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Background: Pancreatic cancer is a leading cause of cancer-related death globally. Risk factors for pancreatic cancer include common genetic variants and potentially heavy alcohol consumption. We assessed if genetic variants modify the association between heavy alcohol consumption and pancreatic cancer risk., Methods: We conducted a genome-wide interaction analysis of single-nucleotide polymorphisms (SNP) by heavy alcohol consumption (more than three drinks per day) for pancreatic cancer in European ancestry populations from genome-wide association studies. Our analysis included 3,707 cases and 4,167 controls from case-control studies and 1,098 cases and 1,162 controls from cohort studies. Fixed-effect meta-analyses were conducted., Results: A potential novel region of association on 10p11.22, lead SNP rs7898449 (interaction P value (Pinteraction) = 5.1 × 10-8 in the meta-analysis; Pinteraction = 2.1 × 10-9 in the case-control studies; Pinteraction = 0.91 in the cohort studies), was identified. An SNP correlated with this lead SNP is an expression quantitative trait locus for the neuropilin 1 gene. Of the 17 genomic regions with genome-wide significant evidence of association with pancreatic cancer in prior studies, we observed suggestive evidence that heavy alcohol consumption modified the association for one SNP near LINC00673, rs11655237 on 17q25.1 (Pinteraction = 0.004)., Conclusions: We identified a novel genomic region that may be associated with pancreatic cancer risk in conjunction with heavy alcohol consumption located near an expression quantitative trait locus for neuropilin 1, a protein that plays an important role in the development and progression of pancreatic cancer., Impact: This work can provide insights into the etiology of pancreatic cancer, particularly in heavy drinkers., (©2024 American Association for Cancer Research.)

Background: High red meat and/or processed meat consumption are established colorectal cancer risk factors. We conducted a genome-wide gene-environment (GxE) interaction analysis to identify genetic variants that may modify these associations., Methods: A pooled sample of 29,842 colorectal cancer cases and 39,635 controls of European ancestry from 27 studies were included. Quantiles for red meat and processed meat intake were constructed from harmonized questionnaire data. Genotyping arrays were imputed to the Haplotype Reference Consortium. Two-step EDGE and joint tests of GxE interaction were utilized in our genome-wide scan., Results: Meta-analyses confirmed positive associations between increased consumption of red meat and processed meat with colorectal cancer risk [per quartile red meat OR = 1.30; 95% confidence interval (CI) = 1.21-1.41; processed meat OR = 1.40; 95% CI = 1.20-1.63]. Two significant genome-wide GxE interactions for red meat consumption were found. Joint GxE tests revealed the rs4871179 SNP in chromosome 8 (downstream of HAS2); greater than median of consumption ORs = 1.38 (95% CI = 1.29-1.46), 1.20 (95% CI = 1.12-1.27), and 1.07 (95% CI = 0.95-1.19) for CC, CG, and GG, respectively. The two-step EDGE method identified the rs35352860 SNP in chromosome 18 (SMAD7 intron); greater than median of consumption ORs = 1.18 (95% CI = 1.11-1.24), 1.35 (95% CI = 1.26-1.44), and 1.46 (95% CI = 1.26-1.69) for CC, CT, and TT, respectively., Conclusions: We propose two novel biomarkers that support the role of meat consumption with an increased risk of colorectal cancer., Impact: The reported GxE interactions may explain the increased risk of colorectal cancer in certain population subgroups., (©2023 American Association for Cancer Research.)

Background: There are conflicting data on whether nonalcoholic fatty liver disease (NAFLD) is associated with susceptibility to pancreatic cancer. Using Mendelian randomization (MR), we investigated the relationship between genetic predisposition to NAFLD and risk for pancreatic cancer., Methods: Data from genome-wide association studies (GWAS) within the Pancreatic Cancer Cohort Consortium (PanScan; cases n = 5,090, controls n = 8,733) and the Pancreatic Cancer Case Control Consortium (PanC4; cases n = 4,163, controls n = 3,792) were analyzed. We used data on 68 genetic variants with four different MR methods [inverse variance weighting (IVW), MR-Egger, simple median, and penalized weighted median] separately to predict genetic heritability of NAFLD. We then assessed the relationship between each of the four MR methods and pancreatic cancer risk, using logistic regression to calculate ORs and 95% confidence intervals (CI), adjusting for PC risk factors, including obesity and diabetes., Results: No association was found between genetically predicted NAFLD and pancreatic cancer risk in the PanScan or PanC4 samples [e.g., PanScan, IVW OR, 1.04; 95% confidence interval (CI), 0.88-1.22; MR-Egger OR, 0.89; 95% CI, 0.65-1.21; PanC4, IVW OR, 1.07; 95% CI, 0.90-1.27; MR-Egger OR, 0.93; 95% CI, 0.67-1.28]. None of the four MR methods indicated an association between genetically predicted NAFLD and pancreatic cancer risk in either sample., Conclusions: Genetic predisposition to NAFLD is not associated with pancreatic cancer risk., Impact: Given the close relationship between NAFLD and metabolic conditions, it is plausible that any association between NAFLD and pancreatic cancer might reflect host metabolic perturbations (e.g., obesity, diabetes, or metabolic syndrome) and does not necessarily reflect a causal relationship between NAFLD and pancreatic cancer., (©2023 American Association for Cancer Research.)

