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Background: What are the major determinants of women's breast cancer risk? Rare mutations such as those in the BRCA1/2 genes, polygenic scores of common alleles identified by genome-wide association studies, or nongenetic factors? Methods: The population-based Nordic Twin Study of Cancer, with 3,933 breast cancer cases among 21,054 monozygotic (MZ) and 30,939 dizygotic (DZ) female twin pairs, provides three key clues to this question: (i) the average lifetime risk, approximately 8%, does not differ by twin zygosity; (ii) the mean time interval between diagnoses when both twins develop disease (i.e., disease concordance) also does not differ by zygosity; but, (iii) conditioning on one twin having developed disease, the incidence rate in the co-twin is approximately 1% per year if the pair is MZ and 0.5% per year if DZ. Results: Assuming that nongenetic risk factors are shared similarly between twins regardless of zygosity, we can draw two conclusions from (i) to (iii). Conclusions: First, (i) and (iii) imply that the chief determinant of risk is in the germline DNA, because the conditional incidence rate is several-fold higher than the average risk (8% lifetime) in MZ twins but only half as much in DZ twins. Second, the seeming inconsistency between the two-fold conditional incidence rate (iii) and the equality of the mean inter-twin disease intervals in disease concordance (ii) can be resolved if the risk factors in the germline DNA are rare variants, not common variants. Impact: This paper details simple deductive reasoning for these conclusions and draws a critical inference regarding breast cancer etiology. [ABSTRACT FROM AUTHOR]

Background: Childhood cancer survivors experience reduced physiologic reserve, or frailty, earlier and more frequently than peers. In other populations, frailty is impacted by one's neighborhood. This study's purpose was to evaluate associations between neighborhood characteristics and frailty in childhood cancer survivors. Methods: Participants in the St. Jude Lifetime Cohort Study with geocoded residential addresses were analyzed. Pre-frailty/Frailty was defined as having 1-2/=3 of sarcopenia, muscle weakness, poor endurance, slow walking speed, and exhaustion from direct assessments. Neighborhood characteristics [e.g., access to exercise opportunities and healthy food, neighborhood socioeconomic status (nSES), and rurality/urbanicity] were determined using publicly available geospatial data. Nested multivariable logistic regression models identified associations between neighborhood characteristics and pre-frailty/frailty, adjusting for chronic health conditions, individual health behaviors and socio-demographics, and high-risk cancer treatment exposures. Results: For our cohort (N = 3,806, 46.79% female, 81.40% white, mean age 33.63±9.91 years), compared with non-frail survivors (n = 2,573; 67.6%), pre-frail (n = 900; 23.6%) and frail survivors (n = 333; 8.7%) were more likely to live in neighborhoods with decreased exercise opportunities (frail OR: 1.62, 1.26-2.09), reduced healthy food access (pre-frail OR: 1.28, 1.08-1.51; frail OR: 1.36, 1.06-1.75), and lower nSES (pre-frail OR: 1.31, 1.12-1.52; frail OR: 1.64, 1.30-2.07). Participants had 8% increased odds (95% confidence interval, 2%-14%) of being pre-frail/frail if they lived in "resource poor" neighborhoods as opposed to "resource rich" neighborhoods after adjusting for other pre-frailty/frailty risk factors. Conclusions: The neighborhood a childhood cancer survivor resides in as an adult is associated with pre-frailty/frailty. [ABSTRACT FROM AUTHOR]

Background: Gonadotoxic 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. Methods: Leveraging 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). Results: In 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. Conclusions: We were not able to replicate our findings of SNPs associated with pregnancy in childhood cancer survivors. [ABSTRACT FROM AUTHOR]

Background: Survivors of childhood cancer are at risk for therapy-related subsequent malignant neoplasms (SMN), including thyroid SMN. Telomere length (TL) is associated with cancer risk, but the relationship between TL and SMN risk among survivors is less clear. Methods: We conducted a nested, matched case-control study of radiation-exposed 15-year+ adult survivors of childhood cancer with thyroid SMN (cases) and without SMN (controls). Forty-six cases were matched to 46 controls by primary diagnosis, chemotherapy (yes/no), radiation field, and follow-up duration. Lymphocyte TL (LTL) was measured by telomere flow-FISH cytometry using blood samples banked at a mean of 38.9 years (cases), 39.2 years (controls). Genetic variation in telomere genes was assessed by whole genome sequencing. Point estimates for LTL <10th percentile were determined for cases and controls. Results: Cases had shorter median LTL than controls in three out of four leukocyte subsets. Cases were more likely to have NK cell LTL <10th percentile (P = 0.01), and 2.8-fold more likely to have naïve T-cell LTL <10th percentile than controls (CI, 1.07-8.78). Five out of 15 cases with a rare indel or missense variant had naïve T-cell LTL <10th percentile, compared with one out of eight controls. Conclusions: Long-term survivors have shorter than expected LTL, a finding that is more pronounced among survivors with thyroid SMN. Impact: The long-term impact of childhood cancer treatment on immune function is poorly understood. Our findings support immune function studies in larger survivor cohorts to assess long-term deficits in adaptive and innate immunity that may underlie SMN risk. [ABSTRACT FROM AUTHOR]

