Childhood Cancer Survivor Study Research Articles

Adverse Childhood Experiences, Resilience, and Cardiovascular Disease in Adult Survivors of Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

The impact of Adverse Childhood Experiences (ACEs: e.g., abuse, neglect and/or household dysfunction experienced before age 18) and resilience on risk for cardiovascular disease (CVD) has not previously been investigated in adult survivors of childhood cancer. We conducted a nested case-control study among long-term, adult-aged survivors of childhood cancer from the Childhood Cancer Survivor Study (CCSS). Self-report questionnaires ascertained ACEs and resilience, and scores were compared between cases with serious/life-threatening CVD and controls without CVD matched on demographic and cardiotoxic treatment factors. Among 95 cases and 261 controls, the mean ACE score was 1.4 for both groups; 53.4% of survivors endorsed ≥1 ACE. There was no association between ACEs or resilience and CVD in adjusted models. ACEs and resilience do not appear to contribute to CVD risk for adult survivors of childhood cancer with cardiotoxic treatment exposures. Although not associated with CVD in this population, ACEs are associated with serious health issues in other populations. Therefore, future studies could investigate effects of ACEs on other health outcomes affecting childhood cancer survivors.

Chronic Health Conditions and Longitudinal Employment in Survivors of Childhood Cancer

Employment is an important factor in quality of life and provides social and economic support. Longitudinal data on employment and associations with chronic health conditions for adult survivors of childhood cancer are lacking. To evaluate longitudinal trends in employment among survivors of childhood cancer. Retrospective cohort study of 5-year cancer survivors diagnosed at age 20 years or younger between 1970 and 1986 enrolled in the multi-institutional Childhood Cancer Survivor Study (CCSS). Sex-stratified employment status at baseline (2002 to 2004) and follow-up (2014 to 2016) was compared with general population rates from the Behavioral Risk Factor Surveillance System cohort. Data were analyzed from July 2021 to June 2022. Cancer therapy and preexisting and newly developed chronic health conditions. Standardized prevalence ratios of employment (full-time or part-time, health-related unemployment, unemployed, not in labor force) among adult (aged ≥25 years) survivors between baseline and follow-up compared with the general population. Longitudinal assessment of negative employment transitions (full-time to part-time or unemployed at follow-up). Female participants (3076 participants at baseline; 2852 at follow-up) were a median (range) age of 33 (25-53) years at baseline and 42 (27-65) years at follow-up; male participants (3196 participants at baseline; 2557 at follow-up) were 33 (25-54) and 43 (28-64) years, respectively. The prevalence of full-time or part-time employment at baseline and follow-up was 2215 of 3076 (71.3%) and 1933 of 2852 (64.8%) for female participants and 2753 of 3196 (85.3%) and 2079 of 2557 (77.3%) for male participants, respectively, with declining standardized prevalence ratios over time (female participant baseline, 1.01; 95% CI, 0.98-1.03; follow-up, 0.94; 95% CI, 0.90-0.98; P < .001; male participant baseline, 0.96; 95% CI, 0.94-0.97; follow-up, 0.92; 95% CI, 0.89-0.95; P = .02). While the prevalence of health-related unemployment increased (female participants, 11.6% to 17.2%; male participants, 8.1% to 17.1%), the standardized prevalence ratio remained higher than the general population and declined over time (female participant baseline, 3.78; 95% CI, 3.37-4.23; follow-up, 2.23; 95% CI, 1.97-2.51; P < .001; male participant baseline, 3.12; 95% CI, 2.71-3.60; follow-up, 2.61; 95% CI, 2.24-3.03; P = .002). Among survivors employed full-time at baseline (1488 female participants; 1933 male participants), 285 female participants (19.2%) and 248 male participants (12.8%) experienced a negative employment transition (median [range] follow-up, 11.5 [9.4-13.8] years). Higher numbers and grades of chronic health conditions were significantly associated with these transitions. In this retrospective analysis of adult survivors of childhood cancer, significant declines in employment and increases in health-related unemployment among cancer survivors compared with the general population were identified. A substantial portion of survivors in the midcareer age range fell out of the workforce. Awareness among clinicians, caregivers, and employers may facilitate clinical counseling and occupational provisions for supportive work accommodations.

Multilevel Characteristics of Cumulative Symptom Burden in Young Survivors of Childhood Cancer