Background: Tobacco smoking is an established risk factor for colorectal cancer. However, genetically defined population subgroups may have increased susceptibility to smoking-related effects on colorectal cancer., Methods: A genome-wide interaction scan was performed including 33,756 colorectal cancer cases and 44,346 controls from three genetic consortia., Results: Evidence of an interaction was observed between smoking status (ever vs. never smokers) and a locus on 3p12.1 (rs9880919, P = 4.58 × 10-8), with higher associated risk in subjects carrying the GG genotype [OR, 1.25; 95% confidence interval (CI), 1.20-1.30] compared with the other genotypes (OR <1.17 for GA and AA). Among ever smokers, we observed interactions between smoking intensity (increase in 10 cigarettes smoked per day) and two loci on 6p21.33 (rs4151657, P = 1.72 × 10-8) and 8q24.23 (rs7005722, P = 2.88 × 10-8). Subjects carrying the rs4151657 TT genotype showed higher risk (OR, 1.12; 95% CI, 1.09-1.16) compared with the other genotypes (OR <1.06 for TC and CC). Similarly, higher risk was observed among subjects carrying the rs7005722 AA genotype (OR, 1.17; 95% CI, 1.07-1.28) compared with the other genotypes (OR <1.13 for AC and CC). Functional annotation revealed that SNPs in 3p12.1 and 6p21.33 loci were located in regulatory regions, and were associated with expression levels of nearby genes. Genetic models predicting gene expression revealed that smoking parameters were associated with lower colorectal cancer risk with higher expression levels of CADM2 (3p12.1) and ATF6B (6p21.33)., Conclusions: Our study identified novel genetic loci that may modulate the risk for colorectal cancer of smoking status and intensity, linked to tumor suppression and immune response., Impact: These findings can guide potential prevention treatments., (©2022 American Association for Cancer Research.)

Background: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer., Methods: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1-28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models., Results: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose-response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06-1.17; OR for AA genotype = 1.22; 95% CI, 1.14-1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif., Conclusions: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region., Impact: The study identifies multifaceted evidence of a possible functional effect for rs1318920., (©2022 American Association for Cancer Research.)

Background: Cancer is the leading cause of death in Asian Americans (AA), the fastest-growing U.S. population group. Despite heterogeneity in socioeconomic status and health behaviors by ethnicity, few studies have assessed cancer outcomes across AA ethnic groups. We examined differences in gynecologic cancer mortality between AA ethnic groups and non-Hispanic Whites (NHW)., Methods: Using the Surveillance, Epidemiology, and End Results database, we identified ovarian (n = 69,113), uterine (n = 157,340), and cervical cancer cases (n = 41,460) diagnosed from 1991-2016. Competing risk regression was used to compare cancer-specific mortality for AAs by ethnicity, using NHW as the reference population., Results: In adjusted analyses, AAs had a lower risk of ovarian [HR, 0.90; 95% confidence interval (CI), 0.86-0.94] and cervical cancer death (HR, 0.80; 95% CI, 0.75-0.87) than NHWs, with stronger associations among those ≥50 years at diagnosis [(HRovary, 0.87; 95% CI, 0.82-0.92); (HRcervix, 0.74; 95% CI, 0.67-0.81)]. No overall difference was noted for uterine cancer death (HR, 1.03; 95% CI, 0.97-1.10); however, AAs <50 years at diagnosis had a higher risk of uterine cancer death than NHWs (HR, 1.26; 95% CI, 1.08-1.46). Patterns of cancer mortality were heterogeneous, with Filipino and Chinese women at the highest risk of uterine cancer death and Indian/Pakistani women at the lowest risk of ovarian and cervical cancer death., Conclusions: There are significant differences in gynecologic cancer mortality between AAs and NHWs, with heterogeneity by AA ethnicity., Impact: Disaggregated analysis of AA is needed to better understand the burden of gynecologic cancer and identify high-risk groups for cancer prevention efforts., (©2021 American Association for Cancer Research.)

Background: Our objective was to determine the association between racialized economic segregation and the hazard of breast cancer mortality in Maryland., Methods: Among 35,066 women (24,540 White; 10,526 Black) diagnosed with incident invasive breast cancer in Maryland during 2007 to 2017, exposure to racialized economic segregation was measured at the census tract level using Index of Concentration at the Extremes metrics. HRs and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression for the association between racialized economic segregation and the hazard of breast cancer mortality, accounting for clustering at the census tract level. Models were adjusted for age and stratified by race, median age (<60 years, ≥60 years), and clinical characteristics., Results: Overall, the hazard of breast cancer mortality was 1.84 times as high (95% CI, 1.64-2.06) for the least privileged quintile of racialized economic segregation compared with the most privileged quintile. This association differed significantly ( P interaction < 0.05) by race and age, with 1.20 (95% CI, 0.90-1.60) times the hazard of breast cancer mortality for Black women versus 1.66 (95% CI, 1.41-1.95) times the hazard for White women, and with greater hazards for younger women (HR, 2.17; 95% CI, 1.83-2.57) than older women (HR, 1.62; 95% CI, 1.40-1.88)., Conclusions: Our results suggest that breast cancer survival disparities exist in Maryland among women residing in the least privileged census tracts with lower income households and higher proportions of Black residents., Impact: Our findings provide new insights into the breast cancer mortality disparities observed among women in Maryland., (©2021 American Association for Cancer Research.)

