ALBERT

Description: DLBCL is a curable subtype of non-Hodgkin lymphoma, although a significant number of patients do not achieve a remission or they relapse with conventional chemotherapy. While clinical variables (e.g., IPI), tumor (somatic) genetic alterations, and gene expression profiling have all been shown to predict outcome, there remains a need for additional prognostic biomarkers. One understudied class of biomarkers is host genetic background. We evaluated the hypothesis that germline variability in 73 SNPs from 44 candidate immune genes was associated with overall survival in DLBCL. We addressed this hypothesis in 365 DLBCL patients aged 20–70 years who participated in a population-based case-control study conducted from 1998–2000 (prior to the use of R-CHOP) through the Surveillance, Epidemiology, and End Results (SEER) cancer registries in Detroit, Seattle, Iowa, and Los Angeles. Germline DNA was extracted from a venous blood sample or mouthwash buccal cell sample, which was collected a median of 4.8 months after diagnosis in this population-based study. All genotyping was conducted at the National Cancer Institute Core Genotyping Facility using the Taqman platform, and was successful in over 95% of the DNA samples for the SNPs evaluated. Histology, stage, presence of B-symptoms, first course of therapy, date of last follow-up, and vital status were derived from linkage to registry databases at each study site in the spring of 2005. Cox proportional hazards analysis was used to evaluate the association between individual SNPs, adjusted for age, demographic and clinical factors. Parallel modeling strategies were used to identify the best summary multi-SNP risk score to predict survival. At a median follow-up of 56 months (range, 27-78 months) for surviving patients, there were 96 deaths in 365 patients (26%). In multivariate modeling, SNPs in IL1A (rs1800587; HRCT/TT=1.90, 1.26–2.87), IL6 (rs1800795; HRGG=1.48, 0.99–2.23), IL-10 (rs1800896; HRAG/GG=1.48, 0.91–2.38), and IFNGR2 (rs2070385; HRAG/GG=1.35, 0.86–2.11) were the strongest and most robust predictors of overall survival. A summary score of the number of deleterious genotypes from these four genes in combination with clinical and demographic variables was strongly associated with survival (p=9.3 x 10−12); Kaplan-Meier 5-year survival estimates for low, intermediate, and high risk patients were 89%, 68%, and 47% respectively. In conclusion, host genetic background as measured by germline polymorphisms in immune genes including IL1A, IL6, IL10, and IFNGR2 were associated with overall survival in DLBCL after accounting for clinical and demographic factors. These promising results require confirmation and need further evaluation in patients treated with R-CHOP in conjunction with tumor and other prognostic biomarkers.

Description: Background: Mantle cell lymphoma (MCL) is an incurable non-Hodgkin lymphoma. MCL is characterized by the chromosomal translocation t(11;14) leading to overexpression of cyclin D1 (CCND1), a regulator of the cell cycle. NF-κB plays a central role in key cellular processes, including cell cycle regulation and apoptosis, and it has been shown to be constitutively activated in MCL cell lines and in patient biopsy samples and to play a key role in the growth and survival of MCL cells. In an exploratory study, we evaluated the hypothesis that germline variation in candidate genes from the cell cycle and NF-κB pathways predict overall survival in MCL. Methods: We genotyped 235 SNPs from 29 cell cycle genes and 447 SNPs from 55 NF-κB genes in 39 MCL patients aged 38–64 years who participated in a population-based study conducted from 1998–2000 through the Surveillance, Epidemiology, and End Results (SEER) cancer registries in Detroit, Seattle, Iowa, and Los Angeles county. Tagging single nucleotide polymorphisms (SNPs) were selected from HapMap. Stage, presence of B-symptoms, first course of therapy, date of last follow-up, and vital status were derived from linkage to registry databases at each study site. To assess the statistical significance of a gene, we first used principal components analysis to capture the genetic variation of the SNPs within a gene. Cox proportional hazards analysis was then used to assess the association between the top principal components from a gene with overall survival. Results: Through early 2005, there were 22 deaths in 39 patients (56%). The median follow-up of the 17 surviving patients was 56 months (range 36–70). Eleven of the 55 genes (TNFSF14 p=0.0007, NF-κBIA p=0.003, IL1R2 p=0.01, TNFRSF25 p=0.02, TNFSF13B p=0.02, FAS p=0.03, TLR2 p=0.04, TNFSF10D p=0.04, TNFSF10 p=0.06, MAP3K2 p=0.06) in the NF-κB pathway were associated with overall survival. In the cell cycle pathway, only 3 of the 29 genes (CASP5 p=0.06, CASP9 p=0.09, BCL2 p=0.09) were associated with overall survival, and a previously reported SNP in CCND1 (rs603965) showed no association (p=0.5). Permutation p-values for observing at least this number of associated tests in each pathway due to chance (from multiple testing) was p=0.8 for the cell cycle pathway and p=0.03 for NF-κB pathway. The small sample size precluded multi-gene modeling. Conclusion: In a population series of MCL patients, we found suggestive evidence that host genetic variation in candidate NF-κB pathway genes affects overall survival. These results complement tumor expression data implicating this pathway in the pathogenesis of MCL. In addition, such findings further support the value of developing therapeutic targets from this pathway.