Symptom burden and its characteristics among survivors of pediatric cancers aged 8 to 18 years remain understudied. To examine the prevalence of symptom burden among young childhood cancer survivors and identify associations with sociodemographic, clinical, and psychological resilience skills, and health-related quality of life (HRQOL). A cross-sectional analysis using data collected from November 1, 2017, to January 31, 2019, in a survivorship clinic at a US-based comprehensive cancer center was conducted. Participants included 302 dyads of children aged 8 to 18 years who survived at least 5 years beyond diagnosis and their primary caregivers. Data analysis was performed from March 13, 2023, to February 29, 2024. Diagnosis, caregiver-reported family conflict, self-reported caregiver anxiety, neighborhood-level social vulnerability, and survivor-reported meaning and purpose. Novel symptom-level burden, integrating the attributes of severity and daily activity interference using the pediatric version of the Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events, global cumulative symptom burden, and HRQOL using the EuroQol-5D. Multinomial logistic regression identified characteristics associated with symptom burden; linear regression assessed symptom burden and HRQOL associations. Among 302 survivors (mean [SD] age, 14.2 [2.9] years, mean [SD] time since diagnosis, 10.9 [2.9] years; 153 [50.7%] male), 186 (62.0%) had low, 77 (25.7%) moderate, and 37 (12.3%) high global cumulative symptom burden. Greater caregiver anxiety was associated with moderate (risk ratio [RR], 1.56; 95% CI, 1.09-2.24) global symptom burden. Greater neighborhood deprivation was associated with moderate global symptom burden (RR, 4.86; 95% CI, 1.29-18.26). Survivors with greater meaning/purpose were less likely to have moderate (RR, 0.42; 95% CI, 0.29-0.61) and high (RR, 0.27; 95% CI, 0.16-0.46) global symptom burden. The burden of individual symptoms displayed similar patterns. Low (Cohen d, -0.60; 95% CI, -0.87 to -0.32) and moderate/high (d, -0.98; 95% CI, -1.53 to -0.43) general pain, moderate/high numbness (d, -0.99; 95% CI, -1.69 to -0.29), and moderate/high worry (d, -0.55; 95% CI, -0.99 to -0.11) were associated with lower HRQOL. In this cross-sectional study of young childhood cancer survivors, symptom burden was prevalent. Caregiver anxiety and disparity-related neighborhood factors were associated with greater symptom burden, whereas meaning and purpose was a protective factor. Greater specific symptom burden contributed to poorer HRQOL. The findings suggest that interventions targeting resilience and neighborhood adversity may alleviate symptom burden and improve HRQOL.

Financial Hardship & Neighborhood Socioeconomic Disadvantage in Long-term Childhood Cancer Survivors.

Long-term survivors of childhood cancer face elevated risk for financial hardship. We evaluate whether childhood cancer survivors live in areas of greater deprivation and the association with self-reported financial hardships. Cross-sectional analysis of data from the Childhood Cancer Survivor Study (CCSS) between 1970 and 1999, and self-reported financial information from 2017-2019. We measured neighborhood deprivation with the Area Deprivation Index (ADI) based on current zip code. Financial hardship was measured with validated surveys that captured behavioral, material/financial sacrifice, and psychological hardship. Bivariate analyses described neighborhood differences between survivors and siblings. Generalized linear models estimated effect sizes between ADI and financial hardship adjusting for clinical factors and personal socioeconomic status. Analysis was restricted to 3,475 long-term childhood cancer survivors and 923 sibling controls. Median ages at time of evaluation was 39 [IQR 33,46] and 47 [39,59] years, respectively. Survivors resided in areas with greater deprivation (ADI ≥ 50: 38.7% survivors vs 31.8% siblings, P < .001). One quintile increases in deprivation were associated with small increases in behavioral (2nd quintile P = .017) and psychological financial hardship (2nd quintile P = .009; 3rd quintile, P = .014). Lower psychological financial hardship was associated with individual factors including greater household income ($60,000+ income, P < .001) and being single (P = .048). Childhood cancer survivors were more likely to live in areas with socioeconomic deprivation. Both neighborhood level disadvantage and personal socioeconomic circumstances should be evaluated when trying to assist childhood cancer survivors with financial hardships.

Exercise and QUality diet After Leukemia (EQUAL): A randomized weight loss trial among adult survivors of childhood leukemia in the Childhood Cancer Survivor Study.

Obesity is prevalent in childhood cancer survivors and interacts with cancer treatments to potentiate risk for cardiovascular (CV) death. We tested a remote weight-loss intervention that was effective among adults with CV risk factors in a cohort of adult survivors of childhood acute lymphoblastic leukemia (ALL) with overweight/obesity. In this phase 3 efficacy trial, survivors of ALL enrolled in the Childhood Cancer Survivor Study with body mass index (BMI)≥25 kg/m2 were randomized to a remotely-delivered weight-loss intervention versus self-directed weight loss, stratified by history of cranial radiotherapy (CRT). The primary endpoint was the difference in weight loss at 24-months in an intent-to-treat analysis. Analyses were performed using linear mixed effects models. Among 358 survivors (59% female, median attained age: 37 years, IQR: 33-43), baseline mean (SD) weight was 98.6 kg (24.0) for the intervention group (n=181) and 94.9 kg (20.3) for controls (n=177). Adherence to the intervention was poor; 15% of individuals in the intervention completed 24/30 planned coaching calls. Weight at 24-months was available for 274 (77%) participants. After controlling for CRT, sex, race/ethnicity, and age, the mean (SE) change in weight from baseline to 24-months was -0.4 kg (0.8) for intervention and 0.2 kg (0.6) for control participants (p=0.59). A remote weight-loss intervention that was successful among adults with CV conditions did not result in significant weight loss among adult survivors of childhood ALL. Future interventions in this population must be tailored to the unique needs of survivors to encourage engagement and adherence.

Trans-Ancestral Genetic Risk Factors for Treatment-Related Type 2 Diabetes Mellitus in Survivors of Childhood Cancer.