Background: Bilateral oophorectomy during a nonmalignant hysterectomy is frequently performed for ovarian cancer prevention in premenopausal women. Oophorectomy before menopause leads to an abrupt decline in ovarian hormones that could adversely affect body composition. We examined the relationship between oophorectomy and whole-body composition., Methods: Our study population included cancer-free women 35 to 70 years old from the 1999-2006 National Health and Nutrition Examination Survey, a representative sample of the U.S., Population: A total of 4,209 women with dual-energy x-ray absorptiometry scans were identified, including 445 with hysterectomy, 552 with hysterectomy and oophorectomy, and 3,212 with no surgery. Linear regression was used to estimate the difference in total and regional (trunk, arms, and legs) fat and lean body mass by surgery status., Results: In multivariable models, hysterectomy with and without oophorectomy was associated with higher total fat mass [mean percent difference (β); β oophorectomy : 1.61%; 95% confidence interval (CI), 1.00-2.28; β hysterectomy : 0.88%; 95% CI, 0.12-1.58] and lower total lean mass [β oophorectomy : -1.48%; 95% CI, -2.67, -1.15; β hysterectomy : -0.87%; 95% CI, -1.50, -0.24) compared with no surgery. Results were stronger in women with a normal body mass index (BMI) and those <45 years at surgery. All body regions were significantly affected for women with oophorectomy, whereas only the trunk was affected for women with hysterectomy alone., Conclusions: Hysterectomy with oophorectomy, particularly in young women, may be associated with systemic changes in fat and lean body mass irrespective of BMI., Impact: Our results support prospective evaluation of body composition in women undergoing hysterectomy with oophorectomy at a young age., (©2021 American Association for Cancer Research.)

Background: The association between prediagnostic antibody responses to Fusobacterium nucleatum ( F. nucleatum ) and subsequent risk of colorectal cancer is not established., Methods: We conducted a nested case-control study of 8,126 participants in a consortium of 10 prospective cohorts in the United States., Results: Higher seroprevalence of any F. nucleatum antibody was observed among non-White participants (51.1%) compared with White participants (31.2%). We did not find any statistically significant association between seropositivity to any of the eight F. nucleatum proteins and colorectal cancer risk., Conclusions: Prediagnostic antibody responses to F. nucleatum proteins were not associated with the risk of colorectal cancer., Impact: Future studies may consider a more specific detection of the immunoglobulin isotypes or focus on examining F. nucleatum in stool or tissue samples., (©2021 American Association for Cancer Research.)

Background: Whether circulating polyunsaturated fatty acid (PUFA) levels are associated with pancreatic cancer risk is uncertain. Mendelian randomization (MR) represents a study design using genetic instruments to better characterize the relationship between exposure and outcome., Methods: We utilized data from genome-wide association studies within the Pancreatic Cancer Cohort Consortium and Pancreatic Cancer Case-Control Consortium, involving approximately 9,269 cases and 12,530 controls of European descent, to evaluate associations between pancreatic cancer risk and genetically predicted plasma n-6 PUFA levels. Conventional MR analyses were performed using individual-level and summary-level data., Results: Using genetic instruments, we did not find evidence of associations between genetically predicted plasma n-6 PUFA levels and pancreatic cancer risk [estimates per one SD increase in each PUFA-specific weighted genetic score using summary statistics: linoleic acid odds ratio (OR) = 1.00, 95% confidence interval (CI) = 0.98-1.02; arachidonic acid OR = 1.00, 95% CI = 0.99-1.01; and dihomo-gamma-linolenic acid OR = 0.95, 95% CI = 0.87-1.02]. The OR estimates remained virtually unchanged after adjustment for covariates, using individual-level data or summary statistics, or stratification by age and sex., Conclusions: Our results suggest that variations of genetically determined plasma n-6 PUFA levels are not associated with pancreatic cancer risk., Impact: These results suggest that modifying n-6 PUFA levels through food sources or supplementation may not influence risk of pancreatic cancer., (©2020 American Association for Cancer Research.)

Background: Auto-antibodies to tumor suppressor p53 are found in a subset of patients with colorectal cancer. A recent prospective study in the United States has reported a significant 1.8-fold increased odds for colorectal cancer development with prediagnostic seropositivity to p53. In this study, we sought to examine this association in a U.S. colorectal cancer cohort consortium to evaluate the potential utility of p53 auto-antibodies as an early biomarker for colorectal cancer., Methods: Auto-antibodies to p53 were measured in prediagnostic blood samples of 3,702 incident colorectal cancer cases and 3,702 controls, matched by age, race, and sex, from 9 U.S. prospective cohorts. The association of seropositivity to p53 with colorectal cancer risk, overall and by time between blood draw and diagnosis, was determined by conditional logistic regression., Results: Overall, 5% of controls and 7% of cases were seropositive to p53, resulting in a statistically significant 33% increased colorectal cancer risk [odds ratio (OR), 1.33; 95% confidence interval (CI), 1.09-1.61]. By follow-up time, the association was only significant with colorectal cancer diagnoses within 4 years after blood draw (OR, 2.27; 95% CI, 1.62-3.19), but not thereafter (OR, 0.97; 95% CI, 0.76-1.24)., Conclusions: In this large consortium of prospective cohorts, we found that prediagnostic seropositivity to tumor suppressor p53 was significantly associated with an over 2-fold increased odds of developing colorectal cancer within 4 years after blood draw., Impact: Our finding suggests that p53 seropositivity may not be a useful predictor of long-term colorectal cancer risk; however, it might be considered as a marker to aid in the early diagnosis of colorectal cancer., (©2020 American Association for Cancer Research.)

Background: Breast cancer incidence has been associated with hypertension, which might worsen disease prognosis, but few nationwide studies have investigated the association between antihypertensive drug use and breast cancer prognosis., Methods: A cohort of 73,170 women diagnosed with breast cancer during 1995-2013 identified from the Finnish Cancer Registry was combined with information on antihypertensive drug use during the same time period from a national prescription database. Antihypertensive drugs were analyzed in groups categorized by mechanism of action. Usage of antihypertensive drugs, statins, antidiabetic, and anticoagulative drugs was analyzed as time-dependent exposure to model for simultaneous use of multiple drug groups. Influence of protopathic bias was evaluated in lag-time analyses., Results: In prediagnostic use, only angiotensin receptor (ATR)-blockers were associated with decreased risk of breast cancer death as compared with nonusers (HR: 0.76, 95% confidence interval, CI: 0.69-0.82), and there was an inverse association with cumulative dose of use. Postdiagnostic use of ATR-blockers, angiotensin-converting enzyme (ACE)-inhibitors, beta-blockers, and calcium-channel blockers was dose dependently associated with better breast cancer survival compared with nonusers. The risk decrease was strongest for ATR-blockers (HR: 0.69, 95% CI: 0.63-0.75) and remained for exposures occurring up to 3 years earlier., Conclusions: Only ATR-blockers were associated with improved breast cancer survival in both prediagnostic and postdiagnostic use. The association was dose dependent and supported by a biological rationale as a causal explanation. In postdiagnostic use, similar reduction was found also for other antihypertensives, supporting a prognostic role of hypertension control., Impact: Inhibition of angiotensin receptor subtype 1 (AT 1 ) could be a promising novel way to affect breast cancer progression., (©2020 American Association for Cancer Research.)

