Sheetal Hardikar

Association between markers of obesity and progression from barrett's esophagus to esophageal adenocarcinoma

BACKGROUND & AIMS Individuals with Barretts esophagus (BE) have an increased risk of developing esophageal adenocarcinoma (EA). Obesity contributes to the development of BE and its progression to cancer. We investigated the roles of obesity-induced hyperinsulinemia and dysregulation of adipokines in these processes. METHODS We measured fasting levels of glucose, insulin, leptin, and adiponectin in 392 patients enrolled in the Seattle Barretts Esophagus Study. We calculated homeostatic model assessment scores (a measure of insulin sensitivity) and identified subjects with metabolic syndrome. We evaluated the association between these measures and the risk of EA using Cox regression models adjusted for known risk factors. RESULTS Increasing homeostatic model assessment scores were associated with an increasing risk for EA; the strongest association was observed within the first 3 years after participants entered the study (hazard ratio [HR], 2.45; 95% confidence interval [CI], 1.43-4.1; P trend = .001). Leptin level also was associated significantly with an increased risk of EA within 3 years (HR, 2.51; 95% CI, 1.09-5.81; P trend = .03) and 6 years (HR, 2.07; 95% CI, 1.01-4.26; P trend = .048) of baseline. The level of high-molecular-weight adiponectin had a nonlinear inverse association with risk of EA; the strongest associations were observed in the second tertile (HR, 0.34; 95% CI, 0.14-0.82). Metabolic syndrome was not associated with risk of EA. CONCLUSIONS Among patients with BE, increased levels of leptin and insulin resistance are associated with increased risk for EA, whereas increased levels of high-molecular-weight adiponectin is associated inversely with EA. These biomarkers might be used to determine cancer risk among patients with BE.

The Role of Tobacco, Alcohol, and Obesity in Neoplastic Progression to Esophageal Adenocarcinoma: A Prospective Study of Barrett's Esophagus

Background Esophageal adenocarcinoma (EA) incidence in many developed countries has increased dramatically over four decades, while survival remains poor. Persons with Barretts esophagus (BE), who experience substantially elevated EA risk, are typically followed in surveillance involving periodic endoscopy with biopsies, although few progress to EA. No medical, surgical or lifestyle interventions have been proven to safely lower EA risk. Design We investigated whether smoking, obesity or alcohol could predict progression to EA in a prospective cohort of 411 BE patients. Data were collected during personal interview. Adjusted hazard ratios (HR) were estimated using Cox regression. Results 39% had body mass index (BMI) over 30 and 64% had smoked cigarettes. Main analyses focused on those with at least 5 months of follow-up (33,635 person-months), in whom 45 developed EA. Risk increased by 3% per year of age (trend p-value 0.02), with approximate doubling of risk among males. EA risk increased with smoking pack-years (trend p-value 0.04) and duration (p-value 0.05). Compared to never-smokers, the HR for those in the highest pack-year tertile was 2.29 (95%CI 1.04–5.07). No association was found with alcohol or BMI, whereas a suggestion of increased risk was observed in those with higher waist-hip ratio, especially among males. Conclusion EA risk significantly increased with increasing age and cigarette exposure. Abdominal obesity, but not BMI, was associated with a modest increased risk. Continued follow-up of this and other cohorts is needed to precisely define these relationships so as to inform risk stratification and preventive interventions.

Inflammation and Oxidative Stress Markers and Esophageal Adenocarcinoma Incidence in a Barrett's Esophagus Cohort

