Evidence Of Effect Heterogeneity Research Articles

Abstract 5227: Cross-trait genome-wide association meta-analyses of clonal hematopoiesis and solid tumor risk

Abstract Clonal hematopoiesis (CH) is an age-related phenomenon where hematopoietic stem cells and their progeny acquire specific somatic mutations in a small, well-defined set of leukemogenic genes conferring them with fitness advantage leading to clonal proliferation. Mosaic chromosomal alterations (mCAs) are somatic structural variants that are manifestations of genomic instability and a sign of CH when they occur in blood. The recent availability of large-scale cohorts with blood exome sequence and genotype data has powered genome-wide association studies (GWAS) investigating the germline genetic contribution to CH and mCA risk. However, phenotypes of somatic mutation acquisition in driver genes, clonal selection and expansion, and chromosomal mosaicism are processes that are not confined to blood and contribute to neoplastic transformation across tissue types. GWAS of solid tumor susceptibility have so far identified hundreds of germline variants associated with cancer risk and it is likely that a subset of these variants contributes to solid tumor risk by affecting these somatic phenotypes in the corresponding tissues of origin and that some of the variants exert these somatic effects across tissues. We aimed to identify this subset of solid tumor risk variants by undertaking fixed effects inverse-variance weighted meta-analyses combining breast, prostate, ovarian, and endometrial cancer GWAS (total n = 237,483 cases/317,006 controls; no UK Biobank samples included) with UK Biobank-based CH (10,203 “cases”/173,918 controls) and mCA (66,011 “cases”/378,188 controls) risk GWAS in pairs where each pair involved one solid tumor type and one of either CH or mCA (for example, breast cancer and mCA constituted a pair). These analyses collectively identified 61 independent (r2<0.05) lead variants at combined cross-trait genome-wide significance (P<5 × 10−8) across 22 genomic loci where each lead variant was associated with each trait individually at P<10−3, had the same direction of allelic effect across traits, and little evidence of heterogeneity in effect (I2<40%). New loci (>1 Mb away from previously reported risk loci for a given trait) counts were: 14 new loci in the context of mCA risk, 6 new loci for CH risk, 2 for breast cancer risk, and one each for prostate, ovarian, and endometrial cancer risks. In silico functional annotation of these loci suggested lead variant-target genes that could be assigned to the discrete pathways of mitotic spindle assembly (INCENP, CENPN, ZWILCH, MAD1L1), p53 signaling (TP53, MDM4, SPI1), DNA damage repair (ATM, RAD51C, CHEK2, USP28, PARP8), and myeloid oncogenesis (WT1, HOXA9, L3MBTL3). Our novel approach combining the latest and largest blood somatic genomic trait GWAS with large-scale solid tumor risk GWAS thus yielded clear mechanistic insights into the shared inherited genetic basis of solid tumor risk and somatic genomic traits. Citation Format: Victoria Gray, George Richenberg, Pedro Quirós, Matthew Freedman, Paul Pharoah, Simon Gayther, Michelle Jones, George Vassiliou, Kate Lawrenson, Siddhartha Kar. Cross-trait genome-wide association meta-analyses of clonal hematopoiesis and solid tumor risk. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5227.

Alcohol Price Floors and Externalities: The Case of Fatal Road Crashes

AbstractIn May 2018, Scotland introduced a minimum unit price on alcohol. We examine the impact of this policy on traffic fatalities and drunk driving accidents. Using administrative data on the universe of vehicle collisions in Britain and a range of quasi‐experimental modeling approaches, we do not find that the policy had an effect on road crash deaths and drunk driving collisions. The results are robust to several sensitivity exercises. There is no evidence of effect heterogeneity by income and other predictors of alcohol consumption or cross‐border effects. A brief discussion of the policy implications of our findings is provided.

Traffic-related Air Pollution and Lung Cancer Incidence: The California Multiethnic Cohort Study.

Rationale: Although the contribution of air pollution to lung cancer risk is well characterized, few studies have been conducted in racially, ethnically, and socioeconomically diverse populations. Objectives: To examine the association between traffic-related air pollution and risk of lung cancer in a racially, ethnically, and socioeconomically diverse cohort. Methods: Among 97,288 California participants of the Multiethnic Cohort Study, we used Cox proportional hazards regression to examine associations between time-varying traffic-related air pollutants (gaseous and particulate matter pollutants and regional benzene) and lung cancer risk (n = 2,796 cases; average follow-up = 17 yr), adjusting for demographics, lifetime smoking, occupation, neighborhood socioeconomic status (nSES), and lifestyle factors. Subgroup analyses were conducted for race, ethnicity, nSES, and other factors. Measurements and Main Results: Among all participants, lung cancer risk was positively associated with nitrogen oxide (hazard ratio [HR], 1.15 per 50 ppb; 95% confidence interval [CI], 0.99-1.33), nitrogen dioxide (HR, 1.12 per 20 ppb; 95% CI, 0.95-1.32), fine particulate matter with aerodynamic diameter <2.5 μm (HR, 1.20 per 10 μg/m3; 95% CI, 1.01-1.43), carbon monoxide (HR, 1.29 per 1,000 ppb; 95% CI, 0.99-1.67), and regional benzene (HR, 1.17 per 1 ppb; 95% CI, 1.02-1.34) exposures. These patterns of associations were driven by associations among African American and Latino American groups. There was no formal evidence for heterogeneity of effects by nSES (P heterogeneity > 0.21), although participants residing in low-SES neighborhoods had increased lung cancer risk associated with nitrogen oxides, and no association was observed among those in high-SES neighborhoods. Conclusions: These findings in a large multiethnic population reflect an association between lung cancer and the mixture of traffic-related air pollution and not a particular individual pollutant. They are consistent with the adverse effects of air pollution that have been described in less racially, ethnically, and socioeconomically diverse populations. Our results also suggest an increased risk of lung cancer among those residing in low-SES neighborhoods.

