI groups, data were unavailable on duration of infertility.

Wider Implications Of The Findings: The use of ART is associated with increased risks of a major nonchromosomal birth defect, cardiovascular defect and any defect in singleton children, and chromosomal defects in twins; the use of ICSI further increases this risk, the most with male factor infertility. These findings support the judicious use of ICSI only when medically indicated. The relative contribution of ART treatment parameters versus the biology of the subfertile couple to this increased risk remains unclear and warrants further study.

Study Funding/competing Interest(s): This project was supported by grant R01 HD084377 from the National Institute of Child Health and Human Development. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Child Health and Human Development, or the National Institutes of Health, nor any of the State Departments of Health which contributed data. E.W. is a contract vendor for SART; all other authors report no conflicts.

Trial Registration Number: N/A.
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http://dx.doi.org/10.1093/humrep/deaa272DOI Listing
January 2021

Health-related quality of life outcomes among breast cancer survivors.

Cancer 2020 Nov 25. Epub 2020 Nov 25.

Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina.

Background: Data from a nationwide sample of US breast cancer survivors were used to examine associations between patient characteristics (breast cancer clinical features, prognostic factors, and treatments) and health-related quality of life (HRQOL). Associations between postdiagnosis HRQOL and mortality were then evaluated.

Methods: The authors identified female breast cancer survivors (n = 2453) from the Sister Study or Two Sister Study who were at least 1 year from breast cancer diagnosis and who had responded to a survivorship survey in 2012. HRQOL was assessed with the Patient-Reported Outcomes Measurement Information System (PROMIS) Global 10 measures. Multivariable linear regression was used to assess predictors associated with HRQOL. Cox regression was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between HRQOL and all-cause mortality.

Results: HRQOL, assessed an average of 4.9 years after the cancer diagnosis (standard deviation of 1.9 years), was negatively associated with a higher cancer stage at diagnosis; a higher comorbidity score at the survey; experience of surgical complications; dissatisfaction with breast surgery; and experience of any recent recurrence, metastasis, or secondary malignancy. Since the completion of the survey, there were 85 deaths (3.5%) during a mean follow-up of 4 years (standard deviation of 0.5 years). In multivariate models, decreases in PROMIS physical T scores and mental T scores were associated with increased mortality (HR for physical T scores, 1.08; 95% CI, 1.05-1.11; HR for mental T scores, 1.03; 95% CI, 1.01-1.06).

Conclusions: Prognostic and cancer treatment-related factors affect HRQOL in breast cancer survivors and may inform targeted survivorship care. PROMIS global health measures may offer additional insights into patients' well-being and mortality risk.

Lay Summary: Findings from a study suggest that prognostic and cancer treatment-related factors affect health-related quality of life (HRQOL) in breast cancer survivors and that poor HRQOL may increase the mortality risk. The evaluation of HRQOL is important because it may hold potential as a tool for optimizing survivorship care.
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http://dx.doi.org/10.1002/cncr.33348DOI Listing
November 2020

Measurement of mitochondrial DNA copy number in dried blood spots: A pilot study.

Mitochondrion 2021 01 18;56:35-39. Epub 2020 Nov 18.

Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA. Electronic address:

Background: We evaluated the feasibility of mitochondrial DNA (mtDNA) copy number measurement in dried blood spots (DBS), its comparability with measurement in whole blood samples, and stability of mtDNA copy number from DBS over time.

Methods: Women in this pilot study were participants in the Sister Study, a large prospective cohort. Sister Study participants provided a whole blood sample and DBS at enrollment. A second DBS sample was collected 5-10 years later from a subcohort of women with and without an incident breast cancer diagnosis between collections. Among 54 women (27 with breast cancer, 27 without) we measured mtDNA copy number from whole blood at enrollment and from DBS at both time points.

Results: The average age at enrollment was 58.7 years (range:50-69). Values of mtDNA copy number measured in whole blood samples and DBS from enrollment were moderately correlated (Spearman R = 0.45; p = 0.005). Stability of mtDNA copy number in DBS from the two time points was moderate overall (ICC = 0.50) and similar between women with (ICC = 0.50) and without (ICC = 0.51) a breast cancer diagnosis between the two collections.

Conclusions: Our results suggest that measurement of mtDNA copy number in DBS is feasible and may be a valid alternative to measurement in whole blood samples.
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http://dx.doi.org/10.1016/j.mito.2020.11.006DOI Listing
January 2021

Assessment of Birth Defects and Cancer Risk in Children Conceived via In Vitro Fertilization in the US.

JAMA Netw Open 2020 10 1;3(10):e2022927. Epub 2020 Oct 1.

Epidemiology Program, Texas Children's Cancer and Hematology Centers, Baylor College of Medicine, Houston.

Importance: Children with birth defects have a greater risk of developing cancer, but this association has not yet been evaluated in children conceived with in vitro fertilization (IVF).

Objective: To assess whether the association between birth defects and cancer is greater in children conceived via IVF compared with children conceived naturally.

Design, Setting, And Participants: This cohort study of live births, birth defects, and cancer from Massachusetts, New York, North Carolina, and Texas included 1 000 639 children born to fertile women and 52 776 children conceived via IVF (using autologous oocytes and fresh embryos) during 2004-2016 in Massachusetts and North Carolina, 2004-2015 in New York, and 2004-2013 in Texas. Children were followed up for an average of 5.7 years (6 008 985 total person-years of exposure). Data analysis was conducted from April 1 to August 31, 2020.

Exposures: Conception by IVF for state residents who gave birth to liveborn singletons during the study period. Birth defect diagnoses recorded by statewide registries.

Main Outcomes And Measures: Cancer diagnosis as recorded by state cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs for birth defect-cancer associations separately in fertile and IVF groups.

