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BackgroundGonadotoxic treatment-related infertility has a significant impact on quality of life in childhood cancer survivors. Genome-wide association analyses to delineate the risk of infertility in childhood cancer survivors have not been previously reported.MethodsLeveraging genotype data from a large survivor cohort, the Childhood Cancer Survivor Study (CCSS), we investigated the role of SNPs on future pregnancy or siring a pregnancy in survivors without pelvic, testicular, or brain radiation who had ever been married. We calculated sex-stratified hazard ratios, using Cox proportional hazards modeling, adjusting for birth cohort (before 1965 vs. 1965 or later) and doses of relevant chemotherapies; replication was attempted in the independent St. Jude Lifetime Cohort study (SJLIFE).ResultsIn the CCSS cohort, nine SNPs were found to be suggestive (P < 10-7) or statistically significantly (P < 5 × 10-8) associated with pregnancy, however, none of the SNPs were replicated in SJLIFE. Cohorts differed based on the overall pregnancy rate, frequency of sterilizing procedures, and birth cohort.ConclusionsWe were not able to replicate our findings of SNPs associated with pregnancy in childhood cancer survivors.ImpactFuture attempts at replication should be considered in cohorts treated in a comparable era. In addition, understanding the role of genetics in fertility in childhood cancer survivors may be better approached using more advanced sequencing techniques.

BackgroundEarly initiation of breast cancer screening is recommended for high-risk women, including survivors of childhood cancer treated with chest radiation. Recent studies suggest that female survivors of childhood leukemia or sarcoma treated without chest radiation are also at elevated early onset breast cancer risk. However, the potential clinical benefits and cost-effectiveness of early breast cancer screening among these women are uncertain.MethodsUsing data from the Childhood Cancer Survivor Study, we adapted 2 Cancer Intervention and Surveillance Modeling Network simulation models to reflect the elevated risks of breast cancer and competing mortality among leukemia and sarcoma survivors. Costs and utility weights were based on published studies and databases. Outcomes included breast cancer deaths averted, false-positive screening results, benign biopsies, and incremental cost-effectiveness ratios.ResultsIn the absence of screening, the lifetime risk of dying from breast cancer among survivors was 6.8% to 7.0% across models. Early initiation of annual mammography with breast magnetic resonance imaging screening between ages 25 and 40 years would avert 52.6% to 64.3% of breast cancer deaths. When costs and quality-of-life impacts were considered, screening starting at age 40 years was the only strategy with an incremental cost-effectiveness ratio below the $100 000 per quality-adjusted life-year (QALY) gained cost-effectiveness threshold ($27 680 to $44 380 per QALY gained across models).ConclusionsAmong survivors of childhood leukemia or sarcoma, early initiation of breast cancer screening at age 40 years may reduce breast cancer deaths by half and is cost-effective. These findings could help inform screening guidelines for survivors treated without chest radiation.

BackgroundSurveillance with annual mammography and breast magnetic resonance imaging (MRI) is recommended for female survivors of childhood cancer treated with chest radiation, yet benefits, harms, and costs are uncertain.ObjectiveTo compare the benefits, harms, and cost-effectiveness of breast cancer screening strategies in childhood cancer survivors.DesignCollaborative simulation modeling using 2 Cancer Intervention and Surveillance Modeling Network breast cancer models.Data sourcesChildhood Cancer Survivor Study and published data.Target populationWomen aged 20 years with a history of chest radiotherapy.Time horizonLifetime.PerspectivePayer.InterventionAnnual MRI with or without mammography, starting at age 25, 30, or 35 years.Outcome measuresBreast cancer deaths averted, false-positive screening results, benign biopsy results, and incremental cost-effectiveness ratios (ICERs).Results of base-case analysisLifetime breast cancer mortality risk without screening was 10% to 11% across models. Compared with no screening, starting at age 25 years, annual mammography with MRI averted the most deaths (56% to 71%) and annual MRI (without mammography) averted 56% to 62%. Both strategies had the most screening tests, false-positive screening results, and benign biopsy results. For an ICER threshold of less than $100 000 per quality-adjusted life-year gained, screening beginning at age 30 years was preferred.Results of sensitivity analysisAssuming lower screening performance, the benefit of adding mammography to MRI increased in both models, although the conclusions about preferred starting age remained unchanged.LimitationElevated breast cancer risk was based on survivors diagnosed with childhood cancer between 1970 and 1986.ConclusionEarly initiation (at ages 25 to 30 years) of annual breast cancer screening with MRI, with or without mammography, might reduce breast cancer mortality by half or more in survivors of childhood cancer.Primary funding sourceAmerican Cancer Society and National Institutes of Health.