HLA-A*03 and response to immune checkpoint blockade in cancer: an epidemiological biomarker study.

Predictive biomarkers could allow more precise use of immune checkpoint inhibitors (ICIs) in treating advanced cancers. Given the central role of HLA molecules in immunity, variation at the HLA loci could differentially affect the response to ICIs. The aim of this epidemiological study was to determine the effect of HLA-A*03 as a biomarker for predicting response to immunotherapy. In this epidemiological study, we investigated the clinical outcomes (overall survival, progression free survival, and objective response rate) after treatment for advanced cancer in eight cohorts of patients: three observational cohorts of patients with various types of advanced tumours (the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets [MSK-IMPACT] cohort, the Dana-Farber Cancer Institute [DFCI] Profile cohort, and The Cancer Genome Atlas) and five clinical trials of patients with advanced bladder cancer (JAVELIN Solid Tumour) or renal cell carcinoma (CheckMate-009, CheckMate-010, CheckMate-025, and JAVELIN Renal 101). In total, these cohorts included 3335 patients treated with various ICI agents (anti-PD-1, anti-PD-L1, and anti-CTLA-4 inhibitors) and 10 917 patients treated with non-ICI cancer-directed therapeutic approaches. We initially modelled the association of HLA amino-acid variation with overall survival in the MSK-IMPACT discovery cohort, followed by a detailed analysis of the association between HLA-A*03 and clinical outcomes in MSK-IMPACT, with replication in the additional cohorts (two further observational cohorts and five clinical trials). HLA-A*03 was associated in an additive manner with reduced overall survival after ICI treatment in the MSK-IMPACT cohort (HR 1·48 per HLA-A*03 allele [95% CI 1·20-1·82], p=0·00022), the validation DFCI Profile cohort (HR 1·22 per HLA-A*03 allele, 1·05-1·42; p=0·0097), and in the JAVELIN Solid Tumour clinical trial for bladder cancer (HR 1·36 per HLA-A*03 allele, 1·01-1·85; p=0·047). The HLA-A*03 effect was observed across ICI agents and tumour types, but not in patients treated with alternative therapies. Patients with HLA-A*03 had shorter progression-free survival in the pooled patient population from the three CheckMate clinical trials of nivolumab for renal cell carcinoma (HR 1·31, 1·01-1·71; p=0·044), but not in those receiving control (everolimus) therapies. Objective responses were observed in none of eight HLA-A*03 homozygotes in the ICI group (compared with 59 [26·6%] of 222 HLA-A*03 non-carriers and 13 (17·1%) of 76 HLA-A*03 heterozygotes). HLA-A*03 was associated with shorter progression-free survival in patients receiving ICI in the JAVELIN Renal 101 randomised clinical trial for renal cell carcinoma (avelumab plus axitinib; HR 1·59 per HLA-A*03 allele, 1·16-2·16; p=0·0036), but not in those receiving control (sunitinib) therapy. Objective responses were recorded in one (12·5%) of eight HLA-A*03 homozygotes in the ICI group (compared with 162 [63·8%] of 254 HLA-A*03 non-carriers and 40 [55·6%] of 72 HLA-A*03 heterozygotes). HLA-A*03 was associated with impaired outcome in meta-analysis of all 3335 patients treated with ICI at genome-wide significance (p=2·01 × 10-8) with no evidence of heterogeneity in effect (I2 0%, 95% CI 0-0·76) INTERPRETATION: HLA-A*03 is a predictive biomarker of poor response to ICI. Further evaluation of HLA-A*03 is warranted in randomised trials. HLA-A*03 carriage could be considered in decisions to initiate ICI in patients with cancer. National Institutes of Health, Merck KGaA, and Pfizer.

Prenatal exposure to lipophilic endocrine-disrupting chemicals and liver injury in children using chemical mixture approaches