Results: A total of 1 000 639 children (51.3% boys; 69.7% White; and 38.3% born between 2009-2012) were in the fertile group and 52 776 were in the IVF group (51.3% boys; 81.3% White; and 39.6% born between 2009-2012). Compared with children without birth defects, cancer risks were higher among children with a major birth defect in the fertile group (hazard ratio [HR], 3.15; 95% CI, 2.40-4.14) and IVF group (HR, 6.90; 95% CI, 3.73-12.74). The HR of cancer among children with a major nonchromosomal defect was 2.07 (95% CI, 1.47-2.91) among children in the fertile group and 4.04 (95% CI, 1.86-8.77) among children in the IVF group. The HR of cancer among children with a chromosomal defect was 15.45 (95% CI, 10.00-23.86) in the fertile group and 38.91 (95% CI, 15.56-97.33) in the IVF group.

Conclusions And Relevance: This study found that among children with birth defects, those conceived via IVF were at greater risk of developing cancer compared with children conceived naturally.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.22927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596575PMC
October 2020

Material and psychological financial hardship related to employment disruption among female adolescent and young adult cancer survivors.

Cancer 2020 Jan 12;127(1):137-148. Epub 2020 Oct 12.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Background: The importance of addressing adverse financial effects of cancer among adolescents and young adults (AYAs) is paramount as survival improves. In the current study, the authors examined whether cancer-related employment disruption was associated with financial hardship among female AYA cancer survivors in North Carolina and California.

Methods: AYA cancer survivors identified through the North Carolina Central Cancer Registry and the Kaiser Permanente Northern/Southern California tumor registries responded to an online survey. Disrupted employment was defined as reducing hours, taking temporary leave, or stopping work completely because of cancer. Financial hardship was defined as material conditions or psychological distress related to cancer. Descriptive statistics and chi-square tests were used to characterize the invited sample and survey respondents. Marginal structural binomial regression models were used to estimate prevalence differences (PDs) and 95% confidence intervals (95% CIs).

Results: Among 1328 women employed at the time of their diagnosis, women were a median age of 34 years at the time of diagnosis and 7 years from diagnosis at the time of the survey and approximately 32% experienced employment disruption. A substantial percentage reported financial hardship related to material conditions (27%) or psychological distress (50%). In adjusted analyses, women with disrupted employment had a 17% higher burden of material conditions (95% CI, 10%-23%) and an 8% higher burden of psychological distress (95% CI, 1%-16%) compared with those without disruption.

Conclusions: Financial hardship related to employment disruption among female AYA cancer survivors can be substantial. Interventions to promote job maintenance and transition back to the workforce after treatment, as well as improved workplace accommodations and benefits, present an opportunity to improve cancer survivorship.
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http://dx.doi.org/10.1002/cncr.33190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7736150PMC
January 2020

Hazardous air pollutants and telomere length in the Sister Study.

Environ Epidemiol 2019 Aug 28;3(4). Epub 2019 Jun 28.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.

Background: Telomeres are vital for genomic integrity and telomere length has been linked to many adverse health outcomes. Some hazardous air pollutants, or air toxics, increase oxidative stress and inflammation, two possible determinants of shortened telomere length. No studies have examined air toxic-telomere length associations in a non-occupational setting.

Methods: This study included 731 Sister Study participants (enrolled 2003-2007) who were randomly selected to assess telomere length in baseline blood samples. Multiplex qPCR was used to determine telomere to single copy gene (T/S) ratios. Census tract concentration estimates of 29 air toxics from the 2005 National Air Toxics Assessment were linked to baseline residential addresses. Air toxics were classified into tertile-based categories of the exposure. Multivariable linear regression was used to estimate coefficients and 95% confidence intervals (CI) in single pollutant models. Multipollutant groups were identified with regression trees.

Results: The average T/S ratio was 1.24. Benzidine (T3vsT1 = -0.08; 95% CI: -0.14, -0.01) and 1,4-dioxane (T3vsT1 = -0.06; 95% CI: -0.13, 0.00) in particular, as well as carbon tetrachloride, chloroprene, ethylene dibromide, and propylene dichloride, were associated with shorter relative telomere length. Benzidine (=0.02) and 1,4-dioxane (=0.06) demonstrated some evidence of a monotonic trend. The regression tree identified age, BMI, physical activity, ethylene oxide, acrylonitrile, ethylidene dichloride, propylene dichloride, and styrene in multipollutant groups related to telomere length.

Conclusions: In this first study of air toxics and telomere length in a non-occupational setting, several air toxics, particularly 1,4-dioxane and benzidine, were associated with shorter relative telomere length.
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http://dx.doi.org/10.1097/ee9.0000000000000053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7517667PMC
August 2019

Associations of Leisure-Time Physical Activity and Television Viewing with Life Expectancy Cancer-Free at Age 50: The ARIC Study.

Cancer Epidemiol Biomarkers Prev 2020 Dec 25;29(12):2617-2625. Epub 2020 Sep 25.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Background: Physical activity has been associated with longer chronic disease-free life expectancy, but specific cancer types have not been investigated. We examined whether leisure-time moderate-to-vigorous physical activity (LTPA) and television (TV) viewing were associated with life expectancy cancer-free.

Methods: We included 14,508 participants without a cancer history from the Atherosclerosis Risk in Communities (ARIC) study. We used multistate survival models to separately examine associations of LTPA (no LTPA,
Results: Compared with no LTPA, participants who engaged in LTPA ≥median had a greater life expectancy cancer-free from colorectal [men-2.2 years (95% confidence interval (CI), 1.7-2.7), women-2.3 years (95% CI, 1.7-2.8)], lung [men-2.1 years (95% CI, 1.5-2.6), women-2.1 years (95% CI, 1.6-2.7)], prostate [1.5 years (95% CI, 0.8-2.2)], and postmenopausal breast cancer [2.4 years (95% CI, 1.4-3.3)]. Compared with watching TV often/very often, participants who seldom/never watched TV had a greater colorectal, lung, and postmenopausal breast cancer-free life expectancy of ∼1 year.