Description: Background. Intracellular one-carbon transfer reactions are essential for nucleotide synthesis and methylation of biologic compounds including DNA. Previous studies have linked genetic variants in one-carbon metabolism genes with risk of developing NHL, but little is known regarding the impact of these variants on disease outcome. We evaluated the hypothesis that inherited genetic variation in genes involved in one-carbon metabolism is associated with overall survival in DLBCL. Methods. We genotyped 30 single nucleotide polymorphisms (SNPs) from 18 candidate one-carbon metabolism genes in 215 DLBCL patients who participated in a population-based case-control study conducted from 1998–2000 using the SEER (Surveillance, Epidemiology and End Results) cancer registries in the Detroit, Iowa, Los Angeles and Seattle. Stage, B-symptoms, first course of therapy, date of last follow-up and vital status through early 2005 were obtained from cancer registry files. Cox proportional hazards analysis was used to estimate hazard ratios (HR) and corresponding 95% confidence intervals for the association between individual SNPs and overall survival, adjusting for age, demographic and clinical factors. We also used parallel modeling strategies to identify the best summary multi-SNP risk score to predict survival. Results. The median age at diagnosis was 57 years (range, 20–74), and 50 (23%) of the patients died during follow-up, with a median follow-up of 57 months (range, 31–78 months) for surviving patients. After adjusting for demographic and clinical variables, SNPs in SHMT1 (rs1979276; HRCT/TT=2.47, 1.31–4.67), BHMT (rs585800; HRAT/TT=2.02, 1.16–3.54), and TCN1 (rs526934; HRTT=1.86, 1.04–3.33) were the strongest and most robust predictors of survival. A summary score of the number of deleterious genotypes (0–3) from these three genes was strongly associated with survival (p=7.9 x 10−5) after accounting for demographic and clinical variables (HR=2.58 per deleterious genotype, 95% CI 1.75–3.80). A risk score combining the three SNPs with clinical and demographic variables (score of 0 to 5) was even more strongly associated with survival (p=1.4 x 10−13); the Kaplan Meier survival curves are shown in the Figure. In a time-dependent ROC analysis, the combined risk score had a concordance index of 0.75 at 5 years of follow-up (95% CI 0.69–0.81). Conclusion: Host genetic variation in the one-carbon metabolism genes SHMT1, BHMT, and TCN1, individually and particularly in combination, was associated with overall DLBCL survival after accounting for clinical and demographic factors, supporting a role for this pathway in disease progression. Future work should evaluate interactions of genes from this pathway with dietary nutrients and therapeutic agents in DLBCL prognosis. Figure Figure

Description: Small lymphocytic lymphoma (SLL) is an incurable indolent lymphoma, and there are relatively few prognostic biomarkers for this important NHL subtype. We evaluated the hypothesis that inherited variability in cytokine and immune-related genes was associated with overall survival in SLL. We genotyped 73 SNPs in 44 candidate genes in 140 SLL patients aged 20–70 years who participated in a population-based case-control study conducted from 1998–2000 through the Surveillance, Epidemiology, and End Results (SEER) cancer registries in Detroit, Seattle, Iowa, and Los Angeles. DNA was extracted from a venous blood sample or mouthwash buccal cell sample. All genotyping was conducted at the National Cancer Institute Core Genotyping Facility using the Taqman platform. Histology, stage, presence of B-symptoms, first course of therapy, date of last follow-up, and vital status were derived from linkage to registry databases at each study site in the spring of 2005. Cox proportional hazards analysis was used to estimate the hazard ratio (HR) and 95% confidence interval for the association between individual SNPs and overall survival, adjusted for age, demographic and clinical factors. Multiple simultaneous modeling strategies were used to identify the best summary multi-SNP risk score to predict survival. At last follow-up, there were 45 deaths in 140 patients (32%). The median follow-up of the 95 surviving patients was 58 months (range 24–75 months). In multivariate modeling, SNPs in IL13 (rs1800925; HRCC=2.36, 1.24–4.49), IL7R (rs1494555; HRGG =2.20, 0.84–5.76), and TNF-alpha (rs1800630; HRAC/AA=1.73, 0.95–3.17) were the strongest and most robust predictors of survival. Two or more deleterious genotypes from these three SNPs increased the risk of death (HR=2.2, 1.2–4.1) compared with one or fewer deleterious genotypes (p=0.009). Three groups (low, intermediate, and high risk) were defined by combining the SNP score and a clinical/demographic score. The 5-year Kaplan-Meier survival estimates for these groups were 85%, 65%, and 11%, respectively. Compared to patients with a low risk score, patients with intermediate (HR=2.5, 1.2–5.1) or high (HR=11, 4.3–27.7) risk scores had poorer overall survival (p=3.9 x 10−8). Our preliminary results suggest that SNPs in IL13, IL7R, and TNF-alpha alone and in combination predict overall survival in SLL, lending support to the hypothesis that host genetic background is a promising class of prognostic biomarkers in SLL.

