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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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Parity is widely recognized as protective for breast cancer, but breast cancer risk may be increased shortly after childbirth. Whether this risk varies with breastfeeding, family history of breast cancer, or specific tumor subtype has rarely been evaluated.Objective: To characterize breast cancer risk in relation to recent childbirth.Design: Pooled analysis of individual-level data from 15 prospective cohort studies.Setting: The international Premenopausal Breast Cancer Collaborative Group.Participants: Women younger than 55 years.Measurements: During 9.6 million person-years of follow-up, 18 826 incident cases of breast cancer were diagnosed. Hazard ratios (HRs) and 95% CIs for breast cancer were calculated using Cox proportional hazards regression.Results: Compared with nulliparous women, parous women had an HR for breast cancer that peaked about 5 years after birth (HR, 1.80 [95% CI, 1.63 to 1.99]) before decreasing to 0.77 (CI, 0.67 to 0.88) after 34 years. The association crossed over from positive to negative about 24 years after birth. The overall pattern was driven by estrogen receptor (ER)-positive breast cancer; no crossover was seen for ER-negative cancer. Increases in breast cancer risk after childbirth were pronounced when combined with a family history of breast cancer and were greater for women who were older at first birth or who had more births. Breastfeeding did not modify overall risk patterns.Limitations: Breast cancer diagnoses during pregnancy were not uniformly distinguishable from early postpartum diagnoses. Data on human epidermal growth factor receptor 2 (HER2) oncogene overexpression were limited.Conclusion: Compared with nulliparous women, parous women have an increased risk for breast cancer for more than 20 years after childbirth. Health care providers should consider recent childbirth a risk factor for breast cancer in young women.Primary Funding Source: The Avon Foundation, the National Institute of Environmental Health Sciences, Breast Cancer Now and the UK National Health Service, and the Institute of Cancer Research. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease (CVD) risk is an important health concern among survivors of breast cancer. However, few studies to date have examined whether trajectories of CVD risk and major risk factors are worse among women with a breast cancer diagnosis compared with those without.Methods: Changes in weight, body mass index, waist circumference, systolic blood pressure, and 10-year CVD risk were compared between women with (813 women) and without (1049 women) an incident breast cancer diagnosis while they were enrolled in the National Institute of Environmental Health Sciences Sister Study cohort. Blood pressure and adiposity measures were collected by trained examiners at an enrollment visit (≥1 year before breast cancer diagnosis) and a second home visit 4 to 11 years later (≥1 year after breast cancer diagnosis). The non-laboratory-based Framingham risk score, a measure of 10-year general CVD risk, was calculated at both the enrollment and second visits. All analyses were stratified by menopausal status at the time of enrollment.Results: Women who were premenopausal at the time of enrollment experienced moderate increases in weight, waist circumference, systolic blood pressure, and CVD risk over the study period. Those who were postmenopausal at the time of enrollment demonstrated little change in weight, but were found to have increases in waist circumference, systolic blood pressure, and CVD risk. In both groups, changes over time did not differ significantly according to breast cancer status. Neither chemotherapy nor endocrine therapy were found to be associated with greater increases in CVD risk or risk factors.Conclusions: In the current study cohort, changes over time in CVD risk, adiposity measures, and blood pressure were similar between women who developed an incident breast cancer and those who did not. [ABSTRACT FROM AUTHOR]

Background: Women may have incomplete understanding of a breast cancer diagnosis, leading to inaccurate reporting in epidemiological studies. However, it is not feasible to obtain consent for medical records from all women participating in a study. Therefore, it is important to determine how well self-reported breast cancer characteristics correspond with what is found in medical records, but few studies have evaluated agreement of self-reported breast cancer characteristics with abstracted medical records.Methods: We calculated the positive predictive value (PPV) of self-reports compared to medical records and explored whether participant characteristics may have influenced reporting accuracy. We analyzed data from 2518 reported breast cancer cases from the Sister Study, a large nationwide cohort of women with a family history of breast cancer.Results: Medical records or pathology reports were obtained for 2066 of 2518 (82%) women who reported incident breast cancer. Breast cancer was confirmed for over 99% (n = 2054) of women with medical records. Confirmation rates were high for invasive, ductal, hormone receptor positive, and HER2 negative breast cancers, with little variation by race/ethnicity or age. Self-reported in situ breast cancer had a lower PPV (64.2%), with medical records showing invasive breast cancer instead, especially for older and Hispanic women. Hormone receptor (ER and PR) negative and HER2 positive self-reports had lower PPVs (83.0%, 71.6%, and 66.1% respectively). Hispanic women and women ages 65 or older at diagnosis were less able to accurately report breast cancer stage, excluding stage I.Conclusions: Accuracy of reporting overall breast cancer and common subtypes is high. Despite having a family history of breast cancer and voluntarily enrolling in a study evaluating breast cancer risk factors, participants may have greater difficulty distinguishing between in situ and invasive breast cancer and may less accurately report other less common subtypes. Discrepancies may reflect women's poor understanding of information conveyed by health care providers or lack of consistent terminology used to describe subtypes. [ABSTRACT FROM AUTHOR]

Purpose National guidelines encourage counseling high-risk women about pharmacologic breast cancer risk reduction. We evaluated the use of integrated health care data to identify and characterize breast cancer chemoprevention use. Chemoprevention included US Food and Drug Administration-approved use of tamoxifen and raloxifene and off-label use of aromatase inhibitors (AIs). Patients and Methods Using electronic medical and pharmacy records (EMRs) in the Kaiser Permanente Northern California health care system, we sampled cancer-free women age 35 to 69 years who used tamoxifen, raloxifene, exemestane, anastrozole, or letrozole from 2005 to 2013. Risk-benefit profiles were calculated for tamoxifen and raloxifene using published indices. The proportion of days covered was calculated from pharmacy records to assess adherence. Results Among 90 chemoprevention users (confirmed with EMR review from a sample of 371 women),74% used tamoxifen, 11% used raloxifene, and 13% used an AI. For tamoxifen and raloxifene users, the riskbenefit index indicated23%of women had insufficient evidence that benefits would outweigh risks. For all agents, adherence decreased from an average proportion of days covered of 75% at 1 year to 67% at 5 years. Automated EMR searches identified breast cancer chemoprevention users with 60% positive predictive value overall and 75% for tamoxifen after post hoc modifications. Conclusion Our study contributes to an emerging picture of breast cancer chemoprevention use in realworld settings, where evidence of net benefit is not uniform and nonadherence is common. Among breast cancer chemoprevention agents, our automated selection best performed for tamoxifen use. We also identified off-label use of AIs for chemoprevention, suggesting that expansion of risk-benefit indices to include AIs is warranted. [ABSTRACT FROM AUTHOR]

Purpose: National guidelines encourage counseling high-risk women about pharmacologic breast cancer risk reduction. We evaluated the use of integrated health care data to identify and characterize breast cancer chemoprevention use. Chemoprevention included US Food and Drug Administration–approved use of tamoxifen and raloxifene and off-label use of aromatase inhibitors (AIs). Patients and Methods: Using electronic medical and pharmacy records (EMRs) in the Kaiser Permanente Northern California health care system, we sampled cancer-free women age 35 to 69 years who used tamoxifen, raloxifene, exemestane, anastrozole, or letrozole from 2005 to 2013. Risk-benefit profiles were calculated for tamoxifen and raloxifene using published indices. The proportion of days covered was calculated from pharmacy records to assess adherence. Results: Among 90 chemoprevention users (confirmed with EMR review from a sample of 371 women), 74% used tamoxifen, 11% used raloxifene, and 13% used an AI. For tamoxifen and raloxifene users, the risk-benefit index indicated 23% of women had insufficient evidence that benefits would outweigh risks. For all agents, adherence decreased from an average proportion of days covered of 75% at 1 year to 67% at 5 years. Automated EMR searches identified breast cancer chemoprevention users with 60% positive predictive value overall and 75% for tamoxifen after post hoc modifications. Conclusion: Our study contributes to an emerging picture of breast cancer chemoprevention use in real-world settings, where evidence of net benefit is not uniform and nonadherence is common. Among breast cancer chemoprevention agents, our automated selection best performed for tamoxifen use. We also identified off-label use of AIs for chemoprevention, suggesting that expansion of risk-benefit indices to include AIs is warranted. [ABSTRACT FROM AUTHOR]