BACKGROUND AND AIM: Exposure to Endocrine Disrupting Chemicals (EDC) may increase liver injury, but few studies have examined these associations in children and most focused on a single chemical group. We evaluated the associations between a wide range of prenatal EDC exposures and child liver injury. METHODS: We studied 1108 healthy children from the Human Early-Life Exposome (HELIX) project, a collaborative network of six established longitudinal population-based birth cohort studies in Europe. Thirty lipophilic EDCs (including 3 organochlorine pesticides, 5 polychlorinated-biphenyl, 2 polybrominated-diphenyl-ethers [PBDEs], 5 high molecular weight phthalates (HMWP), 5 low molecular weight phthalates, 6 phenols and 4 organophosphate pesticides) were measured in maternal pregnancy blood or urine. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT) and cytokeratin 18 (CK18) were measured in child serum at follow-up between age 6-11 years. Liver injury was defined as having any liver enzyme (ALT, AST or GGT) above the 90th percentile. We used Bayesian generalized linear mixed regressions (Bglmr) to estimate associations of individual chemicals, Bayesian Weighted Quantile Sum (BWQS) and Bayesian Kernel Machine Regression (BKMR) to assess the overall association of each chemical group with liver injury and CK18, adjusting for confounders. RESULTS:BWQS results indicated that organochlorine pesticides and PBDEs were associated with increased odds of liver injury (OR[95%CI] by chemical mixture quartile increase=1.44[1.23, 1.72] and 1.59[1.37, 1.90], respectively); whereas HMWP were associated with decreased odds of liver injury (OR[95%CI]=0.71[0.59, 0.85]). A quartile increase of PBDEs was positively associated with CK18 (Estimate[95%CI]=5.33 Units/Liter [2.52,8.16]). Bglmr and BKMR showed associations in same direction as the BWQS results. There was evidence of effect heterogeneity by sex for organochlorine pesticides and HMWPs with liver injury status. CONCLUSIONS:Using multiple chemical mixture approaches we found that prenatal exposures to persistent pollutants, especially to organochlorine compounds, and PBDEs, may be associated with increased risk for liver injury in childhood. KEYWORDS: Chemical exposures, Endocrine disrupting chemicals, Mixtures analysis, Modeling, Environmental epidemiology

Does education predict gender role attitudes?: Evidence from European datasets

This paper presents the first empirical evidence of the causal impact of individuals' education on their attitudes towards traditional gender roles. We employ two national panel datasets from the UK and Switzerland and a repeated cross-sectional dataset with information from 13 Western European countries for the analysis. The causal impact of education on gender role attitudes is estimated by exploiting the exogenous variation in individuals' education induced by the compulsory school reforms undertaken in European countries in the second half of the 20th century. We find evidence that an additional year of education instigates egalitarian gender role attitudes equivalent of 0.1-0.3 of a standard deviation. While education's moderating effect is particularly prominent among women, no evidence of effect heterogeneity is found concerning the individuals' religiosity. Our findings are robust to numerous checks performed and are briefly discussed for their policy relevance.

Do benefits of own education for cognition differ by parental education? Influence of intergenerational educational trajectories and cognitive performance in the Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort

AbstractBackgroundLittle is known about the influence of parental education on late life cognition or whether parental education modifies the association between own education and cognitive outcomes. Parental education influences own educational access/attainment as well as early cognitive environments and resources (social, financial capital) known to affect health. We investigated whether benefits of own education differed by parental education using intergenerational education trajectories.MethodsThe Kaiser Healthy Aging and Diverse Life Experiences (KHANDLE) cohort is a diverse sample (approximately equal White, African‐American, Asian, and Latinx) of long‐term members of a managed care organization; cognitive domains of verbal episodic memory, semantic memory, and executive functioning were obtained using the Spanish and English Neuropsychological Assessment Scales (SENAS). Parental education (low defined as either parent with &lt;9 years of schooling) and own education (low defined &lt;college degree; includes some college) were reported by 1,633 participants. Intergenerational education was categorized as stable low (reference), low‐high, high‐low, and stable high. Cognitive domains were analyzed as a z‐score composite and as independent domains using linear mixed models adjusting for age, gender, race, and nativity; potential effect heterogeneity was evaluated as interactions between educational trajectories and (1) SENAS domains, (2) race/ethnicity, (3) gender.ResultsAll participants with high own education had higher average cognitive scores than those with low own education; those with low‐high trajectories had higher average cognitive scores (B̂=0.33; 95% CI: 0.23, 0.42) than those with stable high trajectories (B̂=0.19; 95% CI: 0.09, 0.29). Those with high‐low trajectories had lower average cognitive scores (B̂=‐0.16; 95% CI: ‐0.25, ‐0.07) than those with stable low trajectories. Effect sizes but not overall patterns differed by cognitive domain (p&lt;.0001) and gender (p=0.0097); there was no evidence of effect heterogeneity by race (interaction P‐value=0.6691).ConclusionOwn education was associated with late‐life cognition across all levels of parental education. Effect estimates were largest for an upward trajectory of intergenerational education with similar patterns across cognitive domains. Education may open cognitively beneficial opportunities for individuals with low parental education indicating the importance of supporting college entry/completion, though this may reflect the selection process of individuals who complete college despite low parental education.

An exploration of the heterogeneity in effects of SGLT2 inhibition on cardiovascular and all-cause mortality in the EMPA-REG OUTCOME, CANVAS Program, DECLARE-TIMI 58, and CREDENCE trials

BackgroundLarge-scale outcome trials of sodium glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes have identified consistent effects on major adverse cardiovascular events, heart failure, and progression of kidney disease. However, the magnitude of effects on cardiovascular and all-cause death appeared to vary between some of the studies. MethodsWe explored the impact of differences in trial methodologies, participant characteristics, types of deaths, follow-up duration, effects on intermediate markers of risk, and drug selectivity for SGLT2 on the magnitude of the protective effect against fatal events achieved in the 4 trials. ResultsThe trial populations differed substantively in the proportions with baseline atherosclerotic cardiovascular disease history (99.2% in EMPA-REG OUTCOME to 40.6% in DECLARE-TIMI 58), and macroalbuminuria (88.0% in CREDENCE to 7.6% in the CANVAS Program). Meta-regression analyses identified no clear effect of these (both P > 0.09) or other participant characteristics on mortality benefits (all P > 0.55). Other differences between the trials (duration, selectivity of the SGLT2 inhibitor, or effects on intermediate markers of risk) also did not explain the heterogeneity in effects on mortality observed (all P > 0.30). ConclusionNo clear explanation for the statistical evidence of heterogeneity in effects of SGLT2 inhibition on fatal outcomes between the trials could be identified. While the analyses had limited statistical power, these results raise the possibility that the observed variations in treatment effects on fatal outcomes between trials may be at least partly due to chance.