BackgroundPoor socioeconomic and health-related quality of life (HRQOL) outcomes in survivors of childhood cancer can lead to distress and overall negatively impact the lives of these individuals. The current report has highlighted the impact of stroke and stroke recurrence on mortality, psychological HRQOL, and socioeconomic outcomes within the Childhood Cancer Survivor Study (CCSS).MethodsThe CCSS is a retrospective cohort study with longitudinal follow-up concerning survivors of pediatric cancer who were diagnosed between 1970 and 1986. Mortality rates per 100 person-years were calculated across 3 periods: 1) prior to stroke; 2) after first stroke and before recurrent stroke; and 3) after recurrent stroke. Socioeconomic outcomes, the standardized Brief Symptoms Inventory-18, the Medical Outcomes Study 36-Item Short Form Health Survey, and the CCSS-Neurocognitive Questionnaire also were assessed.ResultsAmong 14,358 participants (median age, 39.7 years), 224 had a stroke after their cancer diagnosis (single stroke in 161 patients and recurrent stroke in 63 patients). Based on 2636 deaths, all-cause late mortality rates were 0.70 (95% CI, 0.68-0.73) prior to stroke, 1.03 (95% CI, 0.73-1.46) after the first stroke, and 2.42 (95% CI, 1.48-3.94) after the recurrent stroke. Among 7304 survivors, those with stroke were more likely to live with a caregiver (single stroke odds ratio [OR], 2.3 [95% CI, 1.4-3.8]; and recurrent stroke OR, 5.3 [95% CI, 1.7-16.8]) compared with stroke-free survivors. Stroke negatively impacted task efficiency (single stroke OR, 2.4 [95% CI, 1.4-4.1] and recurrent stroke OR, 3.3 [95% CI, 1.1-10.3]) and memory (single stroke OR, 2.1 [95% CI, 1.2-3.7]; and recurrent stroke OR, 3.5 [95% CI, 1.1-10.5]).ConclusionsStroke and stroke recurrence are associated with increased mortality and negatively impact HRQOL measures in survivors of pediatric cancer.

BackgroundEwing sarcoma survivors (ESSs) are at increased risk for treatment-related complications. The incidence of treatment-related morbidity and late mortality with aging is unknown.MethodsThis study reports survival probabilities, estimated with the Kaplan-Meier method, and the cumulative incidence of cause-specific mortality and chronic conditions among ESSs in the Childhood Cancer Survivor Study who were treated between 1970 and 1986. Piecewise exponential models were used to estimate relative rates (RRs) and 95% confidence intervals (CIs) for these outcomes. Chronic conditions were graded with the Common Terminology Criteria for Adverse Events (version 4.03).ResultsAmong 404 5-year ESSs (median age at last follow-up, 34.8 years; range, 9.1-54.8 years), the 35-year survival rate was 70% (95% CI, 66%-74%). Late recurrence (cumulative incidence at 35 years, 15.1%) was the most common cause of death, and it was followed by treatment-related causes (11.2%). There were 53 patients with subsequent neoplasms (SNs; cumulative incidence at 35 years, 24.0%), and 38 were malignant (14.3% at 35 years). The standardized incidence ratios were 377.1 (95% CI, 172.1-715.9) for osteosarcoma, 28.9 (95% CI, 3.2-104.2) for acute myeloid leukemia, 14.9 (95% CI, 7.9-25.5) for breast cancer, and 13.1 (95% CI, 4.8-28.5) for thyroid cancer. Rates of chronic conditions were highest for musculoskeletal (RR, 18.1; 95% CI, 12.8-25.7) and cardiac complications (RR, 1.8; 95% CI, 1.4-2.3). Thirty-five years after the diagnosis, the cumulative incidences of any chronic conditions and 2 or more chronic conditions were 84.6% (95% CI, 80.4%-88.8%) and 73.8% (95% CI, 67.8%-79.9%), respectively.ConclusionsWith extended follow-up, ESSs' risk for late mortality and SNs does not plateau. Treatment-related chronic conditions develop years after therapy, and this supports the need for lifelong follow-up. Cancer 2017;123:2551-60. © 2017 American Cancer Society.