Black women experience higher rates of hysterectomy than other women in the United States. Although research indicates that premenopausal hysterectomy with bilateral oophorectomy decreases the risk of breast cancer in black women, it remains unclear how hysterectomy without ovary removal affects risk, whether menopausal hormone therapy use attenuates inverse associations, and whether associations vary by cancer subtype. In the population-based, case-control Carolina Breast Cancer Study of invasive breast cancer in 1,391 black (725 cases, 666 controls) and 1,727 white (939 cases, 788 controls) women in North Carolina (1993-2001 ), we investigated the associations of premenopausal hysterectomy and oophorectomy with breast cancer risk. Compared with no history of premenopausal surgery, bilateral oophorectomy and hysterectomy without oophorectomy were associated with lower odds of breast cancer (for bilateral oophorectomy, multivariable-adjusted odds ratios = 0.60, 95% confidence interval: 0.47, 0.77; for hysterectomy without oophorectomy, multivariable-adjusted odds ratios = 0.68, 95% confidence interval: 0.55, 0.84). Estimates did not vary by race and were similar for hormone receptor-positive and hormone receptor-negative cancers. Use of estrogen-only menopausal hormone therapy did not attenuate the associations. Premenopausal hysterectomy, even without ovary removal, may reduce the long-term risk of hormone receptor-positive and hormone receptor-negative breast cancers. Varying rates of hysterectomy are a potentially important contributor to differences in breast cancer incidence among racial/ethnic groups. [ABSTRACT FROM AUTHOR]

[Display omitted] Light at night (LAN) may alter estrogen regulation through circadian disruption. High levels of outdoor LAN may increase breast cancer risk, but studies have largely not considered possible residual confounding from correlated environmental exposures. We evaluated the association between indoor and outdoor LAN and incident breast cancer. In 47,145 participants in the prospective Sister Study cohort living in the contiguous U.S., exposure to outdoor LAN was determined using satellite-measured residential data and indoor LAN was self-reported (light/TV on, light from outside the room, nightlight, no light). We used Cox proportional hazards models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations between outdoor and indoor LAN and breast cancer risk. Models were adjusted for age, race/ethnicity, educational attainment, annual household income, neighborhood disadvantage, latitude, and population density as a proxy for urbanicity. To evaluate the potential for residual confounding of the outdoor LAN and breast cancer relationship by factors associated with urbanicity, we considered further adjustment for exposures correlated with outdoor LAN including NO 2 [Spearman correlation coefficient, rho (ρ) = 0.78], PM 2.5 (ρ = 0.36), green space (ρ = − 0.41), and noise (ρ = 0.81). During 11 years of follow-up, 3,734 breast cancer cases were identified. Outdoor LAN was modestly, but non-monotonically, associated with a higher risk of breast cancer (Quintile 4 vs 1: HR = 1.10, 95% CI: 0.99–1.22; Quintile 5 vs 1: HR = 1.04, 95% CI: 0.93–1.16); however, no association was evident after adjustment for correlated ambient exposures (Quintile 4 vs 1: HR = 0.99, 95% CI: 0.86–1.14; Quintile 5 vs 1: HR = 0.89, 95% CI: 0.74–1.06). Compared to those with no indoor LAN exposure, sleeping with a light or TV on was associated with a HR = 1.09 (95% CI: 0.97–1.23) in the adjusted model. Outdoor LAN does not appear to increase the risk of breast cancer after adjustment for correlated environmental exposures. [ABSTRACT FROM AUTHOR]

Background: Greater body mass index (BMI), a measure of overall adiposity, is associated with a higher risk of postmenopausal breast cancer. The role of central adiposity, often measured by waist circumference, is less well understood, especially among premenopausal women. The objective of the current study was to examine multiple measures of adiposity in relation to breast cancer in a prospective cohort study.Methods: A total of 50,884 Sister Study cohort participants aged 35 to 74 years were enrolled from 2003 through 2009. Inclusion criteria for the cohort included having a sister previously diagnosed with breast cancer. Trained study personnel measured height, weight, and waist and hip circumference during a home visit and study participants completed a detailed questionnaire. Using Cox regression analysis, we estimated multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs) for breast cancer risk associated with adiposity measurements, considering tumor subtype and menopausal status.Results: In total, 2009 breast cancers were diagnosed during follow-up (mean = 5.4 years). Weight, BMI, waist circumference, and waist-to-hip ratio were found to be positively associated with overall breast cancer risk and HRs were greater among postmenopausal women, those with hormonally responsive tumors, and women who were not currently using postmenopausal hormones. In models that adjusted for BMI, waist circumference associations persisted among both postmenopausal women (81-88 cm vs ≤80 cm: HR = 1.16 [95% CI 1.01-1.35] and >88 cm vs ≤80 cm: HR = 1.30 [95% CI 1.10-1.54]) and premenopausal women (81-88 cm vs ≤80 cm: HR = 1.56 [95% CI 1.19-2.04] and >88 cm vs ≤80 cm: HR = 1.30 [95% CI 0.91-1.87]).Conclusions: Findings from this large, prospective study with examiner-measured body size indicate that waist circumference is independently and positively associated with both premenopausal and postmenopausal breast cancer risk. [ABSTRACT FROM AUTHOR]

The article discusses the results of a study that determined if the premenopausal bilateral oophorectomy's protective effect on breast cancer risk is mitigated by the use of estrogen therapy after surgery. The study showed a 14 percent increase in breast cancer risk among women using estrogens after total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAHBSO). It concludes that unopposed use of estrogen does not negate breast cancer risk reduction associated with oophorectomy.

Bilateral oophorectomy is often performed during hysterectomy for benign conditions and can reduce breast cancer risk by 20%–50% when performed at younger ages. Accuracy of estimating the decrease in breast cancer risk associated with bilateral oophorectomy could be affected by common conditions that lead to surgery, such as uterine fibroids or endometriosis. The authors examined the potential for confounding by nonmalignant indications for surgery on breast cancer risk estimates in a population-based case-control study of invasive breast cancer newly diagnosed in 1992–1995. Breast cancer cases (N = 4,935) aged 50–79 years were identified from Wisconsin, Massachusetts, and New Hampshire tumor registries; similarly aged controls (N = 5,111) were selected from driver's license and Medicare lists. Reproductive and medical history was obtained from structured telephone interviews. Odds ratios and 95% confidence intervals were estimated with multivariate logistic regression. Women who underwent bilateral oophorectomy with hysterectomy at age ≤40 years had significantly reduced odds of breast cancer (odds ratio = 0.74, 95% confidence interval: 0.60, 0.90) compared with women with intact ovaries and uterus. Effect estimates were virtually unchanged after adjustment for uterine fibroids or endometriosis history. Results indicate that breast cancer risk reductions conferred by bilateral oophorectomy are not strongly confounded by failure to account for nonmalignant indications for surgery. [ABSTRACT FROM PUBLISHER]

Objective: To evaluate obstetric and neonatal outcomes of the first live birth conceived 1 or more years after breast cancer diagnosis.Methods: We performed a population-based study to compare live births between women with a history of breast cancer (case group) and matched women with no cancer history (control group). Individuals in the case and control groups were identified using linked data from the California Cancer Registry and California Office of Statewide Health Planning and Development data sets. Individuals in the case group were diagnosed with stage I-III breast cancer at age 18-45 years between January 1, 2000, and December 31, 2012, and conceived 12 or more months after breast cancer diagnosis. Individuals in the control group were covariate-matched women without a history of breast cancer who delivered during 2000-2012. The primary outcome was preterm birth at less than 37 weeks of gestation. Secondary outcomes were preterm birth at less than 32 weeks of gestation, small for gestational age (SGA), cesarean delivery, severe maternal morbidity, and neonatal morbidity. Subgroup analyses were used to assess the effect of time from initial treatment to fertilization and receipt of additional adjuvant therapy before pregnancy on outcomes of interest.Results: Of 30,021 women aged 18-45 years diagnosed with stage I-III breast cancer during 2000-2012, 553 met the study inclusion criteria. Those with a history of breast cancer and matched women in the control group had similar odds of preterm birth at less than 37 weeks of gestation (odds ratio [OR], 1.29; 95% CI 0.95-1.74), preterm birth at less than 32 weeks of gestation (OR 0.77; 95% CI 0.34-1.79), delivering an SGA neonate (less than the 5th percentile: OR 0.60; 95% CI 0.35-1.03; less than the 10th percentile: OR 0.94; 95% CI 0.68-1.30), and experiencing severe maternal morbidity (OR 1.61; 95% CI 0.74-3.50). Patients with a history of breast cancer had higher odds of undergoing cesarean delivery (OR 1.25; 95% CI 1.03-1.53); however, their offspring did not have increased odds of neonatal morbidity compared with women in the control group (OR 1.15; 95% CI 0.81-1.62).Conclusion: Breast cancer 1 or more years before fertilization was not strongly associated with obstetric and neonatal complications. [ABSTRACT FROM AUTHOR]