Type 2 diabetes mellitus (T2D) is a prevalent long-term complication of treatment in survivors of childhood cancer, with marked racial/ethnic differences in burden. In this study, we investigated trans-ancestral genetic risks for treatment-related T2D. Leveraging whole-genome sequencing data from the St Jude Lifetime Cohort (N = 3,676, 304 clinically ascertained cases), we conducted ancestry-specific genome-wide association studies among survivors of African and European genetic ancestry (AFR and EUR, respectively) followed by trans-ancestry meta-analysis. Trans-/within-ancestry replication including data from the Childhood Cancer Survivor Study (N = 5,965) was required for prioritization. Three external general population T2D polygenic risk scores (PRSs) were assessed, including multiancestry PRSs. Treatment risk effect modification was evaluated for prioritized loci. Four novel T2D risk loci showing trans-/within-ancestry replication evidence were identified, with three loci achieving genome-wide significance (P < 5 × 10-8). Among these, common variants at 5p15.2 (LINC02112), 2p25.3 (MYT1L), and 19p12 (ZNF492) showed evidence of modifying alkylating agent-related T2D risk in both ancestral groups, but showed disproportionately greater risk in AFR survivors (AFR odds ratios [ORs], 3.95-17.81; EUR ORs, 2.37-3.32). In survivor-specific RNA-sequencing data (N = 207), the 19p12 locus variant was associated with greater ZNF492 expression dysregulation after exposures to alkylators. Elevated T2D risks across ancestry groups were only observed with increasing values for multiancestry T2D PRSs and were especially increased among survivors treated with alkylators (top v bottom quintiles: ORAFR, 20.18; P = .023; OREUR, 13.44; P = 1.3 × 10-9). Our findings suggest therapy-related genetic risks contribute to the increased T2D burden among non-Hispanic Black childhood cancer survivors. Additional study of how therapy-related genetic susceptibility contributes to this disparity is needed.

[A PhD completed. Long-term effects of childhood cancer therapy on oral health].

In recent years, the five-year survival rate for childhood cancer has increased to about 80%. However, childhood cancer therapy can have serious long-term adverse effects on general health later in life. Of survivors, 75% experience 1 or more late effects. This PhD research aimed to gain more insight into the long-term effects on oral health of childhood cancer therapy, 15 years or more after diagnosis. This study, which is part of the Dutch Childhood Cancer Survivor Study Late Effects 2 (DCCSS LATER 2 Study), showed that oral complications such as dental developmental disorders and hyposalivation occur frequently. Most important risk factors were head and neck radiotherapy of the salivary glands, (alkylating) cytostatic agents, and age at the time of the cancer diagnosis. Dentists should be aware of childhood cancer in the medical history of their patient and of the type of therapy received. Regular dental visits are an essential part of long-term follow-up care of childhood cancer survivors.

Incidence and prevalence of musculoskeletal health conditions in survivors of childhood and adolescent cancers: A report from the Swiss childhood cancer survivor study.

Childhood cancer and its treatment can cause damage to the musculoskeletal system. We aimed to determine the incidence and prevalence of musculoskeletal health conditions (MSHC) in survivors, and to investigate differences by cancer-related characteristics. We used data from the Childhood Cancer Registry and the Swiss Childhood Cancer Survivor Study, including survivors (≥5 years since diagnosis; diagnosed 1976-2015 at <20 years of age) aged ≥15 years at study. Cumulative incidence and prevalence of MSHCs (osteoporosis, limb length discrepancy, limited joint mobility, bone/joint pain, scoliosis, changes to chest/ribs and amputation) were calculated from self-reported data. We included 2645 survivors (53% men; median age 24 years, range 15-59 years). Prevalence and cumulative incidence of any MSHC was 21% and 26%, respectively. Incidence rate for any MSHC was 15.6/1000 person-years. Scoliosis (8%), bone/joint pain (7%) and limited joint mobility (7%) were the most prevalent MSHC. MSHC co-occurred with other health conditions in 87% of survivors. We found increased rates of MSHC in women (RR = 1.4, 95%CI: 1.2-1.7), bone tumour survivors (RR = 6.0, 95%CI: 4.5-7.9), survivors older at diagnosis (11-15 years: RR = 1.8, 95%CI: 1.5-2.3), after a relapse (RR = 1.5, 95%CI: 1.3-1.9), treatment with surgery (RR = 1.2, 95%CI: 1.0-1.5), chemotherapy (RR = 1.4, 95%CI: 1.1-1.8) or stem cell transplantation (RR = 1.6, 95%CI: 1.0-2.5), and more recent year of diagnosis (2011-2015: RR = 4.3, 95%CI: 2.8-6.8). MSHCs are prevalent in survivors, the risk is increasing in younger survivor cohorts, and MSHCs usually occur in multimorbid survivors. Strengthening of rehabilitation services and appropriate referrals are needed to mitigate the effects of the cancer and cancer treatment.