Background Early efforts at risk-adapted therapy for neuroblastoma are predicted to result in differential late effects; the magnitude of these differences has not been well described. Methods Late mortality, subsequent malignant neoplasms (SMNs), and severe/life-threatening chronic health conditions (CHCs), graded according to CTCAE v4.03, were assessed among 5-year Childhood Cancer Survivor Study (CCSS) survivors of neuroblastoma diagnosed 1987-1999. Using age, stage at diagnosis, and treatment, survivors were classified into risk groups (low [n = 425]; intermediate [n = 252]; high [n = 245]). Standardized mortality ratios (SMRs) and standardized incidence ratios (SIRs) of SMNs were compared with matched population controls. Cox regression models estimated hazard ratios (HRs) and 95% confidence intervals for CHC compared with 1029 CCSS siblings. Results Among survivors (49.8% male; median age = 21 years, range = 7-42; median follow-up = 19.3 years, range = 5-29.9), 80% with low-risk disease were treated with surgery alone, whereas 79.1% with high-risk disease received surgery, radiation, chemotherapy ± autologous stem cell transplant (ASCT). All-cause mortality was elevated across risk groups (SMRhigh = 27.7 [21.4-35.8]; SMRintermediate = 3.3 [1.7-6.5]; SMRlow = 2.8 [1.7-4.8]). SMN risk was increased among high- and intermediate-risk survivors (SIRhigh = 28.0 [18.5-42.3]; SIRintermediate = 3.7 [1.2-11.3]) but did not differ from the US population for survivors of low-risk disease. Compared with siblings, survivors had an increased risk of grade 3-5 CHCs, particularly among those with high-risk disease (HRhigh = 16.1 [11.2-23.2]; HRintermediate = 6.3 [3.8-10.5]; HRlow = 1.8 [1.1-3.1]). Conclusion Survivors of high-risk disease treated in the early days of risk stratification carry a markedly elevated burden of late recurrence, SMN, and organ-related multimorbidity, whereas survivors of low/intermediate-risk disease have a modest risk of late adverse outcomes. [ABSTRACT FROM AUTHOR]

PurposeInterindividual variability in the dose-dependent association between anthracyclines and cardiomyopathy suggests that genetic susceptibility could play a role. The current study uses an agnostic approach to identify genetic variants that could modify cardiomyopathy risk.MethodsA genome-wide association study was conducted in childhood cancer survivors with and without cardiomyopathy (cases and controls, respectively). Single-nucleotide polymorphisms (SNPs) that surpassed a prespecified threshold for statistical significance were independently replicated. The possible mechanistic significance of validated SNP(s) was sought by using healthy heart samples.ResultsNo SNP was marginally associated with cardiomyopathy. However, SNP rs1786814 on the CELF4 gene passed the significance cutoff for gene-environment interaction (Pge = 1.14 × 10(-5)). Multivariable analyses adjusted for age at cancer diagnosis, sex, anthracycline dose, and chest radiation revealed that, among patients with the A allele, cardiomyopathy was infrequent and not dose related. However, among those exposed to greater than 300 mg/m(2) of anthracyclines, the rs1786814 GG genotype conferred a 10.2-fold (95% CI, 3.8- to 27.3-fold; P < .001) increased risk of cardiomyopathy compared with those who had GA/AA genotypes and anthracycline exposure of 300 mg/m(2) or less. This gene-environment interaction was successfully replicated in an independent set of anthracycline-related cardiomyopathy. CUG-BP and ETR-3-like factor proteins control developmentally regulated splicing of TNNT2, the gene that encodes for cardiac troponin T (cTnT), a biomarker of myocardial injury. Coexistence of more than one cTnT variant results in a temporally split myofilament response to calcium, which causes decreased contractility. Analysis of TNNT2 splicing variants in healthy human hearts suggested an association between the rs1786814 GG genotype and coexistence of more than one TNNT2 splicing variant (90.5% GG v 41.7% GA/AA; P = .005).ConclusionWe report a modifying effect of a polymorphism of CELF4 (rs1786814) on the dose-dependent association between anthracyclines and cardiomyopathy, which possibly occurs through a pathway that involves the expression of abnormally spliced TNNT2 variants.