Simple Summary: Adolescents and young adults (AYAs) experiencing cancer have support needs that differ from older adult cancer patients. The aim of our qualitative study was to determine the holistic needs of AYA cancer survivors and to develop a patient-centered conceptual model of AYA survivorship care. Analysis of our interview results reveals eight key domains critical to holistic patient-centered AYA survivorship care. We offer a conceptual model that differs from current conceptual models of AYA survivorship care by centering the patient and their support systems, emphasizing the need for continuing supportive navigation, and the importance of repeated support along the identified domains over time. Purpose: Conceptual models provide frameworks to illustrate relationships among patient-, provider-, system-, and community-level factors that inform care delivery and research. Existing models of cancer survivorship care focus largely on pediatric or adult populations whose needs differ from adolescents and young adults (AYAs). We developed a patient-centered conceptual model of AYA survivorship care. Methods: We conducted a narrative literature review of current conceptual and theoretical models of care. We engaged AYA cancer survivors (n = 25) in semi-structured one-hour telephone interviews. Most participants were in their 20s and 30s, and the majority (84%) were women. Recruitment was stratified by age and time since cancer diagnosis. We conducted a thematic analysis of interview transcripts to identify themes that exemplified patient-centered care. Results: Most participants identified as white and female. Leukemia and breast cancer were the most common cancer types. Main themes included the need for (1) care coordination, (2) ongoing mental health support, (3) connection to AYA peer support, (4) support during fertility preservation efforts, (5) support with financial burden, (6) support for quality of life, (7) information about and support with side effects and late effects, and (8) attention to the unique needs of young adults. Conclusions: We present a patient-centered conceptual model of AYA survivorship care needs that can inform future cancer care delivery and research. [ABSTRACT FROM AUTHOR]

BACKGROUND: Improvements in cancer survival mean that an increasing number of survivors may live long enough beyond their initial cancer to be diagnosed with additional independent primary cancers. The proportion of newly diagnosed cancers that are second‐ or higher‐order primaries and how this proportion has changed over the past several decades were examined. METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER) program were used to identify incident malignant primaries diagnosed between 1975 and 2017. Using the SEER sequence number, the authors tabulated the proportion of all cancers in each calendar year that were second‐ or higher‐order primaries. The average annual percent change (AAPC) was then calculated to assess how this proportion has changed over time. RESULTS: Analyses included nearly 4.9 million incident cancers diagnosed during 1975‐2017. The proportion of all cancers that were second‐ or higher‐order increased steadily from 9.77% during 1975‐1984 to 21.03% during 2015‐2017, reflecting an AAPC of 2.41% (95% CI, 2.16%‐2.65%). In 2015‐2017, second‐ or higher‐order cancers were most prevalent among cancers of the bladder (28.79%), followed by lung and bronchus (28.07%), melanoma (27.88%), and leukemia (26.10%). The highest AAPCs over the study period were observed for melanoma (4.05%), leukemia (3.51%), and lung and bronchus (3.36%). CONCLUSIONS: The proportion of newly diagnosed cancers that are second‐ or higher‐order has grown rapidly over the past several decades and currently exceeds 20%. Continued monitoring of second and later primaries will be critical for anticipating the future impact on cancer treatment and survivorship care. In the United States, the proportion of newly diagnosed cancers that are second‐ or higher‐order has grown rapidly over the past several decades and currently exceeds 20%. Because the challenges associated with 2 or more primary cancer diagnoses may be substantial and unique, continued monitoring of second‐ or higher‐order cancers will be critical for anticipating the future impact on cancer treatment and survivorship care. [ABSTRACT FROM AUTHOR]

Background: Cancer survivors have increased risk of endocrine complications, but there is a lack of information on the occurrence of specific endocrinopathies at the population-level. Methods: We used data from the California Cancer Registry (2006–2018) linked to statewide hospitalisation, emergency department, and ambulatory surgery databases. We estimated the cumulative incidence of and factors associated with endocrinopathies among adolescents and young adults (AYA, 15–39 years) who survived ≥2 years after diagnosis. Results: Among 59,343 AYAs, 10-year cumulative incidence was highest for diabetes (4.7%), hypothyroidism (4.6%), other thyroid (2.2%) and parathyroid disorders (1.6%). Hypothyroidism was most common in Hodgkin lymphoma, leukaemia, breast, and cervical cancer survivors, while diabetes was highest among survivors of leukaemias, non-Hodgkin lymphoma, colorectal, cervical, and breast cancer. In multivariable models, factors associated with increased hazard of endocrinopathies were treatment, advanced stage, public insurance, residence in low/middle socioeconomic neighbourhoods, older age, and non-Hispanic Black or Hispanic race/ethnicity. Haematopoietic cell transplant was associated with most endocrinopathies, while chemotherapy was associated with a higher hazard of ovarian dysfunction and hypothyroidism. Conclusions: We observed a high burden of endocrinopathies among AYA cancer survivors, which varied by treatment and social factors. Evidence-based survivorship guidelines are needed for surveillance of these diseases. [ABSTRACT FROM AUTHOR]

Venous thromboembolism (VTE), a common complication in cancer patients, occurs more often during the initial phase of treatment. However, information on VTE beyond the first two years after diagnosis ('late VTE') is scarce, particularly in young survivors. We examined the risk of, and factors associated with, late VTE among adolescents and young adults (AYA, 15–39 years) diagnosed with cancer (2006–2018) who survived ≥2 years. Data were obtained from the California Cancer Registry linked to hospitalization, emergency department and ambulatory surgery data. We used non-parametric models and Cox proportional hazard regression for analyses. Among 59,343 survivors, the 10-year cumulative incidence of VTE was 1.93 % (CI 1.80–2.07). The hazard of VTE was higher among those who had active cancer, including progression from lower stages to metastatic disease (Hazard Ratio (HR) = 10.41, 95 % confidence interval (CI): 8.86–12.22), second primary cancer (HR = 2.58, CI:2.01–3.31), or metastatic disease at diagnosis (HR = 2.38, CI:1.84–3.09). The hazard of late VTE was increased among survivors who underwent hematopoietic cell transplantation, those who received radiotherapy, had a VTE history, public insurance (vs private) or non-Hispanic Black/African American race/ethnicity (vs non-Hispanic White). Patients with leukemias, lymphomas, sarcoma, melanoma, colorectal, breast, and cervical cancers had a higher VTE risk than those with thyroid cancer. VTE risk remained elevated ≥2 years following cancer diagnosis in AYA survivors. Active cancer is a significant risk factor for VTE. Future studies might determine if late VTE should prompt evaluation for recurrence or second malignancy, if not already known. • Risk of VTE persists after cancer treatment in adolescents and young adults. • Hematopoietic cell transplant, prior VTE, and active cancer are VTE risk factors. • Black race/ethnicity and public insurance are associated with increased VTE risk. • If not already known, late VTE may prompt second cancer or recurrence evaluation. [ABSTRACT FROM AUTHOR]