Abstract 6618: Pleiotropic GATA3 locus is associated with multiple childhood cancers: harnessing the existing data from the St. Jude Lifetime Cohort and the Childhood Cancer Survivor Study for genetic etiology research

Abstract Background: A genetic variant (rs3824662) at GATA3 was previously associated with risk of Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) and relapse. Our recently published childhood Hodgkin lymphoma (HL) study identified a genome-wide significant association for another genetic variant (rs3781093) in high linkage disequilibrium (D’=1.0, R2=0.91) with rs3824662. We hypothesize that GATA3 is a pleiotropic locus associated with multiple childhood cancers. Methods: The study was performed by combining 3 cohorts of childhood cancer survivors: the St Jude Lifetime Cohort Study (SJLIFE), the original and expansion cohorts of the Childhood Cancer Survivor Study (CCSS). The CCSS original cohort had SNP array genotyping and imputation, and the SJLIFE and CCSS expansion cohort underwent whole-genome sequencing. Associations between the variants mapped to GATA3 and risks of different cancer types were analyzed (a specific cancer type was selected as the case group and all other unselected cancer types served as controls, then repeated for 13 cancer types). Summary statistics were subsequently analyzed with the ASSET (Association analysis for SubSETs) method which is powerful for pooling association signals across multiple cancer types when true effects may exist only in a subset and be in opposite directions across cancer types. Results: Genotype data were available for 11623 childhood cancer survivors (5325 from the CCSS original cohort, 2428 from the CCSS expansion cohort, and 3870 from the SJLIFE, all European ancestry) were initially considered. After excluding individuals with dual enrollment or as outliers in the principal components analysis (n=667), a total of 10956 individuals remained for genetic association analysis. We identified a bi-directional association for a subset of childhood cancers with rs3781093 (2-sided P value of 6.22 × 10−19): the same effect allele (C) was associated with increased risk of ALL or soft tissue sarcoma [STS] (OR=1.21; 95% CI=1.13-1.29; P=7.4 × 10−9), and was associated with decreased risk of HL (OR=0.66; 95% CI=0.59-074; P=1.80 × 10−12). The frequencies of the effect allele (C) for rs3781093 in ALL cases (17.9%), STS cases (17.8%) and HL cases (12.5%) relative to non-cancer community controls in the SJLIFE (15.6%) and non-cancer gnomAD samples (14.9%) corroborate this finding. In our combined dataset, there were 1380 Hodgkin lymphoma cases, 2961 ALL cases and 692 STS cases. Conclusion: We discovered a novel variant in the GATA3 locus exhibiting pleiotropy with both tumor-promoting and protective effects, suggesting a shared mechanistic pathway involving GATA3 may underlie the carcinogenesis for ALL, STS and HL. Conducting systematic searches for childhood cancer pleiotropy represents an important research direction. Citation Format: Cheng Chen, Xijun Zhang, Qian Dong, Heather L. Mulder, John Easton, Xiaotu Ma, Jinghui Zhang, Jun Yang, Kim E. Nichols, Gregory T. Armstong, Kirsten K. Ness, Melissa M. Hudson, Hui Wang, Nilanjan Chatterjee, Cindy Im, Zhaoming Wang. Pleiotropic GATA3 locus is associated with multiple childhood cancers: harnessing the existing data from the St. Jude Lifetime Cohort and the Childhood Cancer Survivor Study for genetic etiology research [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6618.

Abstract 3954: Increased mosaic chromosomal alterations among survivors of childhood acute myeloid leukemia

Abstract Background: We previously characterized point mutations of clonal hematopoiesis (CH) including single nucleotide variants or small insertion/deletions residing in a set of cancer-related genes (e.g., DNMT3A and TET2), and found that CH point mutations occurred at a much higher prevalence in childhood cancer survivors (CCS) than in age-sex-race matched community controls. However, mosaic chromosomal alterations (mCAs), another form of CH with megabase-scale structural alterations (copy gain, copy loss and copy-neutral loss of heterozygosity), have not been examined. Methods: Detection of mCAs was performed on whole-genome sequencing (WGS, 30X) data from 5-year CCS with the Mosaic Chromosomal Alterations (MoChA) caller which utilizes phased genotypes, coverage, and B allele frequency (BAF) at heterozygous sites (HETS). We implemented the pipeline established by the TOPMed consortium to detect low mutant cell fractions (CF ≥1%). Variant filtration criteria: minor allele frequency &amp;lt;1%, the read depth of either allele &amp;lt;5, and only one variant retained in each 1Kb window. Called mCA filtration criteria: &amp;lt;100 HETS; lod score &amp;lt;5; relative coverage &amp;gt;2.9 or BAF deviation &amp;gt;0.16 and relative coverage &amp;gt;2.5. Autosomal mCAs (CF ≥1%, HETS &amp;gt;100 and length &amp;gt;1Mb) retained. Multivariable Cox models evaluated the association between mCAs and specific late-effects including all-cause mortality, obesity, myocardial infarction (MI) or cardiomyopathy (CMP); multivariable logistic models evaluated the association between mCAs and childhood cancer diagnoses. All models were adjusted for age, sex and therapeutic exposures. Results: In our evaluation of 4,330 CCS (median age at blood draw: 26.8 years) and 433 controls (33.6 years) with WGS data from the St. Jude Lifetime Cohort, the prevalence of mCAs was slightly higher among CCS than community controls (4.83% vs. 4.16%). Among CCS, mCAs were associated with therapeutic exposures (alkylating agents: odds ratio [OR]=1.48, 95% CI=1.09-2.00; antimetabolites: 1.53, 1.02-2.31; corticosteroids: 0.60, 0.40-0.91). In contrast to recent mCA studies in the general population, we observed no co-occurrence with CH point mutations, and no associations with late-effects including all-cause mortality, obesity, MI or CMP. Interestingly, mCAs were significantly associated with the primary diagnosis of acute myeloid leukemia (AML, OR=2.86, 95% CI=1.63-5.01). Furthermore, this finding was replicated in 2898 5-year survivors from the Childhood Cancer Survivor Study (OR=3.77, 95% CI=1.94-7.33). Conclusion: mCAs were not associated with age-related morbidities and mortality among CCS. However, we identified a striking association between mCAs and previous diagnoses of AML independent of treatment exposures. If validated among AML patients at the time of diagnosis, mCAs, which reflect the underlying genome instability, may serve as a diagnostic biomarker for AML. Citation Format: Xijun Zhang, Na Qin, Qian Dong, Cheng Chen, John Easton, Heather Mulder, Xiang Chen, Kyla Shelton, Cindy Im, Yutaka Yasui, Greg Armstrong, Kirsten K. Ness, Melissa M. Hudson, Paul Auer, Jinghui Zhang, Zhaoming Wang. Increased mosaic chromosomal alterations among survivors of childhood acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3954.