Conclusions: Participating in LTPA was associated with longer life expectancy cancer-free from colorectal, lung, prostate, and postmenopausal breast cancer. Viewing less TV was associated with more years lived cancer-free from colorectal, lung, and postmenopausal breast cancer.

Impact: Increasing physical activity and reducing TV viewing may extend the number of years lived cancer-free.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-0870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710595PMC
December 2020

Genetic variants in anti-Müllerian hormone-related genes and breast cancer risk: results from the AMBER consortium.

Breast Cancer Res Treat 2021 Jan 22;185(2):469-478. Epub 2020 Sep 22.

Department of Epidemiology, University of North Carolina Gillings School of Global Public Health, 2104F McGavran-Greenberg Hall, Chapel Hill, NC, 27599-7435, USA.

Purpose: Circulating anti-Müllerian hormone (AMH) levels are positively associated with time to menopause and breast cancer risk. We examined breast cancer associations with single nucleotide polymorphisms (SNPs) in the AMH gene or its receptor genes, ACVR1 and AMHR2, among African American women.

Methods: In the AMBER consortium, we tested 65 candidate SNPs, and 1130 total variants, in or near AMH, ACVR1, and AMHR2 and breast cancer risk. Overall, 3649 cases and 4230 controls contributed to analyses. Odds ratios (OR) and 95% confidence intervals (CI) for breast cancer were calculated using multivariable logistic regression.

Results: After correction for multiple comparisons (false-discovery rate of 5%), there were no statistically significant associations with breast cancer risk. Without correction for multiple testing, four candidate SNPs in ACVR1 and one near AMH were associated with breast cancer risk. In ACVR1, rs13395576[C] was associated with lower breast cancer risk overall (OR 0.84; 95% CI 0.72, 0.97) and for ER+ disease (OR 0.75; CI 0.62, 0.89) (p < 0.05). Rs1220110[A] and rs1220134[T] each had ORs of 0.89-0.90 for postmenopausal and ER+ breast cancer (p ≤ 0.03). Conversely, rs1682130[T] was associated with higher risk of ER+ breast cancer (OR 1.17; 95% CI 1.04, 1.32). Near AMH, rs6510652[T] had ORs of 0.85-0.90 for breast cancer overall and after menopause (p ≤ 0.02).

Conclusions: The present results, from a large study of African American women, provide limited support for an association between AMH-related polymorphisms and breast cancer risk and require replication in other studies.
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http://dx.doi.org/10.1007/s10549-020-05944-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7867570PMC
January 2021

Menopausal hormone therapy use and long-term all-cause and cause-specific mortality in the Long Island Breast Cancer Study Project.

Int J Cancer 2020 Dec 30;147(12):3404-3415. Epub 2020 Jul 30.

Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina, USA.

Previous studies have observed a reduced mortality risk associated with menopausal hormone therapy (MHT) use among breast cancer survivors. We sought to clarify whether such association could be explained by tumor heterogeneity, specific causes of death, confounding from comorbidities or health behaviors, and a comparison group of women without breast cancer. We interviewed 1508 women newly diagnosed with first primary breast cancer in 1996 to 1997 (~3 months after diagnosis), and 1556 age-matched women without breast cancer, about MHT use history. The National Death Index was used to ascertain vital status after a median of 17.6 years of follow-up (N = 597 deaths for breast cancer subjects). Multivariable-adjusted Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (95%CIs) for all-cause mortality, and cause-specific HR (cHR) for breast cancer and cardiovascular disease (CVD). The Fine-Gray model was used to account for competing causes of death. Among women with breast cancer, ever vs never MHT use was inversely associated with all-cause (HR = 0.77, 95%CI = 0.62-0.95), breast cancer-specific (cHR = 0.69, 95%CI = 0.48-0.98), and CVD-specific mortality (cHR = 0.57, 95%CI = 0.38-0.85). Difference of the association was observed in breast cancer-specific mortality according to hormone receptor status (negative tumors: cHR = 0.44, 95%CI = 0.19-1.01; positive tumors: cHR = 0.96, 95%CI = 0.60-1.53). Among the comparison group, we observed similar, but more modest inverse associations for all-cause and CVD-specific mortality. MHT use was inversely associated with mortality after breast cancer, even after accounting for competing causes of death and multiple confounders, and was evident among women without breast cancer. Potential heterogeneity by hormone receptor status requires more study.
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http://dx.doi.org/10.1002/ijc.33174DOI Listing
December 2020

The Other Side of Through: Young Breast Cancer Survivors' Spectrum of Sexual and Reproductive Health Needs.

Qual Health Res 2020 11 18;30(13):2019-2032. Epub 2020 Jun 18.

The University of North Carolina at Chapel Hill, North Carolina, USA.

The long-term reproductive health impact of cancer treatments is a concern for premenopausal women with a history of breast cancer. This study examined the unmet sexual and reproductive health needs of breast cancer survivors, as well as concordances and discordances in needs by childbearing status and race. We interviewed 17 women diagnosed with breast cancer between the ages of 18 and 45 years and living in North Carolina. To analyze these data, we used the method, a multidimensional qualitative analysis approach. We learned that breast cancer survivors (a) received limited reproductive health information, (b) desired realistic expectations of conceiving postcancer, (c) struggled with adjusting to their altered physical appearance, and (d) had menopause symptoms that led to sexual health and quality of life issues. Breast cancer survivors are in need of and desire more education and resources to address their sexual and reproductive health concerns.
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http://dx.doi.org/10.1177/1049732320929649DOI Listing
November 2020

Urinary Estrogen Metabolites and Long-Term Mortality Following Breast Cancer.

JNCI Cancer Spectr 2020 Jun 2;4(3):pkaa014. Epub 2020 Mar 2.

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

Background: Estrogen metabolite concentrations of 2-hydroxyestrone (2-OHE) and 16-hydroxyestrone (16-OHE) may be associated with breast carcinogenesis. However, no study has investigated their possible impact on mortality after breast cancer.