Purpose: We assessed the cross-sectional association between healthy dietary patterns [alternate Mediterranean diet (aMED), Dietary Approaches to Stop Hypertension (DASH), alternative Healthy Eating Index (aHEI), and Healthy Eating Index 2015 (HEI-2015)] and urinary biomarkers of oxidative stress. Methods: Between 2003 and 2009, the Sister Study enrolled 50,884 breast cancer-free US women aged 35 to 74 (non-Hispanic White, 83.7%). Data were analyzed for 844 premenopausal and 454 postmenopausal women who had urine samples analyzed for F2-isoprostanes and non-missing covariate data. Food frequency questionnaire responses were used to calculate dietary pattern scores. Concentrations of 8-iso-prostaglandin F2α (8-iso-PGF2α) and its metabolite (8-iso-PGF2α-M) were measured in urine samples by GC/MS for premenopausal women and LC/MS for postmenopausal women. Multivariable linear regression models were used to estimate associations between aMED, DASH, aHEI, and HEI-2015 and urinary F2-isoprostanes by menopausal status. Effect modification by sociodemographic, lifestyle, and clinical characteristics was also evaluated. Results: Among premenopausal women, the four dietary indices were inversely associated with 8-iso-PGF2α (aMED βQ4vsQ1: − 0.17, 95% CI − 0.27, − 0.08; DASH βQ4vsQ1: − 0.18, 95% CI − 0.28, − 0.08; aHEI βQ4vsQ1: − 0.20, 95% CI − 0.30, − 0.10; HEI-2015 βQ4vsQ1: − 0.19, 95% CI − 0.29, − 0.10). In contrast, inverse associations with 8-iso-PGF2α-M were found for the continuous aMED, aHEI, and HEI-2015. Associations between dietary indices and 8-iso-PGF2α were generally stronger among younger women, women with lower income, and women with higher BMI. Similar results were observed among postmenopausal women, though only the continuous DASH and aHEI models were statistically significant. Conclusion: Healthy dietary patterns were associated with lower levels of oxidative stress. [ABSTRACT FROM AUTHOR]

In survival data analysis, a competing risk is an event whose occurrence precludes or alters the chance of the occurrence of the primary event of interest. In large cohort studies with long‐term follow‐up, there are often competing risks. Further, if the event of interest is rare in such large studies, the case‐cohort study design is widely used to reduce the cost and achieve the same efficiency as a cohort study. The conventional additive hazards modeling for competing risks data in case‐cohort studies involves the cause‐specific hazard function, under which direct assessment of covariate effects on the cumulative incidence function, or the subdistribution, is not possible. In this paper, we consider an additive hazard model for the subdistribution of a competing risk in case‐cohort studies. We propose estimating equations based on inverse probability weighting methods for the estimation of the model parameters. Consistency and asymptotic normality of the proposed estimators are established. The performance of the proposed methods in finite samples is examined through simulation studies and the proposed approach is applied to a case‐cohort dataset from the Sister Study. [ABSTRACT FROM AUTHOR]

Purpose: Invasive breast cancers are thought to arise from in situ lesions, but some ductal carcinoma in situ (DCIS) are indolent with low likelihood of progressing to invasive carcinoma. Comparison of risk factor associations between DCIS and invasive disease may elucidate which factors influence early versus late stages of carcinogenesis. Therefore, we determined whether there were differences in risk factor profiles for screen-detected DCIS and invasive breast cancer among Luminal A lesions. Methods: We conducted a case-control analysis using data from the Carolina Breast Cancer Study (1993–2001). Analyses were restricted to Luminal A tumors and screen-detected tumors among mammography-eligible women, to limit confounding by mode of detection (N = 108 DCIS; N = 203 invasive). Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations between risk factors and lesion type. Results: In stratified analyses, we observed qualitative differences in the direction of association for ever smoking, obese BMI, high waist-to-hip-ratio (WHR), and ≥10 years of oral contraceptive use between DCIS and invasive disease. Breastfeeding was inversely associated with invasive disease and was not associated with DCIS. Interaction tests for risk factor associations between Luminal A DCIS and invasive breast cancer were not statistically significant (p>0.05). Conclusions: Among Luminal A tumors, established breast cancer risk factors may exert stronger effects on progression of early lesions to invasive disease, with lesser effects on risk of DCIS. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Weight Gain After Breast Cancer Diagnosis and All-Cause Mortality: Systematic Review and Meta-Analysis."

Background: There are few assessments evaluating associations between birth defects with neural crest cell developmental origins (BDNCOs) and embryonal tumors, which are characterized by undifferentiated cells having a molecular profile similar to neural crest cells. The effect of BDNCOs on embryonal tumors was estimated to explore potential shared etiologic pathways and genetic origins. Methods: With the use of a multistate, registry‐linkage cohort study, BDNCO–embryonal tumor associations were evaluated by generating hazard ratios (HRs) and 95% confidence intervals (CIs) with Cox regression models. BDNCOs consisted of ear, face, and neck defects, Hirschsprung disease, and a selection of congenital heart defects. Embryonal tumors included neuroblastoma, nephroblastoma, and hepatoblastoma. Potential HR modification (HRM) was investigated by infant sex, maternal race/ethnicity, maternal age, and maternal education. Results: The risk of embryonal tumors among those with BDNCOs was 0.09% (co‐occurring n = 105) compared to 0.03% (95% CI, 0.03%–0.04%) among those without a birth defect. Children with BDNCOs were 4.2 times (95% CI, 3.5–5.1 times) as likely to be diagnosed with an embryonal tumor compared to children born without a birth defect. BDNCOs were strongly associated with hepatoblastoma (HR, 16.1; 95% CI, 11.3–22.9), and the HRs for neuroblastoma (3.1; 95% CI, 2.3–4.2) and nephroblastoma (2.9; 95% CI, 1.9–4.4) were elevated. There was no notable HRM by the aforementioned factors. Conclusions: Children with BDNCOs are more likely to develop embryonal tumors compared to children without a birth defect. Disruptions of shared developmental pathways may contribute to both phenotypes, which could inform future genomic assessments and cancer surveillance strategies of these conditions. Associations between nonchromosomal birth defects of neural crest cell developmental origins and pediatric embryonal tumors were investigated based on potential shared developmental pathways. With the use of data from a multistate, registry‐linkage cohort study, children born with these birth defects were found to be more likely (hazard ratio, 4.2; 95% CI, 3.5–5.1) to be diagnosed with the selected embryonal tumors than children without a birth defect, especially hepatoblastoma (hazard ratio, 16.1; 95% CI, 11.3–22.9). [ABSTRACT FROM AUTHOR]

Background: Tamoxifen has been US Food and Drug Administration-approved for primary prevention of breast cancer since 1998 but has not been widely adopted, in part because of increased risk of serious side effects. Little is known about the risk-benefit profiles of women who use chemoprevention outside of a clinical trial. We examined characteristics associated with initiation and discontinuation of tamoxifen for primary prevention of breast cancer within a large cohort of women with a first-degree family history of breast cancer.Methods: This research was conducted within The Sister Study, a cohort of 50884 US and Puerto Rican women age 35 to 74 years enrolled from 2003 to 2009. Eligible women were breast cancer-free at enrollment and had a sister who had been diagnosed with breast cancer. Participants reported tamoxifen use, ages started and stopped taking tamoxifen, and total duration of use at enrollment. We identified 788 tamoxifen users and 3131 nonusers matched on age and year of enrollment who had no history of contraindicating factors (stroke, transient ischemic attack, cataract, endometrial or uterine cancer). Characteristics associated with tamoxifen initiation were evaluated with multivariable conditional logistic regression. All statistical tests were two-sided.Results: Based on published risk-benefit indices, 20% of women who used tamoxifen had insufficient evidence that the benefits of tamoxifen outweigh the risk of serious side effects. After 4.5 years, 46% of women had discontinued tamoxifen.Conclusions: While the majority of women who used tamoxifen for primary prevention of breast cancer were likely to benefit, substantial discontinuation of tamoxifen before five years and use by women at risk of serious side effects may attenuate benefits for breast cancer prevention. [ABSTRACT FROM AUTHOR]