ImportanceBreast cancer is a leading cause of premature mortality among US women. Early detection has been shown to be associated with reduced breast cancer morbidity and mortality.ObjectiveTo update the American Cancer Society (ACS) 2003 breast cancer screening guideline for women at average risk for breast cancer.ProcessThe ACS commissioned a systematic evidence review of the breast cancer screening literature to inform the update and a supplemental analysis of mammography registry data to address questions related to the screening interval. Formulation of recommendations was based on the quality of the evidence and judgment (incorporating values and preferences) about the balance of benefits and harms.Evidence synthesisScreening mammography in women aged 40 to 69 years is associated with a reduction in breast cancer deaths across a range of study designs, and inferential evidence supports breast cancer screening for women 70 years and older who are in good health. Estimates of the cumulative lifetime risk of false-positive examination results are greater if screening begins at younger ages because of the greater number of mammograms, as well as the higher recall rate in younger women. The quality of the evidence for overdiagnosis is not sufficient to estimate a lifetime risk with confidence. Analysis examining the screening interval demonstrates more favorable tumor characteristics when premenopausal women are screened annually vs biennially. Evidence does not support routine clinical breast examination as a screening method for women at average risk.RecommendationsThe ACS recommends that women with an average risk of breast cancer should undergo regular screening mammography starting at age 45 years (strong recommendation). Women aged 45 to 54 years should be screened annually (qualified recommendation). Women 55 years and older should transition to biennial screening or have the opportunity to continue screening annually (qualified recommendation). Women should have the opportunity to begin annual screening between the ages of 40 and 44 years (qualified recommendation). Women should continue screening mammography as long as their overall health is good and they have a life expectancy of 10 years or longer (qualified recommendation). The ACS does not recommend clinical breast examination for breast cancer screening among average-risk women at any age (qualified recommendation).Conclusions and relevanceThese updated ACS guidelines provide evidence-based recommendations for breast cancer screening for women at average risk of breast cancer. These recommendations should be considered by physicians and women in discussions about breast cancer screening.

PurposeFor adult survivors of childhood cancer, knowledge about the long-term risk of intestinal obstruction from surgery, chemotherapy, and radiotherapy is limited.MethodsIntestinal obstruction requiring surgery (IOS) occurring 5 or more years after cancer diagnosis was evaluated in 12,316 5-year survivors in the Childhood Cancer Survivor Study (2,002 with and 10,314 without abdominopelvic tumors) and 4,023 sibling participants. Cumulative incidence of IOS was calculated with second malignant neoplasm, late recurrence, and death as competing risks. Using piecewise exponential models, we assessed the associations of clinical and demographic factors with rate of IOS.ResultsLate IOS was reported by 165 survivors (median age at IOS, 19 years; range, 5 to 50 years; median time from diagnosis to IOS, 13 years) and 14 siblings. The cumulative incidence of late IOS at 35 years was 5.8% (95% CI, 4.4% to 7.3%) among survivors with abdominopelvic tumors, 1.0% (95% CI, 0.7% to 1.4%) among those without abdominopelvic tumors, and 0.3% (95% CI, 0.1% to 0.5%) among siblings. Among survivors, abdominopelvic tumor (adjusted rate ratio [ARR], 3.6; 95% CI, 1.9 to 6.8; P < .001) and abdominal/pelvic radiotherapy within 5 years of cancer diagnosis (ARR, 2.4; 95% CI, 1.6 to 3.7; P < .001) increased the rate of late IOS, adjusting for diagnosis year; sex; race/ethnicity; age at diagnosis; age during follow-up (as natural cubic spline); cancer type; and chemotherapy, radiotherapy, and surgery within 5 years of cancer diagnosis. Developing late IOS increased subsequent mortality among survivors (ARR, 1.8; 95% CI, 1.1 to 2.9; P = .016), adjusting for the same factors.ConclusionThe long-term risk of IOS and its association with subsequent mortality underscore the need to promote awareness of this complication among patients and providers.