Background: Persons with Barretts esophagus experience increased risk of esophageal adenocarcinoma. Prediagnostic inflammation markers predict several cancers, but their role in predicting esophageal adenocarcinoma is unknown. Methods: We investigated whether biomarkers of inflammation [C-reactive protein (CRP), interleukin-6 (IL6), soluble tumor necrosis factor (sTNF) receptors I and II], and of oxidative stress (F2-isoprostanes) predicted progression to esophageal adenocarcinoma in a prospective cohort of 397 patients with Barretts esophagus, 45 of whom developed esophageal adenocarcinoma. Biomarkers were measured in stored plasma samples from two time points during follow-up, the mean of which served as the primary predictor. Adjusted hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox regression. Results: CRP level above the median was associated with an 80% increased risk of esophageal adenocarcinoma. The HR and 95% CI adjusted for age, gender, and further adjusted for waist–hip ratio and smoking were 1.98 (1.05–3.73) and 1.77 (0.93–3.37), respectively, with Ptrend for continuous CRP = 0.04. Persons with IL6 levels above the median also had almost 2-fold increased risk [HR and 95% CI adjusted for age and gender, and further adjusted for waist–hip ratio and smoking were 1.95 (1.03–3.72) and 1.79 (0.93–3.43), respectively, but no evidence of a trend was observed]. Concentrations of TNF receptors and F2-isoprostanes were not associated with esophageal adenocarcinoma risk. Conclusions: Further research is needed to evaluate the role of inflammation and associated markers in esophageal adenocarcinoma development in persons with Barretts esophagus. Impact: This prospective study suggests that inflammation markers, particularly CRP and IL6, may help identify persons at higher risk of progression to esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev; 23(11); 2393–403. ©2014 AACR.

Timing of Aspirin and Other Nonsteroidal Anti-Inflammatory Drug Use Among Patients With Colorectal Cancer in Relation to Tumor Markers and Survival

Purpose Regular use of aspirin is associated with improved survival for patients with colorectal cancer (CRC). However, the timing of and the subtype of CRC that would benefit the most from using aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) in relation to survival is unclear. Patients and Methods In all, 2,419 patients age 18 to 74 years with incident invasive CRC who were diagnosed from 1997 to 2008 were identified from population-based cancer registries in the United States, Canada, and Australia. Detailed epidemiologic questionnaires were administered at study enrollment and at 5-year follow-up. Survival outcomes were completed through linkage to national death registries. BRAF- and KRAS-mutation status, microsatellite instability, and CpG island methylator phenotype were also evaluated. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% CIs for overall survival (OS) and CRC-specific survival. Results After a median of 10.8 years of follow-up since diagnosis, 381 deaths (100 as a result of CRC) were observed. Compared with nonusers, postdiagnostic aspirin-only users had more favorable OS (HR, 0.75; 95% CI, 0.59 to 0.95) and CRC-specific survival (HR, 0.44; 95% CI, 0.25 to 0.71), especially among those who initiated aspirin use (OS: HR, 0.64; 95% CI, 0.47 to 0.86; CRC-specific survival: HR, 0.40; 95% CI, 0.20 to 0.80). The association between any NSAID use after diagnosis and OS differed significantly by KRAS-mutation status ( Pinteraction = .01). Use of any NSAID after diagnosis was associated with improved OS only among participants with KRAS wild-type tumors (HR, 0.60; 95% CI, 0.46 to 0.80) but not among those with KRAS-mutant tumors (HR, 1.24; 95% CI, 0.78 to 1.96). Conclusion Among long-term CRC survivors, regular use of NSAIDs after CRC diagnosis was significantly associated with improved survival in individuals with KRAS wild-type tumors.

Prediagnostic Physical Activity and Colorectal Cancer Survival: Overall and Stratified by Tumor Characteristics

Background: Physical activity is associated with a lower incidence of colorectal cancer; however, the relationship of physical activity with colorectal cancer survival is not yet clear. We evaluated the association between prediagnostic physical activity and colorectal cancer survival, overall and accounting for tumor markers associated with colorectal cancer survival: BRAF and KRAS mutation status and microsatellite instability (MSI) status. Methods: Participants were 20- to 74-year-old colorectal cancer patients diagnosed between 1998 and 2007 from the population-based Seattle Colon Cancer Family Registry (S-CCFR). Self-reported physical activity in the years preceding colorectal cancer diagnosis was summarized as average metabolic equivalent task hours per week (MET-h/wk; n = 1,309). Somatic BRAF and KRAS mutations and MSI status were evaluated on a subset of patients (n = 1043). Cox regression was used to estimate HRs and 95% confidence intervals (CI) for overall and disease-specific survival after adjusting for relevant confounders. Stratified analyses were conducted across categories of BRAF, KRAS, and MSI, as well as tumor stage and site. Results: Higher prediagnostic recreational physical activity was associated with significantly more favorable overall survival (HR for highest vs. lowest category, 0.70; 95% CI, 0.52–0.96); associations were similar for colorectal cancer–specific survival. Results consistently indicated a favorable association with physical activity across strata defined by tumor characteristics. Conclusion: Individuals who were physically active before colorectal cancer diagnosis experienced better survival than those who were inactive or minimally active. Impact: Our results support existing physical activity recommendations for colorectal cancer patients and suggest that the beneficial effect of activity is not specific to a particular molecular phenotype of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(7); 1130–7. ©2015 AACR.