Background: Tamoxifen has been US Food and Drug Administration–approved for primary prevention of breast cancer since 1998 but has not been widely adopted, in part because of increased risk of serious side effects. Little is known about the risk-benefit profiles of women who use chemoprevention outside of a clinical trial. We examined characteristics associated with initiation and discontinuation of tamoxifen for primary prevention of breast cancer within a large cohort of women with a first-degree family history of breast cancer. Methods: This research was conducted within The Sister Study, a cohort of 50884 US and Puerto Rican women age 35 to 74 years enrolled from 2003 to 2009. Eligible women were breast cancer–free at enrollment and had a sister who had been diagnosed with breast cancer. Participants reported tamoxifen use, ages started and stopped taking tamoxifen, and total duration of use at enrollment. We identified 788 tamoxifen users and 3131 nonusers matched on age and year of enrollment who had no history of contraindicating factors (stroke, transient ischemic attack, cataract, endometrial or uterine cancer). Characteristics associated with tamoxifen initiation were evaluated with multivariable conditional logistic regression. All statistical tests were two-sided. Results: Based on published risk-benefit indices, 20% of women who used tamoxifen had insufficient evidence that the benefits of tamoxifen outweigh the risk of serious side effects. After 4.5 years, 46% of women had discontinued tamoxifen. Conclusions: While the majority of women who used tamoxifen for primary prevention of breast cancer were likely to benefit, substantial discontinuation of tamoxifen before five years and use by women at risk of serious side effects may attenuate benefits for breast cancer prevention. [ABSTRACT FROM PUBLISHER]

Background: Many studies have examined long-term outcomes after childhood cancer, but few address outcomes for adolescent and young adult (AYA; those aged 15-39 years) cancer survivors. Conditional survival reflects changing mortality risk with time since cancer diagnosis and is a useful measure for planning long-term follow-up care.Methods: Using the Surveillance, Epidemiology, and End Results registry 9 database, the authors identified a cohort of AYA patients diagnosed with a first malignant cancer between 1973 and 2009 and followed through 2014. They estimated 5-year relative survival at the time of diagnosis and at each additional year survived up to 25 years after diagnosis, conditional on the individual being alive at the beginning of that year.Results: A total of 205,954 AYA patients with cancer were identified. Thyroid cancer, melanoma, testicular cancer, breast cancer, lymphoma, leukemia, and central nervous system (CNS) tumors comprised 67% of all cancers. For all cancers combined, 5-year relative survival was 84.5% (95% confidence interval, 84.3%-84.7%) at 1 year after diagnosis and 94.0% (95% CI, 93.9%-94.2%) at 5 years. The relative survival first exceeded 95%, reflecting minimal excess mortality compared with the general population, at 7 years. Patients with thyroid cancer, testicular cancer, melanoma, and breast cancer reached a relative survival of >95% at the time of diagnosis and at 1, 3, and 18 years after diagnosis, respectively. Estimates for those with Hodgkin lymphoma and leukemia were >95% at 6 and 13 years, respectively, but declined to <95% at 20 years. AYA individuals with CNS tumors did not reach 95% by 25 years after diagnosis.Conclusions: For AYA survivors of breast cancer, CNS tumors, and hematologic malignancies, long-term excess mortality should be considered when planning follow-up care. Cancer 2018;124:3037-43. © 2018 American Cancer Society. [ABSTRACT FROM AUTHOR]

Treatment for endometrial cancer may contribute to bowel dysfunction and other gastrointestinal outcomes. We investigated the risk of several gastrointestinal diagnoses among older women with endometrial cancer and matched women without a history of cancer. Women aged 66 years and older diagnosed with endometrial cancer during 2004–2017 (N = 44,386) and matched women without a known cancer history (N = 221,219) were identified in the SEER-Medicare linked data. An index date was defined as the endometrial cancer diagnosis date in that matched set. ICD-9 and -10 diagnosis codes were used to define gastrointestinal outcomes, including constipation, abdominal pain, IBS, fecal incontinence, bowel obstruction, ileus, radiation enteritis or proctitis, colonic stricture, and vascular insufficiency of the bowel in the Medicare claims. Hazard ratios (HRs) for incident gastrointestinal diagnoses were estimated using multivariable Cox proportional hazards regression models. Compared to women without cancer, women with endometrial cancer had an increased risk of gastrointestinal symptoms after the index date, including constipation (HR = 2.27; 95% CI: 2.22–2.32), abdominal pain (HR = 2.94; 95% CI: 2.89–2.99), and fecal incontinence (HR = 1.96; 95% CI: 1.83–2.10). The risk of other gastrointestinal diagnoses was also higher among women with endometrial cancer (e.g., bowel obstruction: HR = 5.72; 95% CI: 5.47–5.98; ileus: HR = 7.22; 95% CI: 6.89–7.57). These associations were also apparent in sensitivity analyses limited to 1+ and 5+ years after the index date. Older women with endometrial cancer experience an excess risk of gastrointestinal diagnoses that may persist long after cancer diagnosis. Surveillance for these conditions may be a critical part of survivorship care. • Older women with endometrial cancer had a higher incidence of gastrointestinal diagnoses than matched women without cancer. • These diagnoses included constipation, abdominal pain, bowel obstruction, colonic stricture, and other conditions. • The increased risk among women with endometrial cancer persisted even at 5+ years after cancer diagnosis. [ABSTRACT FROM AUTHOR]

To examine whether demographic and cancer-related characteristics and factors such as fertility discussion with a medical provider and fertility preservation use are associated with attempting pregnancy after adolescent and young adult cancer. Cross-sectional online survey. Not applicable. Women with lymphoma, breast cancer, thyroid cancer, or gynecologic cancer diagnosed at 15–39 years from 2004 to 2016 were identified from the North Carolina Cancer Registry and the Kaiser Permanente Northern and Southern California health care systems and responded to an online survey addressing survivorship concerns, including fertility and reproductive outcomes. Demographic characteristics, cancer characteristics, fertility discussion with a medical provider or fertility specialist between cancer diagnosis and starting cancer treatment, use of fertility preservation strategies (freezing embryos or oocytes) after cancer diagnosis. Pregnancy attempt after cancer diagnosis, defined by either a pregnancy or 12 months of trying to become pregnant without pregnancy. Among 801 participants who had not reached their desired family size at diagnosis, 77% had a fertility discussion with any medical provider between cancer diagnosis and treatment initiation, and 8% used fertility preservation after cancer diagnosis. At survey (median =7 years after diagnosis; interquartile range, 4–10), 32% had attempted pregnancy. Neither fertility discussion with any medical provider nor fertility counseling with a fertility specialist was significantly associated with pregnancy attempts. However, the use of fertility preservation was significantly associated with attempting pregnancy (prevalence ratios = 1.74; 95% confidence interval: 1.31–2.32). Other characteristics positively associated with pregnancy attempts included younger age at diagnosis, longer time since diagnosis, having a partner (at diagnosis or at survey), and having a history of infertility before cancer diagnosis. Use of fertility preservation strategies was uncommon in our cohort but was associated with attempting pregnancy after cancer. Ensuring access to fertility preservation methods may help adolescent and young adult cancer survivors to plan and initiate future fertility. [ABSTRACT FROM AUTHOR]

Disparities exist in fertility-sparing treatment and the use of assisted reproductive technology among patients with gynecologic malignancies. OBJECTIVE: To assess the presence of sociodemographic and clinical disparities in fertility-sparing treatment and assisted reproductive technology (ART) use among patients with a history of cervical, endometrial, or ovarian cancer. METHODS: We conducted a population-based cohort study of patients aged 18–45 years who were diagnosed with cervical cancer (stage IA, IB), endometrial cancer (grade 1, stage IA, IB), or ovarian cancer (stage IA, IC) between January 1, 2000, and December 31, 2015, using linked data from the CCR (California Cancer Registry), the California Office of Statewide Health Planning and Development, and the Society for Assisted Reproductive Technology. The primary outcome was receipt of fertility-sparing treatment , defined as surgical or medical treatment to preserve the uterus and at least one ovary. The secondary outcome was fertility preservation , defined as ART use after cancer diagnosis. Multivariable logistic regression analysis was used to estimate odds ratios and 95% CIs for the association between fertility-sparing treatment and exposures of interest: age at diagnosis, race and ethnicity, health insurance, socioeconomic status, rurality, and parity. RESULTS: We identified 7,736 patients who were diagnosed with cervical, endometrial, or ovarian cancer with eligible histology. There were 850 (18.8%) fertility-sparing procedures among 4,521 cases of cervical cancer, 108 (7.2%) among 1,504 cases of endometrial cancer, and 741 (43.3%) among 1,711 cases of ovarian cancer. Analyses demonstrated nonuniform patterns of sociodemographic disparities by cancer type for fertility-sparing treatment, and ART. Fertility-sparing treatment was more likely among young patients, overall, and of those in racial and ethnic minority groups among survivors of cervical and ovarian cancer. Use of ART was low (n=52) and was associated with a non-Hispanic White race and ethnicity designation, being of younger age (18–35 years), and having private insurance. CONCLUSION: This study demonstrates that clinical and sociodemographic disparities exist in the receipt of fertility-sparing treatment and ART use among patients with a history of cervical, endometrial, or ovarian cancer. [ABSTRACT FROM AUTHOR]