Background: Prior studies have identified that survivors of childhood acute lymphoblastic leukemia (ALL) report poor health status. It is unknown how risk-stratified therapy impacts the health status of ALL survivors. Methods: We estimated and compared the prevalence of self-reported poor health status among adult (=18 years) survivors of childhood ALL diagnosed at age <21 years from 1970 to 1999 and sibling controls, excluding proxy reports. Therapy combinations defined treatment groups representative of 1970s therapy (70s), standard- and high-risk 1980s and 1990s therapy (80sSR, 80sHR, 90sSR, 90sHR), and relapse/bone marrow transplant (R/BMT). Log-binomial models, adjusted for clinical and demographic factors, compared outcomes between groups using prevalence ratios (PR) with 95% confidence intervals (CI). Results: Among 5,119 survivors and 4,693 siblings, survivors were more likely to report poor health status in each domain including poor general health (13.5% vs. 7.4%; PR = 1.92; 95% CI, 1.69-2.19). Compared with 70s, 90sSR and 90sHR were less likely to report poor general health (90sSR: PR = 0.75; 95% CI, 0.57-0.98; 90sHR: PR = 0.58; 95% CI, 0.39-0.87), functional impairment (90sSR: PR = 0.56; 95% CI, 0.42-0.76; 90sHR: PR = 0.63; 95% CI, 0.42-0.95), and activity limitations (90sSR: 0.61; 95% CI, 0.45-0.83; 90sHR: PR = 0.59; 95% CI, 0.38-0.91). An added adjustment for chronic conditions in multivariable models partially attenuated 90sSR risk estimates. Conclusions: Risk-stratified ALL therapy has succeeded in reducing risk for poor general health, functional impairment, and activity limitations among more recent survivors of standard- and high-risk therapy. Impact: Future research into the relationship between risk-stratified therapy, health status, and late health outcomes may provide new opportunities to further improve late morbidity among survivors. [ABSTRACT FROM AUTHOR]

Background: Subsequent thyroid cancer (STC) is one of the most common malignancies in childhood cancer survivors. We aimed to evaluate the polygenic contributions to STC risk and potential utility in improving risk prediction. Methods: A polygenic risk score (PRS) was calculated from 12 independent SNPs associated with thyroid cancer risk in the general population. Associations between PRS and STC risk were evaluated among survivors from St. Jude Lifetime Cohort (SJLIFE) and were replicated in survivors from Childhood Cancer Survivor Study (CCSS). A risk prediction model integrating the PRS and clinical factors, initially developed in SJLIFE, and its performance were validated in CCSS. Results: Among 2,370 SJLIFE survivors with a median follow-up of 28.8 [interquartile range (IQR) = 21.9-36.1] years, 65 (2.7%) developed STC. Among them, the standardized PRS was associated with an increased rate of STC [relative rate (RR) = 1.57; 95% confidence interval (CI) = 1.24-1.98; P < 0.001]. Similar associations were replicated in 6,416 CCSS survivors, among whom 121 (1.9%) developed STC during median follow-up of 28.9 (IQR = 22.6-34.6) years (RR = 1.52; 95% CI = 1.25-1.83; P < 0.001). A risk prediction model integrating the PRS with clinical factors showed better performance than the model considering only clinical factors in SJLIFE (P = 0.004, AUC = 83.2% vs. 82.1%, at age 40), which was further validated in CCSS (P = 0.010, AUC = 72.9% vs. 70.6%). Conclusions: Integration of the PRS with clinical factors provided a statistically significant improvement in risk prediction of STC, although the magnitude of improvement was modest. Impact: PRS improves risk stratification and prediction of STC, suggesting its potential utility for optimizing screening strategies in survivorship care. [ABSTRACT FROM AUTHOR]