Precision-Guided or Blunt? The Effects of US Economic Sanctions on Human Rights

This study contributes to the literature that analyzes the consequences of economic sanctions for the target country’s human rights situation. We offer a political economy explanation for different types of human rights infringements or improvements in reaction to economic shocks caused by sanctions. Based on this, we derive hypotheses linking sanctions to four types of human rights: economic rights, political and civil rights, basic human rights, and emancipatory rights. We use endogenous treatment-regression models to estimate the causal average treatment effect of US economic sanctions on each type of human rights within a uniform empirical framework. In contrast to previous studies, we find no adverse effects of sanctions on economic rights, political and civil rights, and basic human rights, once the endogenous selection into sanctions is modeled. With respect to women’s rights, our findings even indicate a positive relationship. Emancipatory rights are, on average, strengthened when a country experiences sanctions by the US. Our findings are robust and we find little evidence for effect heterogeneity between types of target countries or sanctions. Most importantly, this study shows that the endogeneity of treatment assignment must be modeled when the consequences of sanctions are studied empirically.

Estimating patient-specific treatment advantages in the ‘Treatment for Adolescents with Depression Study’

The ‘Treatment for Adolescents with Depression Study’ (TADS, ClinicalTrials.gov, identifier: NCT00006286) was a cornerstone, randomized controlled trial evaluating the effectiveness of standard treatment options for major depression in adolescents. Whereas previous TADS analyses examined primarily effect modifications of treatment-placebo differences by various patient characteristics, less is known about the modification of inter-treatment differences, and hence, patient characteristics that might guide treatment selection. We sought to fill this gap by estimating patient-specific inter-treatment differences as a function of patients' baseline characteristics. We did so by applying the ‘model-based random forest’, a recently-introduced machine learning-based method for evaluating effect heterogeneity that allows for the estimation of patient-specific treatment effects as a function of arbitrary baseline characteristics. Treatment conditions were cognitive-behavioural therapy (CBT) alone, fluoxetine (FLX) alone, and the combination of CBT and fluoxetine (COMB). All inter-treatment differences (CBT vs. FLX; CBT vs. COMB; FLX vs. COMB) were evaluated across 23 potential effect modifiers extracted from previous studies. Overall, FLX was superior to CBT, while COMB was superior to both CBT and FLX. Evidence for effect heterogeneity was found for the CBT-FLX difference and the FLX-COMB difference, but not for the CBT-COMB difference. Baseline depression severity modified the CBT-FLX difference; whereas baseline depression severity, patients' treatment expectations, and childhood trauma modified the FLX-COMB difference. All modifications were quantitative rather than qualitative, however, meaning that the differences varied only in magnitude, but not direction. These findings imply that combining CBT with fluoxetine may be superior to either therapy used alone across a broad range of patients.

Genetic association and differential expression of PITX2 with acute appendicitis

Appendicitis affects 9% of Americans and is the most common diagnosis requiring hospitalization of both children and adults. We performed a genome-wide association study of self-reported appendectomy with 18,773 affected adults and 114,907 unaffected adults of European American ancestry. A significant association with appendectomy was observed at 4q25 near the gene PITX2 (rs2129979, p value = 8.82 × 10−14) and was replicated in an independent sample of Caucasians (59 affected, 607 unaffected; p value = 0.005). Meta-analysis of the associated variant across our two cohorts and cohorts from Iceland and the Netherlands (in which this association had previously been reported) showed strong cumulative evidence of association (OR = 1.12; 95% CI 1.09–1.14; p value = 1.81 × 10−23) and some evidence for effect heterogeneity (p value = 0.03). Eight other loci were identified at suggestive significance in the discovery GWAS. Associations were followed up by measuring gene expression across resected appendices with varying levels of inflammation (N = 75). We measured expression of 27 genes based on physical proximity to the GWAS signals, evidence of being targeted by eQTLs near the signals according to RegulomeDB (score = 1), or both. Four of the 27 genes (including PITX2) showed significant evidence (p values < 0.0033) of differential expression across categories of appendix inflammation. An additional ten genes showed nominal evidence (p value < 0.05) of differential expression, which, together with the significant genes, is more than expected by chance (p value = 6.6 × 10−12). PITX2 impacts morphological development of intestinal tissue, promotes an anti-oxidant response, and its expression correlates with levels of intestinal bacteria and colonic inflammation. Further studies of the role of PITX2 in appendicitis are warranted.