Abstract 6155: Germline variants in cancer susceptibility genes and subsequent neoplasm risks after childhood cancer: A pooled analysis of two large-scale cohorts

Abstract Background: Increasing evidence suggests germline genetic susceptibility influences the risk of developing subsequent neoplasms (SNs)—a major cause of morbidity and mortality—among childhood cancer survivors, but studies have been hampered by sample size and limited gene sets. We pooled two large-scale cohorts of childhood cancer survivors to characterize overall and specific SN risks among individuals carrying germline variants in 88 known cancer susceptibility genes with an autosomal dominant inheritance pattern. Methods: Using whole-genome or whole-exome sequencing data from the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort (median [interquartile range] follow-up, 29.7 [13.8] years), we identified rare, potentially protein-damaging germline variants with SnpEff/ClinVar. Conditional logistic regression evaluated overall SN and SN-specific risk, with up to 100 SN-free controls matched to cases by age, sex, primary childhood cancer type, SN type, radiation dose, chemotherapy, study, and follow-up time. Results: Among 11840 individuals (50.6% female) who survived childhood cancer, 2162 (18.3%) developed at least one SN. The risk of developing any SN was elevated among 288 survivors carrying rare, potentially protein-damaging germline variants in an autosomal dominant cancer susceptibility gene (cases=13.3%; controls=9.6%; odds ratio [OR], 1.48; 95% confidence interval [CI], 1.30-1.70; P=5.12x10-5). A similar proportion of carriers was observed among those who developed common SNs such as basal cell carcinoma (N=107/882, 12.1%), meningioma (N=52/373, 13.9%), breast cancer (N=49/353, 13.9%), and thyroid cancer (N=32/243, 13.2%). Higher frequencies of carriers were observed in less common SNs, specifically sarcoma (N=24/151, 15.9%), colorectal cancer (N=15/72, 20.8%), and glioma (N=16/64, 25.0%). The observed associations were generally consistent regardless of treatment type for first primary childhood cancer. Gene-specific analyses revealed that the risk of developing any SN was most pronounced among individuals carrying variants in TP53 (cases=0.6%; controls=0.04%; OR, 9.93; 95% CI, 4.62-21.34; P=0.001) and FANCM (cases=0.9%; controls=0.5%; OR, 2.45; 95% CI, 1.48-4.03; P=0.018). Conclusion: In large-scale cohorts of childhood cancer survivors with long-term follow-up, individuals carrying potentially protein-damaging germline variants in known autosomal dominant cancer susceptibility genes have substantially increased SN risk, emphasizing the importance of genetic testing and consideration of genetic risk in follow-up guidelines. However, these individuals account for a small fraction of all SN cases, warranting future research on underlying risk factors in this population. Citation Format: Shahriar A. Zamani, Danielle M. Karyadi, Stephen W. Hartley, Joshua N. Sampson, Todd Gibson, Peter Kraft, Stephen J. Chanock, Lindsay M. Morton. Germline variants in cancer susceptibility genes and subsequent neoplasm risks after childhood cancer: A pooled analysis of two large-scale cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6155.