Cancer is the leading disease-related cause of death in adolescents and young adults (AYAs). This population faces many short- and long-term health and psychosocial consequences of cancer diagnosis and treatment, but many programs for cancer treatment, survivorship care, and psychosocial support do not focus on the specific needs of AYA cancer patients. Recognizing this health care disparity, the National Cancer Policy Forum of the Institute of Medicine convened a public workshop to examine the needs of AYA patients with cancer. Workshop participants identified many gaps and challenges in the care of AYA cancer patients and discussed potential strategies to address these needs. Suggestions included ways to improve access to care for AYAs, to deliver cancer care that better meets the medical and psychosocial needs of AYAs, to develop educational programs for providers who care for AYA cancer survivors, and to enhance the evidence base for AYAs with cancer by facilitating participation in research.

Background Treatment of childhood glioma has evolved to reduce radiotherapy exposure with the goal of limiting late toxicity. However, the associations between treatment changes and neurocognition, and the contribution of neurocognition and chronic health conditions to attainment of adult independence, remain unknown. Methods Adult survivors of childhood glioma diagnosed in 1970-1999 in the Childhood Cancer Survivor Study (n = 1284; median [minimum-maximum] 30 [18-51] years of age at assessment; 22 [15-34] years from diagnosis) self-reported neurocognitive impairment and chronic health conditions. Multivariable models evaluated associations between changes in treatment exposures (surgery only, chemotherapy [with or without surgery], cranial radiation [with or without chemotherapy and/or surgery]), and neurocognitive impairment. Latent class analysis with 5 indicators (employment, independent living, assistance with routine and/or personal care needs, driver's license, marital or partner status) identified classes of functional independence. Path analysis tested associations among treatment exposures, neurocognitive impairment, chronic health conditions, and functional independence. Statistical tests were 2-sided. Results Cranial radiation exposure decreased over time (51%, 1970s; 46%, 1980s; 27%, 1990s]. However, compared with siblings, survivors with any treatment exposure were at elevated risk for neurocognitive impairment, including surgery only (eg, memory: relative risk = 2.22; task efficiency: relative risk = 1.88; both P  < .001). Three classes of functional independence were identified: independent (58%), moderately independent (20%), and nonindependent (22%). Cranial radiation was associated with nonindependence through impaired task efficiency (β = 0.06), sensorimotor (β = 0.06), and endocrine (β = 0.10) chronic health conditions and through the associations between these conditions and task efficiency (each β = 0.04). Sensorimotor and endocrine chronic health conditions were associated with nonindependence through memory. Conclusion Most long-term glioma survivors achieve adult independence. However, functional nonindependence is associated with treatment-related neurocognitive impairment and chronic health conditions. [ABSTRACT FROM AUTHOR]

Objective: To examine associations between neurologic late effects and attainment of independence in adult survivors of childhood cancer treated with central nervous system (CNS)‐directed therapies. Methods: A total of 7881 survivors treated with cranial radiation therapy (n = 4051; CRT) and/or intrathecal methotrexate (n = 4193; IT MTX) ([CNS‐treated]; median age [range] = 25.5 years [18–48]; time since diagnosis = 17.7 years [6.8–30.2]) and 8039 without CNS‐directed therapy reported neurologic conditions including stroke, seizure, neurosensory deficits, focal neurologic dysfunction, and migraines/severe headaches. Functional independence was assessed using latent class analysis with multiple indicators (independent living, assistance with routine and personal care needs, ability to work/attend school, attainment of driver's license, marital/partner status). Multivariable regression models, adjusted for age, sex, race/ethnicity, and chronic health conditions, estimated odds ratios (OR) or relative risks (RR) for associations between neurologic morbidity, functional independence, and emotional distress. Results: Among CNS‐treated survivors, three classes of independence were identified: (1) moderately independent, never married, and non‐independent living (78.7%); (2) moderately independent, unable to drive (15.6%); and (3) non‐independent (5.7%). In contrast to 50% of non‐CNS‐treated survivors and 60% of siblings, a fourth fully independent class of CNS‐treated survivors was not identified. History of stroke (OR = 2.50, 95% CI: 1.70–3.68), seizure (OR = 9.70, 95% CI: 7.37–12.8), neurosensory deficits (OR = 2.67, 95% CI: 2.16–3.31), and focal neurologic dysfunction (OR = 3.05, 95% CI: 2.40–3.88) were associated with non‐independence among CNS‐treated survivors. Non‐independence was associated with emotional distress symptoms. Interpretation: CNS‐treated survivors do not attain full independence comparable to non‐CNS‐treated survivors or siblings. Interventions to promote independence may be beneficial for survivors with treatment‐related neurological sequalae. [ABSTRACT FROM AUTHOR]