Background: Epithelial ovarian, fallopian tube, and primary peritoneal cancers have shared developmental pathways. Few studies have prospectively examined heterogeneity in risk factor associations across these three anatomic sites., Methods: We identified 3,738 ovarian, 337 peritoneal, and 176 fallopian tube incident cancer cases in 891,731 women from 15 prospective cohorts in the Ovarian Cancer Cohort Consortium. Associations between 18 putative risk factors and risk of ovarian, peritoneal, and fallopian tube cancer, overall and for serous and high-grade serous tumors, were evaluated using competing risks Cox proportional hazards regression. Heterogeneity was assessed by likelihood ratio tests., Results: Most associations did not vary by tumor site ( P het ≥ 0.05). Associations between first pregnancy ( P het = 0.04), tubal ligation ( P het = 0.01), and early-adult (age 18-21 years) body mass index (BMI; P het = 0.02) and risk differed between ovarian and peritoneal cancers. The association between early-adult BMI and risk further differed between peritoneal and fallopian tube cancer ( P het = 0.03). First pregnancy and tubal ligation were inversely associated with ovarian, but not peritoneal, cancer. Higher early-adult BMI was associated with higher risk of peritoneal, but not ovarian or fallopian tube, cancer. Patterns were generally similar when restricted to serous and high-grade serous cases., Conclusions: Ovarian, fallopian tube, and primary peritoneal cancers appear to have both shared and distinct etiologic pathways, although most risk factors appear to have similar associations by anatomic site., Impact: Further studies on the mechanisms underlying the differences in risk profiles may provide insights regarding the developmental origins of tumors arising in the peritoneal cavity and inform prevention efforts., (©2020 American Association for Cancer Research.)

Background: Obesity and diabetes are major modifiable risk factors for pancreatic cancer. Interactions between genetic variants and diabetes/obesity have not previously been comprehensively investigated in pancreatic cancer at the genome-wide level., Methods: We conducted a gene-environment interaction (GxE) analysis including 8,255 cases and 11,900 controls from four pancreatic cancer genome-wide association study (GWAS) datasets (Pancreatic Cancer Cohort Consortium I-III and Pancreatic Cancer Case Control Consortium). Obesity (body mass index ≥30 kg/m 2 ) and diabetes (duration ≥3 years) were the environmental variables of interest. Approximately 870,000 SNPs (minor allele frequency ≥0.005, genotyped in at least one dataset) were analyzed. Case-control (CC), case-only (CO), and joint-effect test methods were used for SNP-level GxE analysis. As a complementary approach, gene-based GxE analysis was also performed. Age, sex, study site, and principal components accounting for population substructure were included as covariates. Meta-analysis was applied to combine individual GWAS summary statistics., Results: No genome-wide significant interactions (departures from a log-additive odds model) with diabetes or obesity were detected at the SNP level by the CC or CO approaches. The joint-effect test detected numerous genome-wide significant GxE signals in the GWAS main effects top hit regions, but the significance diminished after adjusting for the GWAS top hits. In the gene-based analysis, a significant interaction of diabetes with variants in the FAM63A (family with sequence similarity 63 member A) gene (significance threshold P < 1.25 × 10 -6 ) was observed in the meta-analysis ( P GxE = 1.2 ×10 -6 , P Joint = 4.2 ×10 -7 )., Conclusions: This analysis did not find significant GxE interactions at the SNP level but found one significant interaction with diabetes at the gene level. A larger sample size might unveil additional genetic factors via GxE scans., Impact: This study may contribute to discovering the mechanism of diabetes-associated pancreatic cancer., (©2020 American Association for Cancer Research.)

Background: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies, with few known risk factors and biomarkers. Several blood protein biomarkers have been linked to PDAC in previous studies, but these studies have assessed only a limited number of biomarkers, usually in small samples. In this study, we evaluated associations of circulating protein levels and PDAC risk using genetic instruments., Methods: To identify novel circulating protein biomarkers of PDAC, we studied 8,280 cases and 6,728 controls of European descent from the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium, using genetic instruments of protein quantitative trait loci., Results: We observed associations between predicted concentrations of 38 proteins and PDAC risk at an FDR of < 0.05, including 23 of those proteins that showed an association even after Bonferroni correction. These include the protein encoded by ABO , which has been implicated as a potential target gene of PDAC risk variant. Eight of the identified proteins (LMA2L, TM11D, IP-10, ADH1B, STOM, TENC1, DOCK9, and CRBB2) were associated with PDAC risk after adjusting for previously reported PDAC risk variants (OR ranged from 0.79 to 1.52). Pathway enrichment analysis showed that the encoding genes for implicated proteins were significantly enriched in cancer-related pathways, such as STAT3 and IL15 production., Conclusions: We identified 38 candidates of protein biomarkers for PDAC risk., Impact: This study identifies novel protein biomarker candidates for PDAC, which if validated by additional studies, may contribute to the etiologic understanding of PDAC development., (©2020 American Association for Cancer Research.)