Developing appropriate care models for patients diagnosed with non-Hodgkin lymphoma (NHL) >65y require examination of current healthcare utilization patterns and cost, but non-malignant condition-specific utilization and Medicare spending among older patients has not been characterized. Using SEER-Medicare, 14,533 patients diagnosed with NHL at age > 65 between 2008 and 2015 and a comparable non-cancer cohort (n = 14,533) were identified. Hospitalizations and outpatient visits for 109 non-malignant conditions were grouped into ten categories, allowing condition-specific utilization and spending calculation from diagnosis to 5y, censoring at blood or marrow transplantation, 6mo prior to death or end (12/31/2016). Using the 90th percentile as a cut-off, factors associated with high-hospitalization rates and high-spending were evaluated. Patients with NHL were 1.5-fold more likely to be hospitalized and 1.8-fold more likely to experience outpatient visits when compared with the non-cancer cohort. Patients with NHL had greater aging-related, cardiovascular, and gastrointestinal hospitalizations than controls (p < 0.001). Average Medicare spending/visit was higher for patients with NHL (hospitalization: $16,950 vs. $13,474, p < 0.001; outpatient: $1176 vs. $392, p < 0.001). Factors associated with high-utilization and high-spending included diffuse large B cell lymphoma subtype, non-white race, and residence in low-education area. Older patients with NHL experienced higher utilization and higher spending per-utilization compared to a non-cancer cohort over five years from cancer diagnosis. Clinical and demographic sub-groups demonstrated increased risk for the highest spending and utilization. The substantial utilization and spending for non-malignant conditions among older patients with NHL provides quantifiable evidence for survivor-adapted healthcare management policies. [ABSTRACT FROM AUTHOR]

Background: Childhood cancer survivors are at risk for cardiovascular morbidity and mortality that is not fully explained by cancer-directed therapies. We examined the contribution of emotional stress and distress to cardiac health in adult survivors of childhood cancer. Methods: Participants included 3,267 adult survivors enrolled in the St. Jude Lifetime Cohort Study [median (range) 29.9 (18.1-64.5) years of age; 7.7 (0-24.8) years at diagnosis; 48.4% female]. Survivors completed comprehensive medical assessments and standardized measures of depression, anxiety, posttraumatic stress symptoms (PTSS), and perceived stress. Cardiovascular-related conditions included hypertension, diabetes, dyslipidemia, cardiomyopathy, dysrhythmia, myocardial infarction (severity graded 0-4), and metabolic syndrome (yes/no). Multivariable modified Poisson models examined associations between symptoms of stress/distress and cardiovascular outcomes. Longitudinal associations between stress/distress and new-onset cardiovascular outcomes, defined as a change from grade =1 at initial evaluation to grade =2 at follow-up (median 3.9 years) were examined in 1,748 participants. Results: In multivariable cross-sectional models, stress/distress was associated with hypertension [risk ratio (RR) = 1.24; 95% confidence interval (CI), 1.07-1.43], dyslipidemia (RR = 1.29; 95% CI, 1.03-1.61), and metabolic syndrome (RR = 1.35; 95% CI, 1.17-1.54) independent of known cardiovascular risk factors. In longitudinal models, stress/distress was associated with new-onset dysrhythmia (RR = 2.87; 95% CI, 1.21-6.78), perceived stress with hypertension (RR = 1.42; 95% CI, 1.04-1.95), and PTSS and anxiety with dyslipidemia (RR = 1.72; 95% CI, 1.13-2.62; RR = 1.54; 95% CI, 1.01-2.35, respectively). Conclusions: Stress/distress is independently associated with adverse cardiovascular outcomes among childhood cancer survivors. [ABSTRACT FROM AUTHOR]

Background: Survivors of childhood cancer have an increased risk of therapy-related cardiovascular disease. It is not known whether family history of cardiovascular disease further increases risk of adverse cardiovascular outcomes among survivors. Methods: Family history of cardiovascular disease was collected from 1,260 survivors [median age at diagnosis, 8 years (range, 0-23); age at last follow-up, 35 years (range, 18-66)] of childhood cancer in the St. Jude Lifetime Cohort Study. Multivariable risk models evaluated associations with cardiovascular disease (Common Terminology Criteria for Adverse Events grade 2-4 events) and cardiovascular risk factors. Results: Among survivors exposed to chest-directed radiation and/or anthracycline chemotherapy (n = 824), 7% reported a first-degree family history of heart failure, 19% myocardial infarction, 11% stroke, 26% atherosclerotic disease (myocardial infarction and/or stroke), 62% hypertension, and 31% diabetes mellitus. Eighteen percent of exposed survivors developed heart failure, 9% myocardial infarction, 3% stroke, 11% atherosclerotic disease, 30% hypertension, and 9% diabetes mellitus. Having a first-degree family history of atherosclerotic disease was independently associated with development of treatment-related heart failure [RR, 1.38; 95% confidence interval (CI), 1.01-1.88; P = 0.04] among exposed survivors. Risk for hypertension was increased among exposed survivors with a first-degree family history of hypertension (RR, 1.55; 95% CI, 1.26-1.92; P < 0.0001) or of any cardiovascular disease [myocardial infarction, stroke, or heart failure (RR, 1.30; 95% CI, 1.06-1.59; P = 0.01)]. Conclusions: Family history of cardiovascular disease and cardiovascular risk factors independently increased risk of heart failure and hypertension among survivors of childhood cancer exposed to cardiotoxic therapies. Impact: These data show the importance of cardiovascular family history as a risk factor for cardiovascular disease in survivors of childhood cancer. [ABSTRACT FROM AUTHOR]