Abstract 6382: Risk prediction of dyslipidemia in long-term survivors of childhood cancer: A report from the St. Jude Lifetime Cohort

Abstract Background: Dyslipidemia is a significant contributor to the increased risk of cardiovascular morbidity and premature mortality in long-term survivors of childhood cancer. Identifying individuals at risk at an early stage provides an opportunity for tailored prevention approaches. Methods: Long-term childhood cancer survivors from the St. Jude Lifetime Cohort, (SJLIFE, n=2,559; median age 41 years, range 20-77 years) were directly assessed for dyslipidemia. Risk factors under consideration included demographic characteristics, cancer treatment exposures (cumulative doses of anthracyclines, platinum agents, glucocorticoids, and radiation therapy), comorbid conditions at the time of assessment (hypertension, diabetes mellitus, growth hormone deficiency, hypogonadism, hypothyroidism, cardiomyopathy, and chronic kidney disease), and externally validated multi-ancestry general-population polygenic risk scores (PRSs) for lipid values (total cholesterol, LDL-C, HDL-C, and triglycerides). Multivariable logistic regression predicted a 15-year risk of dyslipidemia (CTCAE grade ≥2 hypercholesterolemia and/or hypertriglyceridemia) including variables selected by the stepwise approach. Performance of the model was assessed by the area under the receiver operating characteristic curve (AUC). Results: Dyslipidemia was clinically identified in 543 (25.1%) SJLIFE survivors. AUC of a clinical model with sex, race, age at prediction, and comorbid conditions (diabetes, growth hormone deficiency, hypogonadism, hypothyroidism, and hypertension) was 0.80 (95% CI, 0.78-0.82). Inclusion of cancer treatment exposures (cumulative doses of anthracyclines, cisplatin, carboplatin, glucocorticoids, abdominal and cranial radiation therapy) significantly increased AUC to 0.82 (95% CI, 0.80-0.84; P=2.1×10-4). Addition of two PRSs for LDL-C (one included only genome-wide significant variants adjusted for statins and another consisted of all genome-wide variants) and the PRS for triglycerides provided further significant improvement in AUC to 0.86 (95% CI, 0.84-0.88; P=4.2×10-12). Conclusions: We developed a prediction model with good performance for identifying the risk of dyslipidemia in childhood cancer survivors. In addition to demographics and comorbidities, cancer treatments and inherited genetic factors contributed significantly to improving the risk prediction of dyslipidemia. Results may refine risk stratification for dyslipidemia in survivors and present opportunities for more precise and personalized preventive strategies to address cardiovascular health. Independent validation in survivors from the Childhood Cancer Survivor Study and the Dutch Childhood Cancer Survivor Study (DCCSS)-LATER is currently underway. Citation Format: Kateryna Petrykey, Kendrick Li, Lu Xie, Achal Neupane, Angela Delaney, Christine Yu, Stephanie B. Dixon, Bonnie Ky, Cindy Im, Isaac B. Rhea, Jeffrey A. Towbin, Jason N. Johnson, Melissa Bolier, Vincent G. Pluimakers, Linda Broer, Sebastian J. Neggers, Marry M. van den Heuvel-Eibrink, Rebecca M. Howell, Kirsten K. Ness, Melissa M. Hudson, Gregory T. Armstrong, Yutaka Yasui, Yadav Sapkota. Risk prediction of dyslipidemia in long-term survivors of childhood cancer: A report from the St. Jude Lifetime Cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6382.

Abstract 6385: St. Jude Survivorship Portal: Sharing and analyzing large clinical and genomic datasets from pediatric cancer survivors

Abstract Survivors of childhood cancer are at risk for developing various adverse health conditions as adults that are attributable to the cancer and treatments they were exposed to as children. Cancer survivorship research relies on large-scale, longitudinal studies that generate a wide range of demographic, clinical, and genetic data on cancer survivors. Nevertheless, the absence of cancer survivorship data portals has made it challenging to broadly share cancer survivorship data. We have created the St. Jude Survivorship Portal (https://survivorship.stjude.cloud), the first data portal for sharing, analyzing, and visualizing childhood cancer survivorship data. The portal hosts data from two large cohorts of pediatric cancer survivors: the St. Jude Lifetime Cohort Study (SJLIFE) and the Childhood Cancer Survivor Study (CCSS). Over 1,600 clinical variables and over 400 million genetic variants from over 7,700 childhood cancer survivors are stored on the portal. The data can be explored using an interactive data dictionary and a genome browser specialized for population genetics analysis. Summary statistics of variables and genetic variants are computed on-the-fly and visualized through interactive and customizable charts. Survivor cohorts can be filtered or customized and may also be divided into groups for comparative analysis. Tools for performing cumulative incidence and regression analyses have been integrated into portal environment, allowing users to perform real-time statistical analyses on the stored survivorship data. Finally, users may also download individual-level clinical and genotype data from the portal using the controlled-access data download feature. Through various use-cases of survivorship research, we used the portal to explore the ototoxic effects of platinum-based chemotherapy, uncover a novel association between limb amputation, age, and long-term mental health, and identify a novel haplotype in MAGI3 strongly associated with cardiomyopathy specifically in survivors of African ancestry. The St. Jude Survivorship Portal provides a comprehensive, powerful, and easy-to-use interface for sharing and analyzing childhood cancer survivorship data that will serve as a valuable research tool for the broader survivorship research community. Citation Format: Gavriel Matt, Edgar Sioson, Jian Wang, Congyu Lu, Airen Zaldívar Peraza, Karishma Gangwani, Robin Paul, Colleen Reilly, Aleksandar Acić, Kyla Shelton, Qi Liu, Stephanie Sandor, Clay McLeod, Weiyu Qiu, Jaimin Patel, Fan Wang, Cindy Im, Zhaoming Wang, Carmen L. Wilson, Nickhill Bhakta, Kirsten Ness, Gregory T. Armstrong, Melissa M. Hudson, Leslie L. Robison, Jinghui Zhang, Yutaka Yasui, Xin Zhou. St. Jude Survivorship Portal: Sharing and analyzing large clinical and genomic datasets from pediatric cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6385.