Methods: This population-based study was initiated in 1996-1997 with spot urine samples obtained shortly after diagnosis (mean = 96 days) from 683 women newly diagnosed with first primary breast cancer and 434 age-matched women without breast cancer. We measured urinary concentrations of 2-OHE and 16-OHE using an enzyme-linked immunoassay. Vital status was determined via the National Death Index (n = 244 deaths after a median of 17.7 years of follow-up). We used multivariable-adjusted Cox proportional hazards to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the estrogen metabolites-mortality association. We evaluated effect modification using likelihood ratio tests. All statistical tests were two-sided.

Results: Urinary concentrations of the 2-OHE to 16-OHE ratio (>median of 1.8 vs ≤median) were inversely associated with all-cause mortality (HR = 0.74, 95% CI = 0.56 to 0.98) among women with breast cancer. Reduced hazard was also observed for breast cancer mortality (HR = 0.73, 95% CI = 0.45 to 1.17) and cardiovascular diseases mortality (HR = 0.76, 95% CI = 0.47 to 1.23), although the 95% confidence intervals included the null. Similar findings were also observed for women without breast cancer. The association with all-cause mortality was more pronounced among breast cancer participants who began chemotherapy before urine collection (n = 118, HR = 0.42, 95% CI = 0.22 to 0.81) than among those who had not (n = 559, HR = 0.98, 95% CI = 0.72 to 1.34; = .008).

Conclusions: The urinary 2-OHE to 16-OHE ratio may be inversely associated with long-term all-cause mortality, which may depend on cancer treatment status at the time of urine collection.
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http://dx.doi.org/10.1093/jncics/pkaa014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7236781PMC
June 2020

Trends in Late Mortality Among Adolescent and Young Adult Cancer Survivors.

J Natl Cancer Inst 2020 Oct;112(10):994-1002

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

Background: Over the past several decades, treatment of cancer in adolescents and young adults (AYAs) has evolved substantially, leading to steady improvements in estimated 5-year survival at diagnosis. However, the impact on late mortality in this population is largely unexamined. We investigated temporal trends in mortality among 5-year AYA cancer survivors.

Methods: The Surveillance, Epidemiology, and End Results database was used to identify AYAs (age 15-39 years) diagnosed with cancer during 1975-2011 who survived at least 5 years beyond diagnosis. Survival months were accrued from 5 years postdiagnosis until death or the end of 2016. Cumulative mortality from all causes, the primary cancer, other cancers, and noncancer or nonexternal causes (ie, excluding accidents, suicide, homicide) were estimated according to diagnosis era.

Results: Among 282 969 five-year AYA cancer survivors, 5-year mortality (ie, from 5 through 10 years postdiagnosis) from all-causes decreased from 8.3% (95% confidence interval = 8.0% to 8.6%) among those diagnosed in 1975-1984 to 5.4% (95% confidence interval = 5.3% to 5.6%) among those diagnosed in 2005-2011. This was largely explained by decreases in mortality from the primary cancer (6.8% to 4.2%) between these periods. However, for specific cancer types, including colorectal, bone, sarcomas, cervical/uterine, and bladder, cumulative mortality curves demonstrated little improvement in primary cancer mortality over time. Some reduction in late mortality from noncancer or nonexternal causes was apparent for Hodgkin lymphoma, leukemia, kidney cancer, head and neck cancers, and trachea, lung, and bronchus cancers.

Conclusion: Over the past four decades, all-cause and cancer-specific mortality have decreased among 5-year AYA cancer survivors overall, but several cancer types have not shared in these improvements.
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http://dx.doi.org/10.1093/jnci/djaa014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566347PMC
October 2020

Adult weight change and premenopausal breast cancer risk: A prospective pooled analysis of data from 628,463 women.

Int J Cancer 2020 Sep 15;147(5):1306-1314. Epub 2020 Feb 15.

Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.

Early-adulthood body size is strongly inversely associated with risk of premenopausal breast cancer. It is unclear whether subsequent changes in weight affect risk. We pooled individual-level data from 17 prospective studies to investigate the association of weight change with premenopausal breast cancer risk, considering strata of initial weight, timing of weight change, other breast cancer risk factors and breast cancer subtype. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained using Cox regression. Among 628,463 women, 10,886 were diagnosed with breast cancer before menopause. Models adjusted for initial weight at ages 18-24 years and other breast cancer risk factors showed that weight gain from ages 18-24 to 35-44 or to 45-54 years was inversely associated with breast cancer overall (e.g., HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.95-0.98) and with oestrogen-receptor(ER)-positive breast cancer (HR per 5 kg to ages 45-54: 0.96, 95% CI: 0.94-0.98). Weight gain from ages 25-34 was inversely associated with ER-positive breast cancer only and weight gain from ages 35-44 was not associated with risk. None of these weight gains were associated with ER-negative breast cancer. Weight loss was not consistently associated with overall or ER-specific risk after adjusting for initial weight. Weight increase from early-adulthood to ages 45-54 years is associated with a reduced premenopausal breast cancer risk independently of early-adulthood weight. Biological explanations are needed to account for these two separate factors.
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http://dx.doi.org/10.1002/ijc.32892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365745PMC
September 2020

Hospitalization after Adolescent and Young Adult (AYA) Cancer: A Population-Based Study in Utah.

Cancer Epidemiol Biomarkers Prev 2020 02 20;29(2):336-342. Epub 2020 Jan 20.

Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.

Background: Adolescents and young adults (AYA, age 15-39 years) with cancer may be at elevated risk for late morbidity following their cancer treatment, but few studies have quantified the excess burden of severe disease in this population. Using population-based data from Utah, we examined the risk of inpatient hospitalizations among AYA cancer survivors compared with their siblings and the general population.

Methods: Survivors of AYA cancer who were ≥2 years from diagnosis and diagnosed from 1994 to 2015 ( = 6,330), their siblings ( = 12,924), and an age- and sex-matched comparison cohort ( = 18,171) were identified using the Utah Population Database (UPDB). Hospitalizations from 1996 to 2017 were identified from statewide discharge records in the UPDB. We estimated multivariable-adjusted hazard ratios (HR) for first hospitalization and rate ratios (RR) for total hospitalizations for survivors relative to the matched comparison cohort and siblings.