Description: Cancer is the leading cause of disease-related death in the Adolescent and young adult (AYA) population; and though strides have been made in survival of children with cancer, cancer patients diagnosed between 15 and 39 years have not had survival improvement in more than 20 years. Individuals within this population may possess a greater need of particular health services in order to cope with disease. AYA cancer patients may present with co-morbidities that pre-date their cancer treatment and could create challenges for appropriate treatment. Previous studies have demonstrated that co-morbidities can result in increased hospitalizations, difficulties with treatment, high health care costs, reduced quality of life and higher mortality. Although the extent of co-morbidities and their association with poor outcomes have been examined extensively in the adult cancer population, there is little data on children, and even less in the AYA cancer population. Methods: In order to determine what co-morbidities exist in the AYA cancer population, we examined the prevalence of co-morbidities in the National Cancer Institute’s Adolescent and Young Adult Health Outcomes and Patient Experience (AYA HOPE) Study, a population-based cohort of AYAs recently diagnosed with cancer. All co-morbidities were abstracted from the medical record at the time of initial diagnosis and during the first course of treatment. We compared the fitness of current co-morbidity indices for chronic conditions (Charlson and National Cancer Institute Index (NCI)) and created an AYA HOPE index that covers more clinically relevant chronic co-morbid conditions in AYA cancer survivors. We examined self-reported services needed or received, and self-reported health status with the count of co-morbidities in the AYA HOPE cohort using the AYA HOPE Index. Results: Four hundred and eighty-five patients were eligible for this study; the mean age of diagnoses was 28 years. The prevalence of co-morbidities in the AYA HOPE participants was examined using the Charlson index, the NCI index and the AYA Hope index. For diabetes, HIV/AIDS, hypertension, liver, asthma/respiratory, and rheumatologic/autoimmune, the co-morbidity counts were the same for the three co-morbidity indices. Mental health and obesity/overweight were not included in the Charlson or the NCI indices but included in the AYA HOPE Index. When compared to Charlson and NCI indices, the prevalence of co-morbidities was higher for cardiovascular, endocrine, gastrointestinal and neurologic conditions with the AYA HOPE index. The prevalence of mental health co-morbid conditions was 8.2% within the population, with 17 of the 40 individuals affected (42.5%) reporting a depressive disorder. Also, the prevalence of obesity/overweight conditions was 5.8%. Of the 485 patients examined, 70 (14.4%) had 2 or more co-morbid conditions using the AYA HOPE index, which was much higher than the number of patients determined to have multiple co-morbidities based on the Charlson and NCI indices (4.9% and 2.7%, respectively). Overall, 39.6% of AYA patients responding to the survey 6-14 months after diagnosis reported needing some type of health service with the most common service needed being mental health (25.2%), followed by support group (17.7%). After controlling for significant clinical factors (e.g., cancer site, health status and treatment received) and socio-demographic predictors (e.g., age, sex, race), AYA patients with 2 or more co-morbidities based on the AYA HOPE index had twice the odds of needing mental health services as those with no co-morbidity (OR: 2.00; 95% CI 1.05-3.81). AYA patients with 2 or more co-morbidities were also three times more likely to report their health status as fair/poor (OR: 3.15; 95% CI 1.56-6.37). Conclusion: The AYA HOPE index is the first co-morbidity index to be developed specifically for the AYA cancer population. The inclusion of mental health and obesity, and the expansion of neurologic and gastrointestinal categories enhances the predictive ability of the AYA HOPE index and allows for a more accurate picture of the conditions prevalent in this unique population; in doing so, it aids in prediction of common healthcare services that should be directed to this population. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 2679 Introduction. Subsequent malignancies are a leading cause of morbidity and mortality among Hodgkin lymphoma (HL) survivors. Stomach cancer is one of the more common second malignancies occurring after HL, yet few studies have quantified stomach cancer risk in relation to radiation dose, and only one investigation has evaluated potential risks associated with chemotherapy. Methods. We conducted a nested case-control study of stomach cancer among 17,447 ≥5-year survivors of HL from six European and North American population-based cancer registries during 1953–2005. Patients included 71 cases diagnosed with HL and subsequent stomach cancer, and 142 individually-matched controls diagnosed with HL only. Data were pooled with a previous hospital-based case-control study from The Netherlands (18 cases, 48 controls), resulting in a total of 89 cases and 190 controls. For all patients, detailed data were abstracted from medical records on HL diagnosis and treatment and, for cases, stomach cancer diagnosis. Based on detailed radiotherapy information, the radiation dose was estimated to the area of the stomach where the case patient's tumor developed and to the comparable location in matched control patients. Chemotherapy data included specific drugs, doses, and number of cycles. The relative risk of stomach cancer was estimated using odds ratios (ORs) derived from conditional logistic regression analyses. Results. Median ages of case patients at HL and stomach cancer diagnosis were 32 years (range, 11–83 years) and 50 years (range, 26–89 years), respectively, with a median interval between HL and stomach cancer of 16 years (range, 5–36 years). Most patients received combined modality treatment (chemotherapy + radiotherapy, 56% cases, 44% controls) or radiotherapy alone (36% cases, 43% controls), whereas few patients received chemotherapy alone (8% cases, 13% controls). Stomach cancer risk increased with increasing radiation dose to the stomach tumor location (Ptrend