Background: Various components of the coagulation cascade have been linked to breast cancer progression. In vivo results suggest that anticoagulants possess anticancer properties, but there are virtually no studies in human populations. Our nationwide study explored the association between anticoagulant use and breast cancer survival., Methods: All anticoagulants used from 1995 to 2015 in women ( n = 73,170) diagnosed with invasive breast cancer in Finland between 1995 and 2013 were identified from the national prescription database; women were identified from the Finnish Cancer Registry. Cox regressions were performed to analyze breast cancer survival as a function of pre- and postdiagnostic anticoagulant use; analyses were conducted for different anticoagulant subtypes and overall. Models were adjusted for age, mammography screening, tumor clinical characteristics, comorbidities, statin use, antidiabetic use, and antihypertensive use. To control for immortal time bias, postdiagnostic anticoagulant use was analyzed as a time-dependent variable., Results: At a median of 5.8 years after breast cancer diagnosis, 10,900 (15%) women had died from breast cancer. In total, 25,622 (35%) women had used anticoagulants during the study period. Postdiagnostic anticoagulant use increased the risk of breast cancer death (HR = 1.41; 95% confidence interval, 1.33-1.49). The risk was especially high for low-molecular weight heparin, although the effect disappeared in long-term users., Conclusions: Anticoagulant use provides no clinical benefit for breast cancer survival; however, the association between thrombosis and cancer might mask potential survival benefits., Impact: Future pharmacoepidemiologic studies should adjust for anticoagulant use. Research should focus on the use of new oral anticoagulants because these are rarely studied and might be associated with improved breast cancer survival., (©2019 American Association for Cancer Research.)

Background: Antibody responses to Streptococcus gallolyticus subspecies gallolyticus (SGG) proteins, especially pilus protein Gallo2178, have been consistently associated with colorectal cancer risk. Previous case-control studies and prospective studies with up to 8 years of follow-up, however, were unable to decipher the temporality of antibody responses to SGG in the context of the long-term multistep development of colorectal cancer. In this study, we analyzed a large U.S. colorectal cancer cohort consortium with follow-up beyond 10 years for antibody responses to SGG. Methods: We applied multiplex serology to measure antibody responses to 9 SGG proteins in participants of 10 prospective U.S. cohorts (CLUE, CPSII, HPFS, MEC, NHS, NYUWHS, PHS, PLCO, SCCS, and WHI) including 4,063 incident colorectal cancer cases and 4,063 matched controls. Conditional logistic regression was used to assess whether antibody responses to SGG were associated with colorectal cancer risk, overall and by time between blood draw and diagnosis. Results: Colorectal cancer risk was increased among those with antibody responses to Gallo2178, albeit not statistically significant [OR, 1.23; 95% confidence interval (CI), 0.99-1.52]. This association was stronger for cases diagnosed <10 years after blood draw (OR, 1.40; 95% CI, 1.09-1.79), but was not found among cases diagnosed ≥10 years after blood draw (OR, 0.79; 95% CI, 0.50-1.24). Conclusions: In a large cohort consortium, we reproduced the association of antibody responses to SGG Gallo2178 with colorectal cancer risk for individuals diagnosed within 10 years after blood draw. Impact: This timing-specific finding suggests that antibody responses to SGG are associated with increased colorectal cancer risk only after tumorigenesis has begun. Cancer Epidemiol Biomarkers Prev; 27(10); 1186-94. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: We describe the expansion of the Atherosclerosis Risk in Communities (ARIC) Study into a cancer cohort. In 1987 to 1989, ARIC recruited 15,792 participants 45 to 64 years old to be sex (55% female), race (27% black), and geographically diverse. ARIC has exceptional data collected during 6 clinical visits and calls every 6 months, repeated biospecimens, and linkage to Medicare claims data. Methods: We established a Cancer Coordinating Center to implement infrastructure activities, convened a Working Group for data use, leveraged ARIC staff and procedures, and developed protocols. We initiated a cancer-specific participant contact, added questions to existing contacts, obtained permission to collect medical records and tissue, abstracted records, linked with state cancer registries, and adjudicated cases and characterizing data. Results: Through 2012, we ascertained and characterized 4,743 incident invasive, first, and subsequent primary cancers among 4,107 participants and 1,660 cancer-related deaths. We generated a total cancer incidence and mortality analytic case file, and analytic case files for bladder, breast, colorectal, liver, lung, pancreas, and prostate cancer incidence, mortality, and case fatality. Adjudication of multiple data sources improved case records and identified cancers not identified via registries. From 2013 onward, we ascertain cases from self-report coupled with medical records. Additional cancer registry linkages are planned. Conclusions: Compared with starting a new cohort, expanding a cardiovascular cohort into ARIC Cancer was an efficient strategy. Our efforts yielded enhanced case files with 25 years of follow-up. Impact: Now that the cancer infrastructure is established, ARIC is contributing its unique features to modern cancer epidemiology research. Cancer Epidemiol Biomarkers Prev; 27(3); 295-305. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Breast cancer is a leading cancer diagnosis among premenopausal women around the world. Unlike rates in postmenopausal women, incidence rates of advanced breast cancer have increased in recent decades for premenopausal women. Progress in identifying contributors to breast cancer risk among premenopausal women has been constrained by the limited numbers of premenopausal breast cancer cases in individual studies and resulting low statistical power to subcategorize exposures or to study specific subtypes. The Premenopausal Breast Cancer Collaborative Group was established to facilitate cohort-based analyses of risk factors for premenopausal breast cancer by pooling individual-level data from studies participating in the United States National Cancer Institute Cohort Consortium. This article describes the Group, including the rationale for its initial aims related to pregnancy, obesity, and physical activity. We also describe the 20 cohort studies with data submitted to the Group by June 2016. The infrastructure developed for this work can be leveraged to support additional investigations. Cancer Epidemiol Biomarkers Prev; 26(9); 1360-9. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Background: This study prospectively examines weight gain in breast cancer survivors compared with cancer-free women from a familial risk cohort., Methods: Absolute and percent weight change over 4 years was compared among 303 breast cancer survivors and 307 cancer-free women matched on age and menopausal status, from the same familial risk cohort. Linear and logistic regression was used to estimate the association between survivor status and weight gain., Results: Overall, breast cancer survivors gained significantly more weight [β = 3.06 pounds; 95% confidence intervals (CI), 0.94-5.17] than cancer-free women. Significant weight gain was observed in survivors diagnosed less than 5 years prior to baseline (β = 3.81 pounds; 95% CI, 1.22-6.29) and women with estrogen receptor (ER)-negative tumors (β = 7.26 pounds; 95% CI, 2.23-12.30). Furthermore, survivors treated with chemotherapy were 2.1 times more likely to gain at least 11 pounds during follow-up compared with cancer-free women (OR, 2.10; 95% CI, 1.21-3.63). Weight gain was even greater among survivors who took statins while undergoing chemotherapy treatment (Pinteraction = 0.01)., Conclusion: This is the first study to demonstrate that weight gain is an important issue in breast cancer survivors with a familial risk. In the first five years posttreatment, breast cancer survivors gain weight at a faster rate than cancer-free women, particularly after chemotherapy and statin use but not after hormone therapy alone., Impact: Our findings provide support for the development of weight gain interventions for young breast cancer survivors with a familial risk., (©2015 American Association for Cancer Research.)