Results: Overall, the risk of a first hospitalization was higher among AYA cancer survivors than the matched population-based cohort [HR = 1.93; 95% confidence interval (CI), 1.81-2.06]. Risk was most elevated for survivors of leukemia (HR = 4.76), central nervous system tumors (HR = 3.45), colorectal cancers (HR = 2.83), non-Hodgkin lymphoma (HR = 2.76), and breast cancer (HR = 2.37). The rate of total hospitalizations was also increased among survivors relative to the comparison cohort (RR = 2.05; 95% CI, 1.95-2.14). Patterns were generally similar in analyses comparing survivors to their siblings.

Conclusions: AYA cancer survivors have a higher burden of inpatient hospitalization than their siblings and the general population.

Impact: Results indicate the importance of long-term, risk-based follow-up care to prevent and treat severe morbidities after cancer treatment.
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http://dx.doi.org/10.1158/1055-9965.EPI-19-1229DOI Listing
February 2020

Tea consumption and breast cancer risk in a cohort of women with family history of breast cancer.

Int J Cancer 2020 08 4;147(3):876-886. Epub 2020 Feb 4.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC.

Laboratory studies have observed chemopreventive effects of black and green tea on breast cancer development, but few epidemiologic studies have identified such effects. We investigated the association between tea consumption and breast cancer risk using data from 45,744 U.S. and Puerto Rican women participating in the Sister Study. Frequency and serving size of black and green tea consumption were measured at cohort enrollment. Breast cancer diagnoses were reported during follow-up and confirmed by medical record review. Multivariable Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI). We further investigated potential variation according to estrogen receptor (ER) status, menopausal status and body mass index (BMI). Overall, 81.6 and 56.0% of women drank black or green tea, respectively. A total of 2,809 breast cancer cases were identified in the cohort. The multivariable model suggested an inverse association between black (≥5 vs. 0 cups/week: HR = 0.88, 95% CI 0.78, 1.00, p-trend = 0.08) and green tea (≥5 vs. 0 cups/week: HR = 0.82, 95% CI 0.70, 0.95, p-trend < 0.01) consumption and breast cancer risk. We did not observe differences by ER characteristics, menopausal status or BMI. In conclusion, our study suggests drinking at least five cups of green or black tea per week may be associated with decreased breast cancer risk.
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http://dx.doi.org/10.1002/ijc.32824DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7283004PMC
August 2020

Premenopausal gynecologic surgery and survival among black and white women with breast cancer.

Cancer Causes Control 2020 Feb 11;31(2):105-112. Epub 2019 Dec 11.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, McGavran-Greenberg Hall, Campus Box 7435, Chapel Hill, NC, 27599, USA.

Purpose: In the United States, hysterectomies and oophorectomies are frequently performed before menopause for benign conditions. The procedures are associated with reduced breast cancer-specific mortality among White women. The relationship between premenopausal gynecologic surgery and mortality in Black women with breast cancer is unknown.

Methods: This investigation used incident invasive cases of breast cancer from Phases 1 and 2 of the Carolina Breast Cancer Study a population-based study that recruited Black and White women in North Carolina between 1993 and 2001. Premenopausal gynecologic surgery was operationalized in three categories: no surgery; hysterectomy with bilateral oophorectomy; hysterectomy with conservation of ≥ 1 ovary. Mortality was ascertained using the National Death Index, last updated in 2016. Multivariable-adjusted Cox Proportional Hazard Models were used to estimate the effect of premenopausal surgery on breast cancer-specific and all-cause mortality RESULTS: Hysterectomy with bilateral oophorectomy was associated with reduced breast cancer-specific mortality (HR 0.68; 95% CI 0.49, 0.96). White and Black women had a similar reduction in breast cancer-specific mortality. (HR among white: 0.66; 95% CI 0.43, 1.02), (HR among Black: 0.67; 95% CI 0.37, 1.21).

Conclusions: There was a similar reduction in breast cancer-specific mortality following premenopausal, pre-diagnosis hysterectomy with bilateral oophorectomy across both Black and White women.
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http://dx.doi.org/10.1007/s10552-019-01255-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6981014PMC
February 2020

Validity of state cancer registry treatment information for adolescent and young adult women.

Cancer Epidemiol 2020 02 5;64:101652. Epub 2019 Dec 5.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, NC, US.

Background: Population-based cancer registries collect information on first course of treatment that may be utilized in research on cancer care quality, yet few studies have investigated the validity of this information. We examined the accuracy and completeness of registry-based treatment information in a cohort of adolescent and young adult women.

Methods: Women diagnosed with breast cancer, lymphoma, thyroid cancer, cervical/uterine cancer or ovarian cancer at ages 15-39 during 2003-2014 were identified using data from the North Carolina Central Cancer Registry (CCR) (N = 2342). CCR data were linked to Medicaid and private insurance claims data, and claims were reviewed for the 12 months following diagnosis to identify cancer treatments received. Using claims data as the gold standard, we calculated the sensitivity and positive predictive value (PPV) of CCR data for receipt of chemotherapy, radiation and hormone therapy. We also compared dates of treatment initiation between the two data sources.

Results: For all cancer types combined, the sensitivity of the CCR data was high for chemotherapy (86%) and moderate for radiation (74%). PPVs were 82% and 83% for chemotherapy and radiation, respectively. Both the sensitivity (67%) and PPV (70%) were lower for hormone therapy for breast cancer. For all three treatment types, dates of initiation in the registry and the claims differed by ≤30 days for most women.

Conclusions: In this cohort of young women, population-based cancer registry data on chemotherapy receipt was reasonably accurate and complete in comparison with insurance claims. Radiation and hormone therapy appeared to be less complete.
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http://dx.doi.org/10.1016/j.canep.2019.101652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983329PMC
February 2020

Reproduction, DNA methylation and biological age.