A genome-wide association study meta-analysis of clinical fracture in 10,012 African American women

BackgroundOsteoporosis is a major public health problem associated with excess disability and mortality. It is estimated that 50–70% of the variation in osteoporotic fracture risk is attributable to genetic factors. The purpose of this hypothesis-generating study was to identify possible genetic determinants of fracture among African American (AA) women in a GWAS meta-analysis. MethodsData on clinical fractures (all fractures except fingers, toes, face, skull or sternum) were analyzed among AA female participants in the Women's Health Initiative (WHI) (N=8155), Cardiovascular Health Study (CHS) (N=504), BioVU (N=704), Health ABC (N=651), and the Johnston County Osteoarthritis Project (JoCoOA) (N=291). Affymetrix (WHI) and Illumina (Health ABC, JoCoOA, BioVU, CHS) GWAS panels were used for genotyping, and a 1:1 ratio of YRI:CEU HapMap haplotypes was used as an imputation reference panel. We used Cox proportional hazard models or logistic regression to evaluate the association of ~2.5 million SNPs with fracture risk, adjusting for ancestry, age, and geographic region where applicable. We conducted a fixed-effects, inverse variance-weighted meta-analysis. Genome-wide significance was set at P<5×10−8. ResultsOne SNP, rs12775980 in an intron of SVIL on chromosome 10p11.2, reached genome-wide significance (P=4.0×10−8). Although this SNP has a low minor allele frequency (0.03), there was no evidence for heterogeneity of effects across the studies (I2=0). This locus was not reported in any previous osteoporosis-related GWA studies. We also interrogated previously reported GWA-significant loci associated with fracture or bone mineral density in our data. One locus (SMOC1) generalized, but overall there was not substantial evidence of generalization. Possible reasons for the lack of generalization are discussed. ConclusionThis GWAS meta-analysis of fractures in African American women identified a potentially novel locus in the supervillin gene, which encodes a platelet-associated factor and was previously associated with platelet thrombus formation in African Americans. If validated in other populations of African descent, these findings suggest potential new mechanisms involved in fracture that may be particularly important among African Americans.

Abstract 221: Mitochondrial genome and the risk of lung cancer: The Multiethnic Cohort

Abstract Background: The human mitochondrial genome (mtDNA) encodes for 13 essential polypeptides of the mitochondrial respiratory complex. Maternally-inherited variation in mtDNA may influence cancer development by altering mitochondrial proteins and complexes involved in the oxidative phosphorylation (OXPHOS) process. In lung cancer, Complex I appears frequently altered, which has been linked to increased cellular proliferation and invasion, and overproduction of reactive oxygen species. Few studies have investigated the associations between mtDNA variants and lung cancer risk. Methods: Within the 16 kb mtDNA, we tested 186 mitochondrial single nucleotide polymorphisms (mtSNPs) located in 13 genes that comprise the 4 complexes of the OXPHOS pathway and mtSNPs for rRNA and tRNA in 773 lung cancer cases and 10,491 controls from the Multiethnic Cohort. Logistic regression was conducted to examine the odds ratio (OR) and corresponding 95% confidence interval (CI) for mtSNPs and haplogroups associated with lung cancer risk. Associations were adjusted for age, sex, maternal self-reported race/ethnicity, principal components of global ancestry, smoking status, and the number of cigarettes smoked per day. The sequence kernel association test was conducted for pathway analysis, adjusting for the same covariates. Stratified analysis was conducted by self-reported maternal race/ethnicity—African American (AA), Japanese American (JA), Latino (LA), European American (EA), and Native Hawaiian (NH). Results: Overall, the most significant lung cancer association was seen with mt15629 (OR: 0.36, 95% CI: 0.22-0.60; p = 8×10-5 that reached a Bonferroni significance threshold of p = 2.7×10-4). This association was largely driven by AA (OR: 0.41, 95% CI: 0.24-0.71; p = 1.6×10-5; MAF = 0.05) and LA (OR: 0.14, 95% CI: 0.03-0.54; p = 4.8×10-5; MAF = 0.007) data with no evidence of heterogeneity in effects by race/ethnicity. Mt15629 was monomorphic in JA, EA, and NH populations. Similar patterns of associations were seen across histological cell types (small cell carcinoma, squamous cell carcinoma, and adenocarcinoma). Furthermore, mt15629 showed no evidence of heterogeneity in effects by smoking status and was not associated with smoking status or cigarette pack years. Haplogroup L1 was associated with lung cancer risk among LAs (OR: 0.14, 95% CI: 0.04-0.48; p = 0.002) for which mt15629 is one of the defining haplogroup mtSNPs. Pathway analysis showed an association between the cumulative effect of 161 polymorphic mtSNPs among LAs (p = 0.002); also the OXPHOS pathway (p = 0.002), 4 mitochondrial complexes (p = 0.001-0.049) and 10 of 15 mitochondrial genes (p = 0.001-0.049) were associated with lung cancer risk among LAs. Conclusion: Our findings demonstrate an association between specific variants in the mitochondrial genome and lung cancer risk, particularly among Latinos. The mechanism underlying this association appears to be independent of smoking status. Citation Format: Li Tao, Yuqing Li, Sung-Shim Lani Park, Kenneth B. Beckman, Christian Caberto, Annette Lum-Jones, Loic Le Marchand, Daniel O. Stram, Richa Saxena, Iona Cheng. Mitochondrial genome and the risk of lung cancer: The Multiethnic Cohort. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 221.