Background: Aspirin use has been associated with significant reductions in breast cancer-related mortality in some observational studies. However, these studies included women who initiated aspirin use before breast cancer diagnosis. It is unclear whether initiating aspirin use after diagnosis is associated with similar reductions in mortality. This study investigates associations between de novo post-diagnostic aspirin use and all cause, breast cancer-specific mortality., Methods: Women, ages 50 to 80, with a diagnosis of stage I-III breast cancer were identified from Ireland's National Cancer Registry (N = 4,540). Initiation of de novo post-diagnostic aspirin use was identified from linked national prescription refill data (N = 764). Adjusted HRs were estimated for associations between de novo aspirin use and all-cause, breast cancer-specific mortality., Results: The median time from diagnosis to aspirin initiation was 1.8 years. The mean number of days' supply of aspirin received was 631, and 95% of users were taking less than 150 mg/d. We found no association between de novo aspirin use and breast cancer-specific mortality [HR, 0.98; 95% confidence interval (CI), 0.74-1.30]. Similar null associations were found in women taking aspirin at high-intensity (HR, 1.03; 95% CI, 0.72-1.47) and women initiating use in the 1.5 years after diagnosis (HR, 1.04; 95% CI, 0.77-1.40). There was no effect modification by estrogen (Pinteraction = 0.81) or progesterone (Pinteraction = 0.41) receptor status., Conclusion: Initiating aspirin use after a breast cancer diagnosis was not associated with a reduction in breast cancer-specific mortality., Impact: On the basis of our findings, we suggest that a clearer understanding of aspirin's mechanism of action is needed to help inform the design of future studies in breast cancer., (©2015 American Association for Cancer Research.)

Background: Sphingosine-1-phosphate (S1P) and ceramides are bioactive signaling sphingolipids that regulate pathways that are central to cancer pathogenesis., Methods: A nested case-control study was implemented to test whether prediagnostic circulating concentrations of S1P and ceramides were associated with future lung cancer risk. In the community-based CLUE II cohort study in Washington County, Maryland, the study consisted of 100 incident lung cancer cases, each matched to two cancer-free controls on age, sex, race, and cigarette smoking status. Plasma stored at -70°C at the beginning of follow-up in 1989 was assayed for sphingolipids using liquid chromatography/tandem mass spectrometry methodology (LC/MS-MS)., Results: Compared with controls, geometric mean plasma concentrations of S1P and total ceramides were 2.9% (P = 0.10) and 5.1% (P = 0.02), respectively, greater in lung cancer cases. For S1P, the ORs and 95% confidence intervals (CI) for lung cancer risk were 2.7 (1.2-5.9), 2.7 (1.1-6.4), and 1.9 (0.8-4.5) for the second, third, and highest fourth, respectively, compared with the lowest fourth (overall P = 0.006). Compared with those with total ceramide concentrations in the lowest fourth, the ORs (and 95% CI) for lung cancer risk were 1.6 (0.7-3.3), 1.5 (0.7-3.4), and 2.1 (0.9-4.7) for the second, third, and highest fourth, respectively (P(trend) = 0.01)., Conclusions: Higher concentrations of S1P and total ceramide in plasma were associated with increased future risk of lung cancer., Impact: These novel findings suggest that perturbation of sphingolipid metabolism and S1P generation may either contribute to the etiology of lung cancer or be a marker of latent lung cancer., (©2013 AACR)

Obesity is a known risk factor for postmenopausal breast cancer; it has been postulated that adipocytokines may mediate this association. We explored the relationship between three markers altered by obesity: leptin, adiponectin, and soluble tumor necrosis factor receptor 2 (sTNF-R2), an inflammatory marker, with breast cancer risk in postmenopausal women. A nested case-control study of postmenopausal women was conducted within CLUE II, a prospective population-based cohort. Baseline plasma levels of leptin, adiponectin, and sTNF-R2 were assayed in 272 female breast cancer cases and 272 controls matched on age, date, and hour of blood draw. Conditional logistic regression was used to estimate matched odds ratios (OR) and 95% confidence intervals (CI). sTNF-R2 and leptin were independently positively associated with breast cancer risk in adjusted models. The OR for breast cancer comparing the highest to lowest tertile was 2.44 (95% CI: 1.30-4.58) for sTNF-R2 and 1.98 (95% CI: 1.20-3.29) for leptin. While higher levels of adiponectin were protective (OR for the lowest tertile = 1.63; 95% CI: 1.02-2.60), there was no dose response. A 20% reduction in the breast cancer risk associated with overweight/obesity was observed when sTNF-R2 alone was included in multivariable models. Including both sTNF-R2 and adiponectin in the models resulted in a 29% reduction in the OR. Adipocytokines and sTNF-R2 are important factors in the etiology of postmenopausal breast cancer due to adiposity. This study informs our understanding of the relationship between obesity, inflammation, and postmenopausal breast cancer and identifies potential biomarkers.