Presence and utility of electrocardiographic abnormalities in long-term childhood cancer survivors

BackgroundWe assessed the prevalence and diagnostic value of ECG abnormalities for cardiomyopathy surveillance in childhood cancer survivors.MethodsIn this cross-sectional study, 1381 survivors (≥5 years) from the Dutch Childhood Cancer Survivor...

Health Insurance Navigation Tools Intervention: A Pilot Trial Within the Childhood Cancer Survivor Study.

Childhood cancer survivors are at increased risk for underinsurance and health insurance-related financial burden. Interventions targeting health insurance literacy (HIL) to improve the ability to understand and use health insurance are needed. We codeveloped a four-session health insurance navigation tools (HINT) intervention, delivered synchronously by a patient navigator, and a corresponding booklet. We conducted a randomized pilot trial with survivors from the Childhood Cancer Survivor Study comparing HINT with enhanced usual care (EUC; booklet). We assessed feasibility, acceptability, and preliminary efficacy (HIL, primary outcome; knowledge and confidence with health insurance terms and activity) on a 5-month survey and exit interviews. Among 231 invited, 82 (32.5%) survivors enrolled (53.7% female; median age 39 years, 75.6% had employer-sponsored insurance). Baseline HIL scores were low (mean = 28.5; 16-64; lower scores better); many lacked knowledge of Affordable Care Act (ACA) provisions. 80.5% completed four HINT sessions, and 93.9% completed the follow-up survey. Participants rated HINT's helpfulness a mean of 8.9 (0-10). Exit interviews confirmed HINT's acceptability, specifically its virtual and personalized delivery and helpfulness in building confidence in understanding one's coverage. Compared with EUC, HINT significantly improved HIL (effect size = 0.94. P < .001), ACA provisions knowledge (effect size = 0.73, P = .003), psychological financial hardship (effect size = 0.64, P < .006), and health insurance satisfaction (effect size = 0.55, P = .03). Results support the feasibility and acceptability of a virtual health insurance navigation program targeted for childhood survivors to improve HIL. Randomized trials to assess the efficacy and sustainability of health insurance navigation on HIL and financial burden are needed.

Very long-term outcomes of pediatric patients treated for optic pathway gliomas: A longitudinal cohort study.

Optic pathway gliomas (OPG) represent 5% of childhood brain tumors. Successive relapses lead to multiple treatments exposing to late complications. We included patients treated at Gustave Roussy (GR) between 01.1980 and 12.2015 for OPG, before 18 years-old and alive at 5 years from diagnosis. Mortality and physical health conditions data were extracted from medical data files and updated thanks to the GR long-term follow-up program and French national mortality registry for patients included in the French Childhood Cancer Survivor Study. We included 182 5y-OPG-childhood survivors in the analysis (sex-ratio M/F 0.8, 35% with NF1). With a median follow-up of 17.2y (range=5-41), we registered 82 relapses, 9 second malignancies and 15 deaths as first events after 5 years, resulting in 20-y conditional overall survival (C-OS) and late events-free survival (LEFS) of 79.9% (95%CI=71-86) and 43.5% (95%CI=36-51) respectively. NF1 (Hazard ratio HR=3, 95%CI=1.4-6.8), hypothalamic involvement (HR=3.2, 95%CI=1.4-7.3), and radiotherapy (HR=2.8, 95%CI=1.1-6.7) were significantly associated with C-OS in multivariable analyses. Ninety-five percent of 5y-OPG survivors suffered from any health condition, especially visual acuity "<1/10" (n=109), pituitary deficiency (n=106) and neurocognitive impairment (n=89). NF1 (HR 2.1) was associated with precocious puberty. With a median time post diagnosis of 4.2 years, 33 cerebrovascular events were observed in 21 patients. Late relapses, second malignancies and cerebrovascular diseases are severe late events resulting in premature mortality. Morbidity is high and needing after-cancer care to improve quality of life. Risk factors could be considered to better stratify long-term follow-up.

Impact of Risk-Based therapy on late morbidity and mortality in neuroblastoma survivors: a report from the childhood cancer survivor study.

Early efforts at risk-adapted therapy for neuroblastoma are predicted to result in differential late effects; the magnitude of these differences have not been well-described. Late mortality, subsequent malignant neoplasms (SMN), and severe/life-threatening chronic health conditions (CHCs), graded according to CTCAE v4.03, were assessed among 5-year 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 (SMR) and standardized incidence ratios (SIR) of SMNs were compared to matched population controls. Cox regression models estimated hazard ratios (HR) and 95% confidence intervals (CI) for CHC compared to 1,029 CCSS siblings. 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, while 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 to 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]). 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 multi-morbidity, while survivors of low/intermediate-risk disease have a modest risk of late adverse outcomes.