Hum Reprod 2019 10;34(10):1965-1973

Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC, USA.

Study Question: Are reproductive characteristics associated with genome-wide DNA methylation and epigenetic age?

Summary Answer: Our data suggest that increasing parity is associated with differences in blood DNA methylation and small increases in epigenetic age.

What Is Known Already: A study of 397 young Filipino women (ages 20-22) observed increasing epigenetic age with an increasing number of pregnancies.

Study Design, Size, Duration: We used data from 2356 non-Hispanic white women (ages 35-74) enrolled in the Sister Study cohort.

Participants/materials, Setting, Methods: Data on reproductive history were ascertained via questionnaire. Of the 2356 women, 1897 (81%) reported at least one live birth. Among parous women, 487 (26%) women reported ever experiencing a pregnancy complication. Three epigenetic clocks (i.e. Hannum, Horvath and Levine) and genome-wide methylation were measured in DNA from whole blood using Illumina's HumanMethylation450 BeadChip. We estimated association β-values and 95% CIs using linear regression.

Main Results And The Role Of Chance: All three epigenetic clocks showed weak associations between number of births and epigenetic age (per live birth; Hannum: β = 0.16, 95% CI = 0.02, 0.29, P = 0.03; Horvath: β = 0.12, 95% CI = -0.04, 0.27, P = 0.14; Levine: β = 0.27, 95% CI = 0.08, 0.45, P = 0.01); however, additional adjustment for current BMI attenuated the associations. Among parous women, a history of abnormal glucose tolerance during pregnancy was associated with increased epigenetic age by the Hannum clock (β = 0.96; 95% CI = 0.10, 1.81; P = 0.03) and Levine clocks (β = 1.69; 95% CI = 0.54, 2.84; P < 0.01). In epigenome-wide analysis, increasing parity was associated with methylation differences at 17 CpG sites (Bonferroni corrected P≤ 1.0 × 10-7).

Limitations, Reasons For Caution: We relied on retrospective recall to ascertain reproductive history and pregnancy complications.

Wider Implications Of The Findings: Our findings suggest that parity is associated with small increases in epigenetic age and with DNA methylation at multiple sites in the genome.

Study Funding/competing Interest(s): This research was supported by the Intramural Research program of the NIH, National Institute of Environmental Health Sciences (Z01-ES049033, Z01-ES049032 and Z01-ES044055). None of the authors have a conflict of interest.

Trial Registration Number: Not applicable.
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http://dx.doi.org/10.1093/humrep/dez149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209774PMC
October 2019

Patient/Provider Discussions About Clinical Trial Participation and Reasons for Nonparticipation Among Adolescent and Young Adult Women with Cancer.

J Adolesc Young Adult Oncol 2020 02 23;9(1):41-46. Epub 2019 Sep 23.

Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Clinical trial enrollment is low among adolescents and young adults (AYAs) with cancer and may contribute to inferior survival gains in recent years in this population compared with other age groups. We investigated clinical trial participation among AYA women with cancer, and examined whether patients discussed clinical trial participation with their doctor and reasons for nonparticipation. Women with a diagnosis of breast cancer, thyroid cancer, melanoma, lymphoma, or gynecologic cancer at ages 15-39 years during 2004-2016 were identified from the North Carolina Central Cancer Registry and the Kaiser Permanente Southern California health system. During 2018-2019, a total of 1264 eligible women completed an online survey (response = 13%), which examined survivorship issues among AYAs. Overall, 5% of participants reported that they had participated in a clinical trial. Most women reported that they had not discussed clinical trial participation with a medical provider (76%) and that they did not know whether a relevant trial was available for their cancer (73%). Among those who knew that a trial was available but did not participate, the most commonly reported reasons for nonparticipation included concerns about side effects of the treatment in the trial and concerns that the treatment had not been sufficiently tested. Only a small proportion of AYA women with cancer in our cohort reported discussing a clinical trial with a provider or knowing whether a relevant trial was available. Our findings point to opportunities to improve patient/provider communication to increase clinical trial enrollment among AYAs with cancer.
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http://dx.doi.org/10.1089/jayao.2019.0078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7047091PMC
February 2020

Associations of Leisure-Time Physical Activity and Television Viewing With Life Expectancy Free of Nonfatal Cardiovascular Disease: The ARIC Study.

J Am Heart Assoc 2019 09 9;8(18):e012657. Epub 2019 Sep 9.

Department of Epidemiology University of North Carolina at Chapel Hill NC.

Background High levels of physical activity have been associated with longer life expectancy free of cardiovascular disease (CVD), but specific types of CVD and sedentary behavior have not been examined. We examined associations of leisure-time moderate-to-vigorous physical activity (LTPA) and television viewing with life expectancy free of 3 types of CVD. Methods and Results We included 13 534 participants from the ARIC (Atherosclerosis Risk in Communities) cohort. We used multistate survival models to estimate associations of LTPA in the past year (no LTPA, less than the median, equal to or greater than the median) and television viewing (often or very often, sometimes, seldom or rarely) with life expectancy at age 50 free of nonfatal coronary heart disease (CHD), stroke, and heart failure (HF). Over 27 years of follow-up, 4519 participants developed one of the 3 nonfatal CVDs and 5475 deaths occurred. Compared with participants who engaged in no LTPA, participants who engaged in LTPA equal to or greater than the median had longer life expectancy free of nonfatal CHD (men: 1.5 years [95% CI, 1.0-2.0]; women: 1.6 years [95% CI, 1.1-2.2]), stroke (men: 1.8 years [95% CI, 1.2-2.3]; women: 1.8 years [95% CI, 1.3-2.3]), and HF (men: 1.6 years [95% CI, 1.1-2.1]; women: 1.7 years [95% CI, 1.2-2.2]). Compared with viewing more television, watching less television was associated with longer life expectancy free of CHD, stroke, and HF (≈0.8 year). Conclusions Higher levels of LTPA and less television viewing were associated with longer life expectancy free of CHD, stroke, and HF. Engaging in LTPA and watching less television may increase the number of years lived free of CHD, stroke, and HF.
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http://dx.doi.org/10.1161/JAHA.119.012657DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6818021PMC
September 2019

Risk versus Benefit of Chemoprevention among Raloxifene and Tamoxifen Users with a Family History of Breast Cancer.