Abstract 2779: A genome-wide analysis of more than 160,000 individuals identifies four novel pleiotropic risk loci shared between breast and ovarian cancer

Abstract Background: Common variants in six genomic regions are known to confer susceptibility to both breast and ovarian cancer. We combined summary results from association studies of these two cancers to identify additional shared risk loci. Methods: We compiled an up-to-date list of the most significant variant at every independent locus known to be associated with ovarian (n = 18) and/or breast (n = 92) cancer risk at genome-wide significance (P &amp;lt; 5×10-8) in women of European ancestry. Subtype specific and unpublished variants were included. We evaluated association at each variant for the other cancer using summary results from the OCAC and BCAC data sets (cases/controls: ovarian ∼15K/31K and breast ∼63K/61K). Each data set was restricted to European ancestry samples, had been imputed into the 1000 Genomes panel, and comprised summary statistics from meta-analysis of GWAS and case-control studies genotyped for ∼200K variants on the iCOGS custom array. We considered the evaluated associations significant at a threshold P-value &amp;lt; 4.6×10-4 after Bonferroni correction for multiple comparisons. In a separate approach, we combined results for all variants with P &amp;lt; 10-3 in both data sets using fixed effects inverse variance meta-analysis. We also conducted a subtype specific meta-analysis by combining results for serous ovarian and estrogen receptor (ER)-negative breast cancer risk. Variants identified within 1 Mb of known risk regions in each data set were excluded and only novel findings are reported here. Results: One ovarian cancer risk variant was also associated with breast cancer risk in the same direction as its known ovarian association at P &amp;lt; 4.6×10-4: rs635634 at 9q34 (P(breast) = 8.1×10-7). The meta-analyses identified three additional risk loci at genome-wide significance. Rs10820599 at 9q31 (P = 4.1×10-9) and rs8037137 at 15q26 (P = 1.9×10-10) were associated with overall ovarian and breast cancer risk and rs201308915 at 2p23 (P = 3.2×10-8) was associated specifically with serous ovarian and ER-negative breast cancer risk. None of the variants demonstrated statistical evidence of heterogeneity in effect between cancers. Tissue-specific annotation, quantitative trait locus and pathway analyses of these loci to identify potential pleiotropic functional mechanisms are ongoing. Conclusion: These results confirm the pleiotropic effects of alleles at four new loci on breast and ovarian cancer susceptibility. Three of them have not previously been associated at genome-wide significance with risk of either cancer. Future cross-cancer analysis based on even larger data sets and incorporating other hormone-related cancers are likely to yield further insights into the shared genetic basis of these common cancers. Citation Format: Siddhartha Kar, Kyriaki Michailidou, Jonathan Tyrer, Deborah Thompson, Diether Lambrechts, Ovarian Cancer Association Consortium (OCAC) and Breast Cancer Association Consortium (BCAC). A genome-wide analysis of more than 160,000 individuals identifies four novel pleiotropic risk loci shared between breast and ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2779. doi:10.1158/1538-7445.AM2015-2779

Intentional weight loss and all-cause mortality: a meta-analysis of randomized clinical trials.

BackgroundObesity is associated with increased mortality, and weight loss trials show rapid improvement in many mortality risk factors. Yet, observational studies typically associate weight loss with higher mortality risk. The purpose of this meta-analysis of randomized controlled trials (RCTs) of weight loss was to clarify the effects of intentional weight loss on mortality.Methods2,484 abstracts were identified and reviewed in PUBMED, yielding 15 RCTs reporting (1) randomization to weight loss or non-weight loss arms, (2) duration of ≥18 months, and (3) deaths by intervention arm. Weight loss interventions were all lifestyle-based. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated for each trial. For trials reporting at least one death (n = 12), a summary estimate was calculated using the Mantel-Haenszel method. Sensitivity analysis using sparse data methods included remaining trials.ResultsTrials enrolled 17,186 participants (53% female, mean age at randomization = 52 years). Mean body mass indices ranged from 30–46 kg/m2, follow-up times ranged from 18 months to 12.6 years (mean: 27 months), and average weight loss in reported trials was 5.5±4.0 kg. A total of 264 deaths were reported in weight loss groups and 310 in non-weight loss groups. The weight loss groups experienced a 15% lower all-cause mortality risk (RR = 0.85; 95% CI: 0.73–1.00). There was no evidence for heterogeneity of effect (Cochran’s Q = 5.59 (11 d.f.; p = 0.90); I2 = 0). Results were similar in trials with a mean age at randomization ≥55 years (RR = 0.84; 95% CI 0.71–0.99) and a follow-up time of ≥4 years (RR = 0.85; 95% CI 0.72–1.00).ConclusionsIn obese adults, intentional weight loss may be associated with approximately a 15% reduction in all-cause mortality.

IL8 polymorphisms and overall survival in pazopanib- or sunitinib-treated patients with renal cell carcinoma.

Background:We evaluated germline single nucleotide polymorphisms (SNPs) for association with overall survival (OS) in pazopanib- or sunitinib-treated patients with advanced renal cell carcinoma (aRCC).Methods:The discovery analysis tested 27 SNPs within 13 genes from a phase III pazopanib trial (N=241, study 1). Suggestive associations were then pursued in two independent datasets: a phase III trial (COMPARZ) comparing pazopanib vs sunitinib (N=729, study 2) and an observational study of sunitinib-treated patients (N=89, study 3).Results:In study 1, four SNPs showed nominally significant association (P≤0.05) with OS; two of these SNPs (rs1126647, rs4073) in IL8 were associated (P≤0.05) with OS in study 2. Because rs1126647 and rs4073 were highly correlated, only rs1126647 was evaluated in study 3, which also showed association (P≤0.05). In the combined data, rs1126647 was associated with OS after conservative multiple-test adjustment (P=8.8 × 10−5; variant vs reference allele hazard ratio 1.32, 95% confidence interval: 1.15–1.52), without evidence for heterogeneity of effects between studies or between pazopanib- and sunitinib-treated patients.Conclusions:Variant alleles of IL8 polymorphisms are associated with poorer survival outcomes in pazopanib- or sunitinib-treated patients with aRCC. These findings provide insight in aRCC prognosis and may advance our thinking in development of new therapies.