Background: Fertility preservation (FP) may be underused after cancer diagnosis because of uncertainty around delays to cancer treatment and subsequent reproductive success. Methods: Women aged 15 to 39 years diagnosed with cancer between 2004 and 2015 were identified from the North Carolina Central Cancer Registry. Use of assisted reproductive technology (ART) after cancer diagnosis between 2004 and 2018 (including FP) was assessed through linkage to the Society for Assisted Reproductive Technology. Linear regression was used to examine time to cancer treatment among women who did (n = 95) or did not (n = 469) use FP. Modified Poisson regression was used to estimate risk ratios (RRs) and 95% CIs for pregnancy and birth based on timing of ART initiation relative to cancer treatment (n = 18 initiated before treatment for FP vs n = 26 initiated after treatment without FP). Results: The median time to cancer treatment was 9 to 33 days longer among women who used FP compared with women who did not, matched on clinical factors. Women who initiated ART before cancer treatment may be more likely to have a live birth given pregnancy compared with women who initiated ART after cancer treatment (age‐adjusted RR, 1.47; 95% CI, 0.98‐2.23), though this may be affected by the more frequent use of gestational carriers in the former group (47% vs 20% of transfer cycles, respectively). Conclusions: FP delayed gonadotoxic cancer treatment by up to 4.5 weeks, a delay that would not be expected to alter prognosis for many women. Further study of the use of gestational carriers in cancer populations is warranted to better understand its effect on reproductive outcomes. In this statewide retrospective cohort, adolescent and young adult women with cancer who used fertility preservation experienced up to a 4.5‐week delay in receipt of first gonadotoxic cancer treatment, but may have an increased likelihood of live birth after achieving pregnancy compared to women with cancer who used assisted reproduction without prior fertility preservation. [ABSTRACT FROM AUTHOR]

Study Question: What are the associations between a history of cancer and outcomes after ART?Summary Answer: Compared to women without cancer, on average, women with cancer had a lower return for embryo transfer and a lower likelihood of clinical pregnancy and live birth after ART.What Is Known Already: Small, single-institution studies have suggested that cancer and its treatment may negatively affect ART outcomes.Study Design, Size, Duration: We conducted a systematic review with meta-analysis of studies comparing ART outcomes between women with and without cancer. PubMed, Embase and Scopus were searched for original, English-language studies published up to June 2021.Participants/materials, Setting, Methods: Inclusion criteria required reporting of ART outcomes after controlled ovarian stimulation (COS) among women with a history of cancer compared to women without cancer who used ART for any indication. Outcomes of interest ranged from duration of COS to likelihood of live birth after embryo transfer. Random-effects meta-analysis was used to calculate mean differences and odds ratios (ORs) with 95% CIs and 95% prediction intervals (PIs). We assessed heterogeneity by age-adjustment, referent group indication for ART, study location and among women with breast cancer and women who initiated ART before cancer treatment. We used visual inspection, Egger's test and the trim-and-fill method to assess funnel plot asymmetry.Main Results and the Role Of Chance: Of 6094 unique records identified, 42 studies met inclusion criteria, representing a median per study of 58 women with cancer (interquartile range (IQR) = 159) and 114 women without cancer (IQR = 348). Compared to women without cancer, on average, women with cancer had a lower return for embryo transfer (OR: 0.22; 95% CI: 0.07, 0.74; 95% PI: 0.00, 64.98); lower likelihood of clinical pregnancy (OR: 0.51; 95% CI: 0.35, 0.73; 95% PI: 0.19, 1.35); and lower likelihood of live birth (OR: 0.56; 95% CI: 0.38, 0.83; 95% PI: 0.19, 1.69). Substantial among-study heterogeneity was observed for COS duration, gonadotropin dose, cycle cancellation, total oocytes and mature oocytes. Fertilization percentage showed less heterogeneity, but study-specific estimates were imprecise. Similarly, number of embryos showed less heterogeneity, and most studies estimated minimal differences by cancer history. Funnel plot asymmetry was observed for estradiol peak and oocyte maturation percentage.Limitations, Reasons For Caution: Appreciable confounding is possible in 11 studies that lacked adequate control for group differences in age, and among-study heterogeneity was observed for most outcomes. Lack of data limited our ability to assess how cancer clinical factors (e.g. cancers other than breast, cancer stage and treatment) and ART cycle characteristics (e.g. fresh versus frozen embryo transfers and use of gestational carriers) may affect outcomes.Wider Implications Of the Findings: Women with cancer may be less likely to achieve pregnancy and live birth after embryo transfer. Further examination of reproductive outcomes and sources of heterogeneity among studies is warranted to improve evidence of the expected success of ART after a cancer diagnosis.Study Funding/competing Interest(s): This research was supported in part by R01 CA211093 and P30 ES010126. C.M. was supported by the University of North Carolina Lineberger Cancer Control Education Program (T32 CA057726) and the National Cancer Institute (F31 CA260787). J.A.R.-H. was supported by the National Cancer Institute (K08 CA234333, P30 CA016672). J.A.R.-H. reports receiving consulting fees from Schlesinger Group and Guidepoint. The remaining authors declare no competing interests.Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Study Question: Is there an association between fertility status, method of conception and the risks of birth defects and childhood cancer?Summary Answer: The risk of childhood cancer had two independent components: (i) method of conception and (ii) presence, type and number of birth defects.What Is Known Already: The rarity of the co-occurrence of birth defects, cancer and ART makes studying their association challenging. Prior studies have indicated that infertility and ART are associated with an increased risk of birth defects or cancer but have been limited by small sample size and inadequate statistical power, failure to adjust for or include plurality, differences in definitions and/or 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 2017 that resulted in live births in 2004-2018 in Massachusetts and North Carolina and live births in 2004-2017 in Texas and New York. A 10:1 sample of non-ART births were chosen within the same time period as the ART birth. Non-ART siblings were identified through the ART mother's information. Children from non-ART births were classified as being born to women who conceived with ovulation induction or IUI (OI/IUI) when there was an indication of infertility treatment on the birth certificate, and 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 165 125 ART children, 31 524 non-ART siblings, 12 451 children born to OI/IUI-treated women and 1 353 440 naturally conceived children. 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), and calculated rates per 1000 children. Logistic regression models were used to generate adjusted odds ratios (AORs) and 95% CIs of the risk of birth defects by conception group (OI/IUI, non-ART sibling and ART by oocyte source and embryo state) with naturally conceived children as the reference, adjusted for paternal and maternal ages; maternal race and ethnicity, education, BMI, parity, diabetes, hypertension; and for plurality, infant sex and State and year of birth. All study children were also linked to their respective State cancer registries. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% CIs of cancer by birth defect status (including presence of a defect, type and number of defects), and conception group.Main Results and the Role Of Chance: A total of 29 571 singleton children (2.0%) and 3753 twin children (3.5%) had a major birth defect (chromosomal or nonchromosomal). Children conceived with ART from autologous oocytes had increased risks for nonchromosomal defects, including blastogenesis, cardiovascular, gastrointestinal and, for males only, genitourinary defects, with AORs ranging from 1.22 to 1.85; children in the autologous-fresh group also had increased risks for musculoskeletal (AOR 1.28, 95% CI 1.13, 1.45) and orofacial defects (AOR 1.40, 95% CI 1.17, 1.68). Within the donor oocyte group, the children conceived from fresh embryos did not have increased risks in any birth defect category, whereas children conceived from thawed embryos had increased risks for nonchromosomal defects (AOR 1.20, 95% CI 1.03, 1.40) and blastogenesis defects (AOR 1.74, 95% CI 1.14, 2.65). The risk of cancer was increased among ART children in the autologous-fresh group (HR 1.31, 95% CI 1.08, 1.59) and non-ART siblings (1.34, 95% CI 1.02, 1.76). The risk of leukemia was increased among children in the OI/IUI group (HR 2.15, 95% CI 1.04, 4.47) and non-ART siblings (HR 1.63, 95% CI 1.02, 2.61). The risk of central nervous system tumors was increased among ART children in the autologous-fresh group (HR 1.68, 95% CI 1.14, 2.48), donor-fresh group (HR 2.57, 95% CI 1.04, 6.32) and non-ART siblings (HR 1.84, 95% CI 1.12, 3.03). ART children in the autologous-fresh group were also at increased risk for solid tumors (HR 1.39, 95% CI 1.09, 1.77). A total of 127 children had both major birth defects and cancer, of which 53 children (42%) had leukemia. The risk of cancer had two independent components: (i) method of conception (described above) and (ii) presence, type and number of birth defects. The presence of nonchromosomal defects increased the cancer risk, greater for two or more defects versus one defect, for all cancers and each type evaluated. The presence of chromosomal defects was strongly associated with cancer risk (HR 8.70 for all cancers and HR 21.90 for leukemia), further elevated in the presence of both chromosomal and nonchromosomal defects (HR 21.29 for all cancers, HR 64.83 for leukemia and HR 4.71 for embryonal tumors). Among the 83 946 children born from ART in the USA in 2019 compared to their naturally conceived counterparts, these risks translate into an estimated excess of 761 children with major birth defects, 31 children with cancer and 11 children with both major birth defects and cancer.Limitations, Reasons For Caution: In the SART CORS database, it was not possible to differentiate method of embryo freezing (slow freezing versus vitrification), and data on ICSI were 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. Since OI/IUI is underreported on the birth certificate, some OI/IUI children were likely included among the naturally conceived children, which will decrease the difference between all the groups and the naturally conceived children.Wider Implications Of the Findings: The use of ART is associated with increased risks of major nonchromosomal birth defects. The presence of birth defects is associated with greater risks for cancer, which adds to the baseline risk in the ART group. Although this study does not show causality, these findings indicate that children conceived with ART, non-ART siblings, and all children with birth defects should be monitored more closely for the subsequent development of cancer.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. M.L.E. reports consultancy for Ro, Hannah, Dadi, Sandstone and Underdog; presidency of SSMR; and SMRU board member. The remaining authors report no conflict of interest.Trial Registration Number: N/A. [ABSTRACT FROM AUTHOR]