Validation of self-reported cardiovascular problems in childhood cancer survivors by contacting general practitioners: feasibility and results

BackgroundEpidemiological studies often rely on self-reported health problems and validation greatly improves study quality. In a study of late effects after childhood cancer, we validated self-reported cardiovascular problems by contacting general practitioners (GPs). This paper describes: (a) the feasibility of this approach; and (b) the agreement between survivor-reports and reports from their GP.MethodsThe Swiss Childhood Cancer Survivor Study (SCCSS) contacts all childhood cancer survivors registered in the Swiss Childhood Cancer Registry since 1976 who survived at least 5 years from cancer diagnosis. We validated answers of all survivors who reported a cardiovascular problem in the questionnaire. Reported cardiovascular problems were hypertension, arrhythmia, congestive heart failure, myocardial infarction, angina pectoris, stroke, thrombosis, and valvular problems. In the questionnaire, we further asked survivors to provide a valid address of their GP and a consent for contact. We sent case-report forms to survivors’ GPs and requested information on cardiovascular diagnoses of their patients. To determine agreement between information reported by survivors and GPs, we calculated Cohen’s kappa (κ) coefficients for each category of cardiovascular problems.ResultsWe used questionnaires from 2172 respondents of the SCCSS. Of 290 survivors (13% of 2172) who reported cardiovascular problems, 166 gave consent to contact their GP and provided a valid address. Of those, 135 GPs (81%) replied, and 128 returned the completed case-report form. Survivor-reports were confirmed by 54/128 GPs (42%). Of the 54 GPs, 36 (28% of 128) confirmed the problems as reported by the survivors; 11 (9% of 128) confirmed the reported problem(s) and gave additional information on more cardiovascular outcomes; and seven GPs (5% of 128) confirmed some, but not all cardiovascular problems. Agreement between GPs and survivors was good for stroke (κ = 0.79), moderate for hypertension (κ = 0.51), arrhythmias (κ = 0.41), valvular problems (κ = 0.41) and thrombosis (κ = 0.56), and poor for coronary heart disease (κ = 0.15) and heart failure (κ = 0.32).ConclusionsDespite excellent GP compliance, it was found unfeasible to validate self-reported cardiovascular problems via GPs because they do not serve as gatekeepers in the Swiss health care system. It is thus necessary to develop other validation methods to improve the quality of patient-reported outcomes.

Temporal changes in treatment and late mortality and morbidity in adult survivors of childhood glioma: a report from the Childhood Cancer Survivor Study.

Pediatric glioma therapy has evolved to delay or eliminate radiation for low-grade tumors. This study examined these temporal changes in therapy with long-term outcomes in adult survivors of childhood glioma. Among 2,501 5-year survivors of glioma in the Childhood Cancer Survivor Study diagnosed 1970-1999, exposure to radiation decreased over time. Survivors from more recent eras were at lower risk of late mortality (≥5 years from diagnosis), severe/disabling/life-threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs). Adjusting for treatment exposure (surgery only, chemotherapy, or any cranial radiation) attenuated this risk (for example, CHCs (1990s versus 1970s), relative risk (95% confidence interval), 0.63 (0.49-0.80) without adjustment versus 0.93 (0.72-1.20) with adjustment). Compared to surgery alone, radiation was associated with greater than four times the risk of late mortality, CHCs and SNs. Evolving therapy, particularly avoidance of cranial radiation, has improved late outcomes for childhood glioma survivors without increased risk for late recurrence.

The ENGAGE study: a 3-arm randomized hybrid type 1 effectiveness and implementation study of an in-home, collaborative PCP model of remote telegenetic services to increase uptake of cancer genetic services in childhood cancer survivors

BackgroundGermline cancer genetic testing has become a standard evidence-based practice, with established risk reduction and screening guidelines for genetic carriers. Access to genetic services is limited in many places, which leaves many genetic carriers unidentified and at risk for late diagnosis of cancers and poor outcomes. This poses a problem for childhood cancer survivors, as this is a population with an increased risk for subsequent malignant neoplasms (SMN) due to cancer therapy or inherited cancer predisposition. The ENGaging and Activating cancer survivors in Genetic services (ENGAGE) study evaluates the effectiveness of an in-home, collaborative PCP model of remote telegenetic services to increase uptake of cancer genetic testing in childhood cancer survivors compared to usual care options for genetic testing.MethodsThe ENGAGE study is a 3-arm randomized hybrid type 1 effectiveness and implementation study within the Childhood Cancer Survivor Study population which tests a clinical intervention while gathering information on its delivery during the effectiveness trial and its potential for future implementation among 360 participants. Participants are randomized into three arms. Those randomized to Arm A receive genetic services via videoconferencing, those in Arm B receive these services by phone, and those randomized to Arm C will receive usual care services.DiscussionWith many barriers to accessing genetic services, innovative delivery models are needed to address this gap and increase uptake of genetic services. The ENGAGE study evaluates the effectiveness of an adapted model of remote delivery of genetic services to increase the uptake of recommended genetic testing in childhood cancer survivors. This study assesses the uptake in remote genetic services and identify barriers to uptake to inform future recommendations and a theoretically-informed process evaluation which can inform modifications to enhance dissemination beyond this study population and to realize the benefits of precision medicine.Trial registrationThis protocol was registered at clinicaltrials.gov (NCT04455698) on July 2, 2020.