GMI 1070: Reduction In Time To Resolution Of Vaso-Occlusive Crisis and Decreased Opioid Use In a Prospective, Randomized, Multi-Center Double Blind, Adaptive Phase 2 Study In Sickle Cell Disease

BackgroundTreatment for vaso-occlusive crisis (VOC) in sickle cell disease (SCD) remains supportive, focusing largely on symptom relief with opioids. Animal models have suggested a role for both red cell and leukocyte selectin-mediated adhesion in VOC, and the pan-selectin inhibitor GMI 1070 restored blood flow in a mouse model of VOC. We therefore explored safety and possible efficacy of GMI 1070 in patients with VOC. MethodsThis prospective, randomized multi-center double blind, adaptive Phase 2 study enrolled patients ages 12-60 yrs with HbSS or HbSβ0 thalassemia presenting with VOC. Patients were randomized 1:1, stratified by site. A loading dose of GMI 1070 to achieve steady state, followed by ≤14 subsequent doses, were given q 12 h. Other treatment was per institutional standard of care. The primary efficacy endpoint was resolution of VOC, defined as: 1.5 cm sustained decrease in visual analog scale (VAS) pain score from baseline and transition to oral analgesia; or documented readiness for discharge; or order for discharge. Pre-planned population PK was examined after 11 subjects, and dose was subsequently escalated, per protocol. Secondary endpoints included cumulative opioid use (morphine equivalent units [MEU]/kg) and adverse events. Differences by treatment were analyzed by ANCOVA (means, adjusted for age and sex) and Kaplan-Meier (KM, medians), stratified by age and dose. ResultsSeventy-six subjects were enrolled (ages 12-51; 45 F, 31 M). Drug dose was doubled to reach target nadir levels after interim PK analysis. All 76 patients reached the primary endpoint: 58 subjects continued study drug until criteria for resolution of VOC were met or the maximum number of doses were given; 18 discontinued drug for AEs, no improvement at day 5, or other reasons. In the primary efficacy analysis, reduction in mean time to VOC resolution was consistently observed in all treatment groups (pooled high and low dose GMI 1070, 103.6 h ± 20.9 (SE), n=43, vs placebo, 144.6 h ± 23.5, n=33, p=0.192). KM analysis showed median times to resolution of 69.6 h (CI 44.3, 115.5) for the GMI 1070 group vs 132.9 h (CI 67.0, 164.2) for the placebo group (p=0.187, Log-rank, Fig 1a). Thus, GMI 1070 resulted in differences in time to resolution of 41 h (mean) and 63 h (median). Similar differences were seen when analysis was stratified by age. Proportionally more subjects receiving GMI 1070 than placebo achieved resolution of VOC at 48, 72, 96 and 120 h. Analyses by how endpoint was reached were consistent with composite findings. The time to transition to oral pain medications was substantially decreased in all treatment groups: this reduction was 76 h in the GMI 1070 group (KM p=0.089) and reached statistical significance in the pediatric population (87.8 h, KM p=0.037). Time to discharge was reduced from a median of 156.1 h (CI 75.4, 185.8) for placebo to 72.2 h (CI 59.9, 121.0) for GMI 1070 (p=0.092). Stratified analysis by age and dose showed similar reductions in time to discharge. Although 24 subjects (31.6%) did not achieve a sustained reduction in VAS while hospitalized, active treatment was associated with a decrease in time to first sustained reduction in VAS. Median times to VAS reduction were: GMI 1070, 72.0 h (CI 34.5, 115.7); placebo, 125.3 h (CI 19.7, 180.2). Time to agreement about readiness for discharge was documented in 88% and 85% of the treatment and placebo groups, with medians of 72.5 h (CI 60.9, 139.1) and 137.4 h (CI 83.2, 165.7), respectively (p=0.151). An 83% reduction in mean cumulative IV opioid analgesic use (mg/kg MEU) was seen across all treatment groups (p=0.010, Fig 1b). The effect on opioid use was seen within 24 h. Total adverse event (AE) rates, serious AEs, and ‘treatment related' AEs were comparable across all groups and ages (high dose, low dose, and pooled GMI 1070, or placebo; pediatric vs. adult). No subjects discontinued the study due to AEs. [Display omitted] ConclusionTreatment with GMI 1070 was associated with substantial reductions in mean and median time to resolution of VOC, analyzed either as a composite or component endpoints, that were near statistical significance. The magnitude of reduction was clinically meaningful. GMI 1070 was also associated with reduction in both hourly and daily opioid use. There was no evidence for heterogeneity of effect among patient groups. These promising results support a role for selectins in the pathophysiology of VOC and justify a Phase 3 study of GMI 1070 for SCD patients with VOC. Disclosures:Telen:Dilaforette, NA: Research Funding; Pfizer, Inc.: Consultancy; GlycoMimetics, Inc.: Research Funding. Wun:Emmaus, Inc.: Clinical Adjudication Committee Other; Pfizer, Inc.: Consultancy; GlycoMimetics: Research Funding. McCavit:GlycoMimetics, Inc.: Research Funding; Pfizer, Inc.: Consultancy. De Castro:GlycoMimetics, Inc.: Research Funding; Novella Clinical: Consultancy. Krishnamurti:GlycoMimetics, Inc.: Research Funding. Lanzkron:GlycoMimetics, Inc.: Research Funding. Hsu:GlycoMimetics, Inc.: Research Funding. Smith:GlycoMimetics, Inc.: Research Funding. Rhee:Rho, Inc.: Employment; GlycoMimetics, Inc.: Research Funding. Magnani:GlycoMimetics, Inc.: Employment, Equity Ownership. Thackray:GlycoMimetics, Inc.: Employment, Equity Ownership.