Endometrial cancer (EC) shares risk factors (e.g. obesity) with cardiovascular disease (CVD), yet little research has investigated CVD diagnoses among EC survivors. We aimed to describe the burden of CVD diagnoses among older women with EC compared to women without a cancer history. Women aged 66+ years with an EC diagnosis during 2004–2017 (N = 44,386) and matched women without cancer (N = 221,219) were identified in the SEER-Medicare linked data. An index date was defined as the cancer diagnosis date of the EC case in that matched set. ICD-9/10 diagnosis codes were used to define CVD outcomes in the Medicare claims. Prevalent CVD was identified using diagnosis codes in the year before the index date. Hazard ratios (HRs) for incident CVD diagnoses after the index date were estimated using multivariable Cox proportional hazards regression. Women with a prevalent CVD were excluded from incidence analyses for that outcome. Compared to women without cancer, women with EC had a higher prevalence of CVD diagnoses at the index date. In analyses beginning follow-up at 1 year post-index date, EC survivors had an increased risk of incident CVD diagnoses including ischemic heart diseases (HR = 1.73; 95% CI: 1.69–1.78), pulmonary heart disease (HR = 1.95; 95% CI: 1.88–2.02), and diseases of the veins and lymphatics (HR = 2.71; 95% CI: 95% CI: 2.64–2.78). Risk of CVD diagnoses among women with EC was also elevated within the first year post-index date. Management of pre-existing CVD and monitoring for incident CVD may be critical during EC treatment and throughout long-term survivorship. • Women with endometrial cancer had a higher prevalence of CVD at their cancer diagnosis than matched women without cancer. • Incidence of new CVD diagnoses was also higher among endometrial cancer survivors than women without cancer. • Monitoring for CVD may be critical during endometrial cancer treatment and throughout long-term survivorship. [ABSTRACT FROM AUTHOR]

Purpose: Carotenoids may protect against chronic diseases including cancer and cardiometabolic disease by mitigating oxidative stress and/or inflammation. We cross-sectionally evaluated associations between carotenoids and biomarkers of oxidative stress or inflammation. Methods: From 2003 to 2009, the Sister Study enrolled 50,884 breast cancer-free US women aged 35–74. Post-menopausal participants (n = 512) were randomly sampled to measure carotenoids and biomarkers of oxidative stress. Dietary carotenoid consumption was assessed using a validated 110-item Block 1998 food frequency questionnaire; use of β-carotene-containing supplements was also assessed. Plasma carotenoids were quantified, adjusting for batch. Urinary markers of lipid peroxidation, 8-iso-prostaglandin F2α (8-iso-PGF2α) and its metabolite (8-iso-PGF2α-M) were also measured. Since the biomarker 8-iso-PGF2α can reflect both oxidative stress and inflammation, we used a modeled 8-iso-PGF2α to prostaglandin F2α ratio approach to distinguish effects reflecting oxidative stress versus inflammation. Multivariable linear regression was used to assess the associations of dietary and plasma carotenoids with the estimated biomarker concentrations. Results: Total plasma carotenoids were inversely associated with 8-iso-PGF2α-M concentrations (P for trend across quartiles = 0.009). Inverse trends associations were also seen for α-carotene and β-carotene. In contrast, lutein/zeaxanthin showed associations with both 8-iso-PGF2α and 8-iso-PGF2α-M concentrations. The inverse association for total carotenoids appeared to be specific for oxidative stress (chemical 8-iso-PGF2α; Phighest vs. lowest quartile = 0.04 and P for trend across quartiles = 0.02). The pattern was similar for α-carotene. However, lutein/zeaxanthin tended to have a stronger association with enzymatic 8-iso-PGF2α, suggesting an additional anti-inflammatory effect. Supplemental β-carotene was inversely associated with both 8-iso-PGF2α and 8-iso-PGF2α-M concentrations, as well as with both chemical and enzymatic 8-iso-PGF2α. Dietary carotenoids were not associated with either biomarker. Conclusion: Plasma carotenoids and supplemental β-carotene were associated with lower concentrations of 8-iso-PGF2α metabolite. Plasma carotenoids associations may reflect antioxidant effects. [ABSTRACT FROM AUTHOR]

Purpose: Functional status deficits are important quality of life concerns for older cancer survivors. We examined the prevalence of falls, walking/balance problems, and limitations in activities of daily living (ADLs) among older women with a history of endometrial cancer. Methods: Cancer registry records from the Surveillance, Epidemiology, and End Results (SEER) program linked with Medicare Health Outcomes Survey (MHOS) data were used to identify endometrial cancer survivors aged ≥ 65 years who completed a survey ≥ 1 year after their cancer diagnosis (N = 3766), as well as an age- and race-matched group of women without a cancer history (N = 3766). We estimated prevalence ratios (PRs) to compare the prevalence of falls, walking or balance problems, and limitations in ADLs (bathing, dressing, eating, getting in/out of chairs, walking, using the toilet) between groups. Results: Difficulty with walking or balance was more common among survivors than the noncancer group (43% vs 36%; PR = 1.19; 95% CI: 1.10–1.27). Fall prevalence was similar between groups (endometrial cancer: 25%; noncancer: 26%; PR = 0.98; 95% CI: 0.89–1.08). Nearly half of endometrial cancer survivors (47%) reported at least one ADL limitation, with several activities (getting in/out of a chair, walking, bathing, using the toilet) more often limited among survivors than among women without cancer. Conclusion: Functional impairments, especially problems with walking and/or balance, are common among older endometrial cancer survivors. Our results highlight the importance of addressing functional problems during the ongoing survivorship care of women with a history of endometrial cancer, with referral to rehabilitation or other relevant services when indicated. [ABSTRACT FROM AUTHOR]