Description: To evaluate the hypothesis that host germ line variation in immune genes is associated with overall survival in diffuse large B-cell lymphoma (DLBCL), we genotyped 73 single nucleotide polymorphisms (SNPs) from 44 candidate genes in 365 DLBCL patients diagnosed from 1998 to 2000. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for the association of SNPs with survival after adjusting for clinical factors. During follow-up, 96 (26%) patients died, and the median follow-up was 57 months for surviving patients. The observed survival of this cohort was consistent with population-based estimates conditioned on surviving 12 months. An IL10 haplotype (global P = .03) and SNPs in IL8RB (rs1126580; HRAG/GG = 2.11; CI, 1.28-3.50), IL1A (rs1800587; HRCT/TT = 1.90; CI, 1.26-2.87), TNF (rs1800629; HRAG/GG = 1.44; CI, 0.95-2.18), and IL4R (rs2107356; HRCC/CT = 1.97; CI, 1.01-3.83) were the strongest predictors of overall survival. A risk score that combined the latter 4 SNPs with clinical factors was strongly associated with survival in a Cox model (P = 6.0 × 10−11). Kaplan-Meier 5-year survival estimates for low, intermediate-low, intermediate-high, and high-risk patients were 94%, 79%, 60%, and 48%, respectively. These data support a role for germ line variation in immune genes, particularly genes associated with a proinflammatory state, as predictors of late survival in DLBCL.

Description: Background Although recent findings suggest that de novo stage IV breast cancer is increasing in premenopausal women in the United States, contemporary incidence and survival data are lacking for stage I–III cancer. Methods Women aged 20–29 (n = 3826), 30–39 (n = 34 585), and 40–49 (n = 126 552) years who were diagnosed with stage I–III breast cancer from 2000 to 2015 were identified from the Surveillance, Epidemiology, and End Results 18 registries database. Age-adjusted, average annual percentage changes in incidence and 5- and 10-year Kaplan-Meier survival curves were estimated by race and ethnicity, stage, and hormone receptor (HR) status and grade (low to well and moderately differentiated; high to poorly and undifferentiated) for each age decade. Results The average annual percentage change in incidence was positive for each age decade and was highest among women aged 20–29 years. Increased incidence was driven largely by HR+ cancer, particularly HR+ low-grade cancer in women aged 20–29 and 40–49 years. By 2015, incidence of HR+ low- and high-grade cancer each independently exceeded incidence of HR− cancer in each age decade. Survival for HR+ low- and high-grade cancer decreased with decreasing age; survival for HR− cancer was similar across age decades. Among all women aged 20–29 years, 10-year survival for HR+ high-grade cancer was lower than that for HR+ low-grade or HR− cancer. Among women aged 20–29 years with stage I cancer, 10-year survival was lowest for HR+ high-grade cancer. Conclusions HR+ breast cancer is increasing in incidence among premenopausal women, and HR+ high-grade cancer was associated with reduced survival among women aged 20–29 years. Our findings can help guide further evaluation of preventive, diagnostic, and therapeutic strategies for breast cancer among premenopausal women.