Cancer Prev Res (Phila) 2019 11 20;12(11):801-808. Epub 2019 Aug 20.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina.

Tamoxifen and raloxifene have been approved for the primary prevention of breast cancer in high-risk women, but are associated with an increased risk of serious side effects. Few studies have characterized risk-benefit profiles for chemoprevention among women who initiate tamoxifen or raloxifene outside of a clinical trial setting. Use of raloxifene and tamoxifen for chemoprevention was self-reported in 2014 to 2016 by participants in The Sister Study, a prospective cohort of women with a sister who had been diagnosed with breast cancer. After exclusions, 432 current raloxifene users and 96 current tamoxifen users were matched to 4,307 and 953 nonusers, respectively, on age and year of cohort enrollment. Conditional logistic regression was used to evaluate characteristics associated with chemoprevention use. Risk-benefit profiles were examined using published indices that assess the level of evidence (none, moderate, strong) that the benefits of chemoprevention outweigh the risk of serious side effects. Among current chemoprevention users, 44% of tamoxifen users and 5% of raloxifene users had no evidence of a net benefit. In analyses of factors associated with chemoprevention use, having strong evidence of benefit was a significant predictor of raloxifene use, but not of tamoxifen use. In our sample of women with a first-degree family history of breast cancer, raloxifene was more commonly used for breast cancer prevention than tamoxifen. Most raloxifene users, but <60% of tamoxifen users, were likely to benefit. Use of risk-benefit tables can help women and their healthcare providers make an informed decision about breast cancer chemoprevention.
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6825574PMC
November 2019

Airborne mammary carcinogens and breast cancer risk in the Sister Study.

Environ Int 2019 09 18;130:104897. Epub 2019 Jun 18.

Epidemiology Branch, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, United States of America.

Introduction: Potentially carcinogenic hazardous air pollutants (air toxics) have been inconsistently associated with breast cancer. Whether metabolic factors modify these associations is unknown. We studied 29 non-metallic air toxics classified as mammary gland carcinogens in animal studies in relation to breast cancer risk.

Methods: Participants included 49,718 women from the Sister Study. Census tract air toxic concentration estimates from the 2005 National Air Toxics Assessment were linked to enrollment residential addresses. Adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for individual air toxics were estimated using Cox regression. Body mass index (BMI) was considered a potential modifier. Relevant mixtures were identified using classification trees.

Results: Over follow-up (average = 8.4 years), 2975 women were newly diagnosed with breast cancer (invasive or ductal carcinoma in situ). Several air toxics, including methylene chloride, polycyclic organic matter, propylene dichloride, and styrene, were associated with increased risk. Of these, methylene chloride was most consistently associated with risk across multiple analyses. It was associated with overall (HR = 1.21 (95%CI = 1.07-1.38)) and estrogen receptor positive (ER+) invasive breast cancer (HR = 1.28 (95%CI = 1.08-1.52)) in individual pollutant models, although no dose-response was observed. Associations were stronger among overweight/obese (vs. non-overweight/obese) women (p < 0.05) for six air toxics. The classification tree identified combinations of age, methylene chloride, BMI, and four other toxics (propylene dichloride, ethylene dibromide, ethylidene dichloride, styrene) related to overall breast cancer.

Conclusions: Some non-metallic air toxics, particularly methylene chloride, were associated with the hazard for overall and ER+ breast cancer. Overweight/obese women may be particularly susceptible to air toxics.
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http://dx.doi.org/10.1016/j.envint.2019.06.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6679994PMC
September 2019

Disparities in Mortality from Noncancer Causes among Adolescents and Young Adults with Cancer.

Cancer Epidemiol Biomarkers Prev 2019 09 17;28(9):1417-1426. Epub 2019 Jun 17.

Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.

Background: Few studies have examined noncancer outcomes among patients diagnosed with cancer as adolescents and young adults (AYA). We examined risk of mortality from noncancer causes after an AYA cancer diagnosis and investigated disparities according to race/ethnicity and other characteristics.

Methods: Patients with a first primary cancer at ages 15 to 39 years diagnosed during 1987 to 2015 were identified in the Surveillance, Epidemiology, and End Results database ( = 242,940 women, 158,347 men). Survival months were accrued from diagnosis until death or December 2015. Multivariable-adjusted HRs were used to examine disparities in mortality from all noncancer causes, cardiovascular diseases (CVD), and infectious diseases (ID) according to race/ethnicity, geographic region, and county-level characteristics.

Results: For all cancer types combined, the 10-year cumulative incidence of noncancer-related death after AYA cancer was 2% and 5% among women and men, respectively. With adjustment for cancer type, all noncancer mortality was increased among non-Hispanic Black AYAs [HR vs. non-Hispanic White: HR = 2.31; 95% confidence interval (CI): 2.16-2.47; HR = 2.17; 95% CI: 2.05-2.30] and those in the South (HR vs. Northeast: HR = 1.18; 95% CI: 1.07-1.29; HR = 1.42; 95% CI: 1.31-1.55) or in rural counties (HR vs. metro: HR = 1.74; 95% CI: 1.47-2.07; HR = 1.57; 95% CI: 1.33-1.86). Mortality from CVD and ID was also elevated among non-Hispanic Black AYAs.

Conclusions: Results of this study suggest that noncancer mortality after AYA cancer is highest among survivors who are non-Hispanic Black or live in the South or in rural counties.

Impact: Our analyses highlight disparities among AYAs with cancer and identify subgroups that may be targeted for increased medical surveillance or behavioral interventions.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-1384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6726505PMC
September 2019

Fertility-related experiences after breast cancer diagnosis in the Sister and Two Sister Studies.