Background: Young adult cancer survivors experience frailty and decreased muscle mass at rates equivalent to much older noncancer populations, which indicate accelerated aging. Although frailty and low muscle mass can be identified in survivors, their implications for health‐related quality of life are not well understood. Methods: Through a cross‐sectional analysis of young adult cancer survivors, frailty was assessed with the Fried frailty phenotype and skeletal muscle mass in relation to functional and quality of life outcomes measured by the Medical Outcomes Survey Short‐Form 36 (SF‐36). z tests compared survivors with US population means, and multivariable linear regression models estimated mean SF‐36 scores by frailty and muscle mass with adjustments made for comorbidities, sex, and time from treatment. Results: Sixty survivors (median age, 21 years; range, 18‐29) participated in the study. Twenty‐five (42%) had low muscle mass, and 25 were either frail or prefrail. Compared with US population means, survivors reported worse health and functional impairments across SF‐36 domains that were more common among survivors with (pre)frailty or low muscle mass. In multivariable linear modeling, (pre)frail survivors (vs nonfrail) exhibited lower mean scores for general health (−9.1; P =.05), physical function (−14.9; P <.01), and overall physical health (−5.6; P =.02) independent of comorbid conditions. Conclusions: Measures of frailty and skeletal muscle mass identify subgroups of young adult cancer survivors with significantly impaired health, functional status, and quality of life independent of medical comorbidities. Identifying survivors with frailty or low muscle mass may provide opportunities for interventions to prevent functional and health declines or to reverse this process. Lay Summary: Young adult cancer survivors age more quickly than peers without cancer, which is evidenced by a syndrome of decreased resilience known as frailty.The relationship between frailty (and one of its common components, decreased muscle mass) and quality of life among young adult cancer survivors was examined.Measuring decreased muscle mass and frailty identifies young survivors with poor quality of life, including worse general health, fatigue, physical function, and overall physical health, compared with nonfrail survivors.Interventions to address components of frailty (low muscle mass and weakness) may improve function and quality of life among young adult cancer survivors. Measuring decreased muscle mass and frailty identifies young adult cancer survivors with poor quality of life, including worse general health, fatigue, physical function, and overall physical health, compared with nonfrail survivors. Interventions to address components of frailty (low muscle mass and weakness) may improve function and quality of life among young adult cancer survivors. [ABSTRACT FROM AUTHOR]

The greatest difference in mortality was observed for >=85-year-old decedents, where annual heart disease crude mortality rates were 2.4 to 3.4 times higher than cancer crude mortality rates. Several studies have examined the accuracy of death certificates to classify heart disease mortality, reporting overestimates of heart disease mortality, particularly for elderly decedents. Finally, for decedents 25-44 years of age, stagnation in crude heart disease mortality rates combined with declines in cancer crude mortality rates resulted in equivalent crude mortality rates by 2018. [Extracted from the article]

Black women suffer a higher mortality from endometrial cancer (EC) than White women. Potential biological causes for this disparity include a higher prevalence of obesity and more lethal histologic/molecular subtypes. We hypothesize that another biological factor driving this racial disparity could be the EC microbiome. Banked tumor specimens of postmenopausal, Black and White women undergoing hysterectomy for early stage endometrioid EC were identified. The microbiota of the tumors were characterized by bacterial 16S rRNA sequencing. The microbial component of endometrioid ECs in The Cancer Genome Atlas (TCGA) database were assessed for comparison. 95 early stage ECs were evaluated: 23 Black (24%) and 72 White (76%). Microbial diversity was increased (p < 0.001), and Firmicutes , Cyanobacteria and OD1 phyla abundance was higher in tumors from Black versus White women (p < 0.001). Genus level abundance of Dietzia and Geobacillus were found to be lower in tumors of obese Black versus obese White women (p < 0.001). Analysis of early stage ECs in TCGA found that microbial diversity was higher in ECs from Black versus White women (p < 0.05). When comparing ECs from obese Black versus obese White women, 5 bacteria distributions were distinct, with higher abundance of Lactobacillus acidophilus in ECs from Black women being the most striking difference. Similarly in TCGA, Dietzia and Geobacillus were more common in ECs from White women compared to Black. Increased microbial diversity and the distinct microbial profiles between ECs of obese Black versus obese White women suggests that intra-tumoral bacteria may contribute to EC disparities and pathogenesis. • The endometrial cancer microbiome differs between obese Black women and obese White women. • Microbial diversity is increased in endometrial cancer tumors of obese Black women versus obese White women. • Intra-tumoral bacteria may contribute to the disparities and pathogenesis of endometrial cancer. [ABSTRACT FROM AUTHOR]

Background: The history of gestational diabetes mellitus (GDM) has been associated with breast cancer risk in some studies, particularly in young women, but results of cohort studies are conflicting.Methods: We pooled data from 257 290 young (age <55 years) women from five cohorts. We used multivariable Cox proportional-hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between GDM history and risk of breast cancer, overall and by oestrogen receptor (ER) status, before age 55 years, adjusted for established breast cancer risk factors.Results: Five percent of women reported a history of GDM and 6842 women reported an incident breast-cancer diagnosis (median follow-up = 16 years; maximum = 24 years). Compared with parous women without GDM, women with a history of GDM were not at increased risk of young-onset breast cancer overall (HR = 0.90; 95% CI: 0.78, 1.03) or by ER status (HR = 0.96; 95% CI: 0.79, 1.16 for ER-positive; HR = 1.07; 95% CI: 0.78, 1.47 for ER-negative). Compared with nulliparous women, parous women with a history of GDM had a lower risk of breast cancer overall (HR = 0.79; 95% CI: 0.68, 0.91) and of ER-positive (HR = 0.82; 95% CI: 0.66, 1.02) but not ER-negative (HR = 1.09; 95% CI: 0.76, 1.54) invasive breast cancer. These results were consistent with the HRs comparing parous women without GDM to nulliparous women.Conclusions: Results of this analysis do not support the hypothesis that GDM is a risk factor for breast cancer in young women. Our findings suggest that the well-established protective effect of parity on risk of ER-positive breast cancer persists even for pregnancies complicated by GDM. [ABSTRACT FROM AUTHOR]

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. Data from a nationwide sample of US breast cancer survivors are used to examine associations between patient characteristics (breast cancer clinical features, prognostic factors, and treatments) and health‐related quality of life (HRQOL). The findings suggest that prognostic and cancer treatment–related factors affect HRQOL in breast cancer survivors and that poor HRQOL may increase mortality risk. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. Female adolescent and young adult cancer survivors can be particularly vulnerable to adverse employment and financial outcomes. Those with cancer‐related employment disruption report increased financial hardship related to material conditions and psychological distress. [ABSTRACT FROM AUTHOR]

• mtDNA copy number (CN) from dried blood spots and whole blood were correlated. • Stability of mtDNA-CN in dried bloods spots from two time points was moderate. • Measuring mtDNA-CN in dried blood spots may be a valid alternative to whole blood. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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 Sort and Sift, Think and Shift© 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. [ABSTRACT FROM AUTHOR]

Purpose: 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. Methods: 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. Results: 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. Conclusion: 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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Although annual breast magnetic resonance imaging (MRI) is recommended for women at high risk for breast cancer as an adjunct to screening mammography, breast MRI use remains low. We examined factors associated with breast MRI use in a cohort of women with a family history of breast cancer but no personal cancer history. Study participants came from the Sister Study cohort, a nationwide, prospective study of women with at least 1 sister who had been diagnosed with breast cancer but who themselves had not ever had breast cancer (n = 17 894). Participants were surveyed on breast cancer beliefs, cancer worry, breast MRI use, provider communication, and genetic counseling and testing. Logistic regression was used to assess factors associated with having a breast MRI overall and for those at high risk. Breast MRI was reported by 16.1% and was more common among younger women and those with higher incomes. After adjustment for demographics, ever use of breast MRI was associated with actual and perceived risk. Odds ratios (OR) were 12.29 (95% CI, 8.85‐17.06), 2.48 (95% CI, 2.27‐2.71), and 2.50 (95% CI, 2.09‐2.99) for positive BRCA1/2 test, lifetime breast cancer risk ≥ 20%, and being told by a health care provider of higher risk, respectively. Women who believed they had much higher risk than others or had higher level of worry were twice as likely to have had breast MRI; OR = 2.23 (95% CI, 1.82‐2.75) and OR = 1.76 (95% CI, 1.52‐2.04). Patterns were similar among women at high risk. Breast cancer risk, provider communication, and personal beliefs were determinants of breast MRI use. To support shared decisions about the use of breast MRI, women could benefit from improved understanding of the chances of getting breast cancer and increased quality of provider communications. [ABSTRACT FROM AUTHOR]