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9 (HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes.

Abstract C51: Molecular markers, prognosis, and efficacy of adjuvant anthracyclines in breast cancer.

Abstract Background: Molecular tumor markers can be used to classify breast cancer into sub-types that have distinct survival patterns. It is not known whether these sub-types respond differently to adjuvant chemotherapy. The purpose of this study was i) to evaluate the prognostic significance of breast cancer sub-types in a cohort of women taking part in the NEAT and BR9601 clinical trials comparing cyclophosphamide, methotrexate, and fluorouracil (CMF) with ECMF (epirubicin and CMF) and ii) to evaluate whether the sub-types were predictive of the added benefit of epirubicin in these trials. Methods: We classified the tumors into six intrinsic sub-types using data generated from tumor tissue microarrays that were stained and scored for ER, PR, HER2, EGFR and CK5/6. We used Cox regression to compare relapse-free survival (RFS), breast cancer specific survival (BSS) and overall survival (OS) in the different subgroups. We also compared the effect of ECMF with CMF by subgroup. Results: IHC data were available for 1725 cases of whom 805 were luminal 1-basal negative, 153 were luminal 1-basal positive, 174 were luminal 2, 192 were HER2-like, 230 were core basal phenotype and 171 5-negative phenotype. Median follow-up time was 7 years. The prognostic effects of the sub-types were similar to those reported for unselected breast cancer cases irrespective of adjuvant therapy. In particular, the luminal 1-basal negative tumors were associated with the best prognosis during the five years after surgery and the HER2-like tumors were associated with the poorest prognosis. ECMF has previously shown to be associated with a 33 percent relative risk reduction for OS compared to CMF. There was little evidence for significant heterogeneity of effect by tumor subtype for any end point (OS P=0.40, BSS P=0.53 RFS P=0.50). However, there was an observed trend towards the largest additional benefit from epirubicin being in women with tumors of the 5-negative phenotype (OS HR=0.39 95% CI 0.21–0.73) and the smallest being in luminal 1-basal negative tumors (OS HR=0.86 95% CI 0.64–1.16). Conclusion: In a clinical trial in which all patients received chemotherapy, we confirmed that breast cancer sub-types show distinct behaviour with differences in short and long term survival. These differences seem to be independent of the type of chemotherapy - the benefit of ECMF over CMF was statistically similar in all disease sub-types. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C51.

Prognosis by breast cancer subtypes in patients treated with adjuvant chemotherapy in a clinical trial.

12 Background: Breast cancer can be classified into molecular subtypes that have distinct survival patterns. The purpose of this study was i) to evaluate the prognostic significance of breast cancer subtypes in a cohort of women taking part in the NEAT and BR9601 clinical trials comparing CMF with ECMF, and ii) to evaluate whether the subtypes were predictive of the added benefit of epirubicin in these trials. Methods: Tumor tissue microarrays were stained and scored for ER, PR, HER2, EGFR and CK5/6. These were used to classify the tumors into six intrinsic subtypes (1). We used Cox regression to compare overall survival (OS), breast cancer specific survival (BSS) and relapse free survival (RFS) in the different subgroups. We also compared the effect of ECMF with CMF by subgroup. Results: IHC data were available for 1725 cases of whom 805 were Luminal 1-basal negative, 153 were Luminal 1-basal positive, 174 were Luminal 2, 192 were HER2-like, 230 were core basal phenotype and 171 were 5-negative phenotype. Median follow-up time was 7 years. The prognostic effects of the subtypes were similar to those reported for unselected breast cancer cases irrespective of adjuvant therapy (Blows FM, et al. PLoS Med 2010;75:e1000279.). In particular, the luminal 1-basal negative tumors were associated with the best prognosis in five years after surgery and the HER2-like tumors were associated with the poorest prognosis. ECMF has previously shown to be associated with a 33% relative risk reduction for OS compared to CMF (Poole CJ et al. N Engl J Med 2006;35518:1851-62.). There was little evidence for significant heterogeneity of effect by tumor subtype for any end point (OS P= 0.40, BSS P=0.53 RFS P=0.50). However, there was an observed trend towards the largest additional benefit from ECMF being in women with tumors of the 5-negative phenotype (OS HR=0.39 95% CI 0.21-0.73) and the smallest being in Luminal 1-basal negative tumors (OS HR=0.86 95% CI 0.64-1.16). Conclusions: In a clinical trial in which all patients received chemotherapy, we confirmed that breast cancer subtypes show distinct behaviour with differences in short and long term survival. The benefit of ECMF over CMF was statistically similar in all disease subtypes.