Background: We aimed to characterize body composition, metabolic impairments, and physical performance among survivors of pediatric abdominal and pelvic solid tumors. Methods: Participants included 431 survivors of abdominal or pelvic tumors [median attained age = 29.9 (range: 18.7-55.1) years]. Relative lean mass and fat mass were assessed with dual X-ray absorptiometry. Metabolic outcomes [insulin resistance (IR), high-density lipoprotein (HDL), low-density lipoprotein, and triglycerides] were based on laboratory values and medication usage. General linear regression evaluated associations between treatment and lifestyle with body composition; binomial regression evaluated associations between body composition and metabolic outcomes and physical performance. Results: Lean mass was lower than values from the National Health and Nutrition Examination Survey (NHANES) in males (Z-score = −0.67 ± 1.27; P < 0.001) and females (Z-score = −0.72 ± 1.28; P < 0.001). Higher cumulative abdominal and pelvic radiation doses were associated with lower lean mass among males [abdominal: β = −0.22 (SE) ± 0.07; P = 0.002 and pelvic: β = −0.23 ± 0.07; P = 0.002] and females (abdominal: β = −0.30 ± 0.09; P = 0.001 and pelvic: β = −0.16 ± 0.08; P = 0.037). Prevalence of IR (40.6% vs. 33.8%; P = 0.006), low HDL (28.9% vs. 33.5%; P = 0.046), and high triglycerides (18.4% vs. 10.0%; P < 0.001) was increased among survivors relative to NHANES. Compared with survivors with normal/high lean mass and normal/low fat mass, survivors with normal/high lean mass and high fat mass had an increased risk of IR (P < 0.001), low HDL (P < 0.001), reduced quadriceps strength at 60°/second (P < 0.001) and 300°/second (P < 0.001), and reduced distance covered in the 6-minute walk (P < 0.01). Conclusions: Abdominal/pelvic radiotherapy is associated with body composition changes that can adversely influence metabolic outcomes and performance status among survivors. [ABSTRACT FROM AUTHOR]

Background: Adult survivors of childhood osteosarcoma and Ewing sarcoma are at risk of developing therapy-related chronic health conditions. We characterized the cumulative burden of chronic conditions and health status of survivors of childhood bone sarcomas. Methods: Survivors (n = 207) treated between 1964 and 2002 underwent comprehensive clinical assessments (history/physical examination, laboratory analysis, and physical and neurocognitive testing) and were compared with community controls (n = 272). Health conditions were defined and graded according to a modified version of the NCI's Common Terminology Criteria for Adverse Events and the cumulative burden estimated. Results: Osteosarcoma and Ewing sarcoma survivors [median age 13.6 years at diagnosis (range 1.7-24.8); age at evaluation 36.6 years (20.7-66.4)] demonstrated an increased prevalence of cardiomyopathy (14.5%; P < 0.005) compared with controls. Nearly 30% of osteosarcoma survivors had evidence of hypertension. By age 35 years, osteosarcoma and Ewing sarcoma survivors had, on average, 12.0 (95% confidence interval, 10.2-14.2) and 10.6 (8.9-12.6) grade 1-4 conditions and 4.0 (3.2-5.1) and 3.5 (2.7-4.5) grade 3-4 conditions, respectively, compared with controls [3.3 (2.9-3.7) grade 1-4 and 0.9 (0.7-1.0) grade 3-4]. Both survivor cohorts exhibited impaired 6-minute walk test, walking efficiency, mobility, strength, and endurance (P < 0.0001). Accumulation of ≥4 grade 3-4 chronic conditions was associated with deficits in executive function [RR: osteosarcoma 1.6 (1.0-2.4), P = 0.049; Ewing sarcoma 2.0 (1.2-3.3), P = 0.01] and attention [RR: osteosarcoma 2.3 (1.2-4.2); P = 0.008]. Conclusions: Survivors of osteosarcoma and Ewing sarcoma experience a high cumulative burden of chronic health conditions, with impairments of physical function and neurocognition. Impact: Early intervention strategies may ameliorate the risk of comorbidities in bone sarcoma survivors. [ABSTRACT FROM AUTHOR]