Cancer 2019 08 23;125(15):2675-2683. Epub 2019 Apr 23.

Department of Epidemiology, UNC Gillings School of Global Public Health, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina.

Background: Commonly used chemotherapies can be toxic to the ovaries. To the authors' knowledge, the majority of studies evaluating receipt of fertility counseling for women in their reproductive years have been performed in specific settings, thereby limiting generalizability.

Methods: A nationwide sample of US women diagnosed with breast cancer before age 45 years completed a survey assessing the prevalence of fertility counseling. Age-adjusted log-binomial regression was used to estimate prevalence ratios (PRs) and 95% CIs for fertility counseling.

Results: Among 432 survivors diagnosed between 2004 and 2011, 288 (67%) had not discussed the effects of treatment on fertility with a health care provider before or during treatment. Fertility discussion was associated with younger age (PR, 3.49 [95% CI, 2.66-4.58] for aged <35 years vs ≥40 years) and lower parity (PR, 1.81 [95% CI, 1.29-2.53] for parity 1 vs 2). Approximately 20% of respondents reported that they were interested in future fertility (87 of 432 respondents) at the time of their diagnosis, but not all of these individuals (66 of 87 respondents) received counseling regarding the impact of treatment on their fertility, and few (8 of 87 respondents) used fertility preservation strategies. Among 68 women with a fertility interest who provided reasons for not taking steps to preserve fertility, reasons cited included concern for an adverse impact on cancer treatment (56%), lack of knowledge (26%), decision to not have a child (24%), and cost (18%).

Conclusions: Across multiple treatment settings, the majority of women of reproductive age who are diagnosed with breast cancer did not discuss fertility with a health care provider or use fertility preservation strategies. Discussing the potential impact of cancer treatment on future fertility is an important aspect of patient education.
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http://dx.doi.org/10.1002/cncr.32126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6935370PMC
August 2019

Noncancer mortality among adolescents and young adults with cancer.

Cancer 2019 06 20;125(12):2107-2114. Epub 2019 Mar 20.

Department of Epidemiology, University of North Carolina, Chapel Hill, North Carolina.

Background: Relative to the general population, cancer patients and survivors may have an elevated risk of mortality from noncancer causes, such as cardiovascular disease and infections, but few studies have examined rates of noncancer mortality among patients diagnosed as adolescents and young adults (AYAs) (ages 15-39 years).

Methods: The Surveillance, Epidemiology, and End Results database was used to identify AYA patients who were diagnosed with a first malignant cancer between 1973 and 2015. Rates of mortality from noncancer causes among AYAs with cancer were compared with those in the general US population using standardized mortality ratios (SMRs), adjusted for age, sex, race, and calendar year.

Results: Among 235,541 AYAs with cancer, a total of 12,948 deaths from noncancer causes occurred over 3.1 million total person-years of follow-up. Overall, noncancer mortality was significantly increased among AYAs with cancer relative to the general population (SMR, 1.84; 95% CI, 1.80-1.87). SMRs were particularly elevated for infectious diseases (SMR, 5.13; 95% CI, 4.95-5.32), cardiovascular disease (SMR, 1.55; 95% CI, 1.50-1.60), and renal diseases (SMR, 2.40; 95% CI, 2.12-2.71). These associations persisted for more than 20 years after cancer diagnosis. Cancer types associated with the highest SMRs for all noncancer mortality included leukemias (SMR, 5.26), Hodgkin lymphoma (SMR, 3.12), non-Hodgkin lymphoma (SMR, 6.33), central nervous system tumors (SMR, 3.38), head and neck cancers (SMR, 2.09), and cervical/uterine cancers (SMR, 2.03).

Conclusions: AYAs with cancer have an elevated burden of mortality from noncancer causes that persists many years after cancer diagnosis, highlighting the importance of comprehensive, long-term follow-up care for noncancer conditions throughout survivorship.
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http://dx.doi.org/10.1002/cncr.32063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001100PMC
June 2019

Breast cancer risk prediction in women aged 35-50 years: impact of including sex hormone concentrations in the Gail model.

Breast Cancer Res 2019 03 19;21(1):42. Epub 2019 Mar 19.

Department of Population Health, New York University School of Medicine, 650 First Avenue, New York, NY, 10016, USA.

Background: Models that accurately predict risk of breast cancer are needed to help younger women make decisions about when to begin screening. Premenopausal concentrations of circulating anti-Müllerian hormone (AMH), a biomarker of ovarian reserve, and testosterone have been positively associated with breast cancer risk in prospective studies. We assessed whether adding AMH and/or testosterone to the Gail model improves its prediction performance for women aged 35-50.

Methods: In a nested case-control study including ten prospective cohorts (1762 invasive cases/1890 matched controls) with pre-diagnostic serum/plasma samples, we estimated relative risks (RR) for the biomarkers and Gail risk factors using conditional logistic regression and random-effects meta-analysis. Absolute risk models were developed using these RR estimates, attributable risk fractions calculated using the distributions of the risk factors in the cases from the consortium, and population-based incidence and mortality rates. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminatory accuracy of the models with and without biomarkers.

Results: The AUC for invasive breast cancer including only the Gail risk factor variables was 55.3 (95% CI 53.4, 57.1). The AUC increased moderately with the addition of AMH (AUC 57.6, 95% CI 55.7, 59.5), testosterone (AUC 56.2, 95% CI 54.4, 58.1), or both (AUC 58.1, 95% CI 56.2, 59.9). The largest AUC improvement (4.0) was among women without a family history of breast cancer.

Conclusions: AMH and testosterone moderately increase the discriminatory accuracy of the Gail model among women aged 35-50. We observed the largest AUC increase for women without a family history of breast cancer, the group that would benefit most from improved risk prediction because early screening is already recommended for women with a family history.
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http://dx.doi.org/10.1186/s13058-019-1126-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6425605PMC
March 2019