Background: Allergic conditions are associated with reduced risk of several malignancies. We hypothesized that blood eosinophil count, a marker for allergic disorders, is inversely associated with the risk of colorectal cancer (CRC) in the Atherosclerosis Risk in Communities prospective cohort. To our knowledge, the association between blood eosinophil count and cancer risk has not been investigated before., Methods: Relative eosinophil and total leukocyte counts were measured in blood at baseline. Absolute eosinophil counts were calculated by multiplying relative count by the total leukocyte count. Proportional hazards regression provided HRs and 95% CIs of CRC in relation to eosinophil count., Results: From 1987-2006, 242 incident CRC cases (187 colon and 56 rectal) occurred in 10,675 initially cancer-free participants. In a multivariate-adjusted model, HRs were 1.0, 0.70 (95% CI: 0.50-0.98) and 0.58 (95% CI: 0.40-0.83) across tertiles of absolute eosinophil count (P(trend) = 0.003). A similar inverse association was observed for relative eosinophil count. Age, sex, race, or smoking status did not modify associations., Conclusions and Impact: We observed an inverse association between blood eosinophil count and CRC risk. This novel finding supports the hypothesis that allergies are protective for CRC, as an increased eosinophil count correlates with allergy in the developed world.

Background: Chronic inflammation has been implicated in the etiology of colorectal cancer (CRC), but epidemiologic findings on the association between circulating inflammatory markers and CRC risk are inconsistent. We hypothesized that increased concentrations of systemic inflammatory markers-white blood cell count (WBC), fibrinogen, von Willebrand factor (VWF), factor VIII (FVIII), and C-reactive protein (CRP)-and decreased albumin concentration would be associated with increased CRC risk in the Atherosclerosis Risk in Communities prospective cohort., Methods: WBC, fibrinogen, VWF, FVIII, and albumin, measured in 1987-1989 in 13,414 men and women, were transformed to z-scores and summed up to construct a blood "inflammation z-score." Albumin was included with a negative sign, because its concentration decreases with greater inflammation. A total of 308 incident CRC cases were identified through 2006 in initially cancer-free participants. CRP was measured in 1996-1998 in 9,836 cancer-free people who developed 166 CRCs through 2006. Proportional hazard models were used to estimate the HR and 95% CI of CRC in relation to each individual marker and the inflammation z-score., Results: After multivariate adjustment, for the highest versus lowest quartile, there was a statistically significant positive association of CRC risk with fibrinogen: HR = 1.50 (95% CI, 1.05-2.15), P = 0.03; inflammation z-score: HR = 1.65 (95% CI, 1.15-2.35), P = 0.01; and CRP: HR = 1.97 (95% CI, 1.13-3.43, P = 0.02., Conclusions: These findings indicate that greater levels of fibrinogen, CRP, and blood inflammation z-score are associated with increased CRC risk., Impact: The study provides further evidence that precancer inflammation may contribute to CRC etiology., (©2011 AACR.)

Background: Subjects with non-O ABO blood group alleles have increased risk of pancreatic cancer. Glycosyltransferase activity is greater for the A(1) versus A(2) variant, whereas O01 and O02 variants are nonfunctioning. We hypothesized: 1) A(1) allele would confer greater risk than A(2) allele, 2) protective effect of the O allele would be equivalent for O01 and O02 variants, 3) secretor phenotype would modify the association with risk., Methods: We determined ABO variants and secretor phenotype from single nucleotide polymorphisms in ABO and FUT2 genes in 1,533 cases and 1,582 controls from 12 prospective cohort studies. Adjusted odds ratios (OR) for pancreatic cancer were calculated using logistic regression., Results: An increased risk was observed in participants with A(1) but not A(2) alleles. Compared with subjects with genotype O/O, genotypes A(2)/O, A(2)/A(1), A(1)/O, and A(1)/A(1) had ORs of 0.96 (95% CI, 0.72-1.26), 1.46 (95% CI, 0.98-2.17), 1.48 (95% CI, 1.23-1.78), and 1.71 (95% CI, 1.18-2.47). Risk was similar for O01 and O02 variant O alleles. Compared with O01/O01, the ORs for each additional allele of O02, A(1), and A(2) were 1.00 (95% CI, 0.87-1.14), 1.38 (95% CI, 1.20-1.58), and 0.96 (95% CI, 0.77-1.20); P, O01 versus O02 = 0.94, A(1) versus A(2) = 0.004. Secretor phenotype was not an effect modifier (P-interaction = 0.63)., Conclusions: Among participants in a large prospective cohort consortium, ABO allele subtypes corresponding to increased glycosyltransferase activity were associated with increased pancreatic cancer risk., Impact: These data support the hypothesis that ABO glycosyltransferase activity influences pancreatic cancer risk rather than actions of other nearby genes on chromosome 9q34., (©2010 AACR.)

Most inherited cancer syndromes are characterized by the familial clustering of cancers at several organ sites. To determine if cancers, other than pancreatic cancer, cluster in pancreatic cancer kindreds, we examined mortality patterns among the relatives of National Familial Pancreatic Tumor Registry probands. Over 200,000 person-years of follow-up from 8,564 first-degree relatives of probands and 1,007 spouse controls were included in these analyses. We compared mortality rates of National Familial Pancreatic Tumor Registry participants to US population rates using weighed standardized mortality ratios (wSMR). Analyses were stratified by family history of pancreatic cancer (sporadic versus familial), family history of young onset pancreatic cancer (<50 years), and family history score. Cancer mortality was increased in both the relatives of sporadic probands [wSMR 1.55, 95% confidence interval (95% CI) 1.39-1.73] and familial probands (wSMR 1.41, 95% CI 1.26-1.58). Relatives of familial probands had a significantly increased risk of dying from breast (wSMR 1.66, 95% CI 1.15-2.34), ovarian (wSMR 2.05, 95% CI 1.10-3.49), and bile duct cancers (wSMR 2.89, 95% CI 1.04-6.39). Relatives of sporadic probands were at increased risk of dying from bile duct cancer (wSMR 3.01, 95% CI 1.09-6.67). Relatives of young onset probands were at higher risk of dying from cancers of the breast (wSMR 1.98, 95% CI 1.01-3.52), colon (wSMR 2.31, 95% CI 1.30-3.81) and prostate (wSMR 2.31, 95% CI 1.14-4.20). Increased cancer mortality was not observed in the spouse controls. Our results show that relatives of pancreatic cancer patients are at higher risk of developing cancers at other sites and highlight the importance of complete family history in clinical risk assessment.

Benign breast disease (BBD) is a risk factor for breast cancer and may have a heritable component. Deficient DNA repair has been implicated in breast cancer etiology and may exert its effect before BBD, a known precursor. The association between allelic variants in DNA repair genes and BBD was examined in a cohort of women in Washington County, Maryland. BBD was defined by two criteria: (a) a physician diagnosis of BBD or fibrocystic disease and/or (b) a benign breast biopsy. 3,212 women without BBD at baseline were genotyped for 12 candidate single nucleotide polymorphisms in seven DNA repair genes. Of these women, 482 subsequently reported a diagnosis of BBD. The Cox model was used to calculate hazard ratios (HR). Variant alleles of XRCC1 Arg(194)Trp (rs1799782) and ERCC4 Arg(415)Gln (rs1800067) were significantly associated with BBD [HR, 1.36; 95% confidence interval (95% CI), 1.06-1.74 and HR, 1.39; 95% CI, 1.09-1.76, respectively]. Similar estimates were also observed for each of the BBD criterion used. The BBD association for ERCC4 was even stronger among women with a family history of breast cancer (HR, 2.68; 95% CI, 1.52-4.66; P(interaction) = 0.02). This study suggests that variant alleles in DNA repair genes may modify BBD risk, a potential intermediate marker of breast cancer risk, particularly among high-risk subgroups.

Purpose: Ductal lavage, a technique used to sample epithelial cells from breast ducts, has potential use in risk assessment and biomarker evaluation among women at increased risk for breast cancer. However, little is known about the reliability of the procedure., Methods: We evaluated the reliability of nipple aspirate (NAF) and ductal lavage at two time points 6 months apart in women at increased risk for breast cancer. Eligible women had a 5-year Gail risk >or=1.66% or lifetime risk of >20%, and/or a family history or personal history of breast cancer. All ducts that produced NAF were cannulated. The kappa statistic was used to evaluate reliability of NAF production, cellular yield, and cytologic diagnosis., Results: Sixty-nine women (mean age, 47 years) were enrolled over 35 months. Forty-seven returned for a second visit. At baseline, 65% of premenopausal and 41% of postmenopausal women produced NAF (P = 0.05), of which 72% underwent successful lavage of at least one duct. Samples of inadequate cellular material for diagnosis were significantly more likely in postmenopausal women than in premenopausal women (P = 0.04). Of the women who returned for a second visit, 18 of 24 who produced NAF had at least one duct successfully cannulated. Twenty-four ducts in 14 women were lavaged twice. Among these ducts, cellular yield for the two time points was inconsistent (kappa = 0.33 +/- 0.13), and only fair cytologic agreement was observed (kappa = 0.32 +/- 0.15). Ductal lavage was associated with moderate discomfort., Conclusion: Currently, the use of ductal lavage is limited by technical challenges in duct cannulation, inconsistent NAF production, a high rate of inadequate cellular material for diagnosis, fair cytologic reproducibility, and low participant return rates.

The reproducibility of a test result is a critical component of its clinical utility. Little information is available concerning the intrarater reproducibility of cytologic assessments. This study evaluated the reproducibility of cytologic interpretation of epithelial cells obtained from ductal lavage (DL), a minimally invasive method used to obtain sample cells from breast tissue. Two cytospin slides were made for each duct sampled. Slides with <10 cells were considered inadequate to make a diagnosis; the remaining slides were classified into mildly atypical, markedly atypical, and malignant cells. Each pair of slides were classified by the more serious diagnosis. DL samples from 100 ducts were independently blind-reviewed by two experienced cytopathologists. All abnormal slides and a random sample of normal slides and slides identified as inadequate for diagnosis (n = 43) were re-reviewed. The kappa for intrarater agreement was 0.59 +/- 0.10 for cytopathologist 1 and 0.33 +/- 0.08 for cytopathologist 2. The kappa for interrater agreement of slides from 100 ducts was 0.46 +/- 0.07. The interrater agreement of the slides that were re-reviewed was kappa = 0.27 +/- 0.09. Fair to moderate intrarater and interrater agreement of DL cytology was observed. Low intrarater and interrater cytologic consistency may compromise the interpretation of clinical studies of DL.