A population-based case-control study of genetic variation in cytokine genes associated with risk of cervical and vulvar cancers

OBJECTIVE Persistent infection with oncogenic human papillomavirus (HPV) is known to be the necessary cause of cervical cancer and a majority of vulvar cancers. Persistent HPV infections must evade host immune responses, including cytokines released by activated T-helper (Th) cells. In this study, we investigated the risk of cervical and vulvar cancers associated with common genetic variations in 560 tagging single-nucleotide polymorphisms (SNPs) in candidate cytokine genes. METHODS The study included 399 invasive squamous cell carcinomas (SCCs) and 502 in situ or invasive adenocarcinomas (AC) of the cervix; 357 in situ or invasive vulvar SCC; and 1109 controls from the Seattle-area case-control studies of HPV-related cancers. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) using a log additive model, with adjustment for multiple testing. RESULTS Statistically significant risks were observed for HPV16-containing SCC of the cervix with the variant allele rs879576 in IL17RA and rs2229094 in TNF [OR, 95% CI and multiple-testing corrected p: 1.91 (1.30-2.79), p=0.018 and 0.61 (0.45-0.83), p=0.02, respectively]. We also observed significantly increased risk of HPV-positive vulvar cancers associated with variant alleles in CSF2 (rs25882 and rs27438, 26-28% increased risk) and IL-12B (rs2569254 and rs3181225, 40-41% increased risk) genes. CONCLUSIONS We found that variation in several Th-cytokine genes is significantly associated with cervical and vulvar cancer risk. The strong association between these HPV-related cancers and common variation in cytokine genes in the Th1 and Th17 pathways may be important for development of new therapies.

Stage IV colorectal cancer primary site and patterns of distant metastasis

BACKGROUND Although colorectal cancer (CRC) usually metastasizes to the liver and/or lungs, factors influencing the anatomic pattern of metastases remain poorly understood. METHODS We assessed the relationship between primary CRC site and pattern of synchronous metastasis among 1202 individuals diagnosed with incident metastatic CRC between 2010 and 2014 and identified through the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) registry. Polytomous logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for the association between primary tumor site and synchronous metastatic pattern. RESULTS Compared to patients with proximal colon primaries, patients with rectal primaries were more likely to present with lungs-only or liver and lungs metastases versus liver-only metastases (ORlungs-onlyvs.liver-only: 2.39, 95% CI: 1.35-4.24, ORliver+lungsvs.liver-only: 2.20, 95% CI: 1.46-3.32). CONCLUSION These findings suggest that patients with rectal primaries are more likely than patients with colon primaries to present with synchronous lung metastases.

Physical activity and outcomes in patients with stage III colon cancer: A correlative analysis of phase III trial NCCTG N0147 (Alliance)

Background: Prior studies have supported an inverse association between physical activity and colon cancer risk and suggest that higher physical activity may also improve cancer survival. Among participants in a phase III adjuvant trial for stage III colon cancer, we assessed the association of physical activity around the time of cancer diagnosis with subsequent outcomes. Methods: Before treatment arm randomization (FOLFOX or FOLFOX + cetuximab), study participants completed a questionnaire including items regarding usual daily activity level and frequency of participation in recreational physical activity (N = 1,992). Using multivariable Cox models, we calculated HRs for associations of aspects of physical activity with disease-free (DFS) and overall survival (OS). Results: Over follow-up, 505 participants died and 541 experienced a recurrence. Overall, 75% of participants reported recreational physical activity at least several times a month; for participants who reported physical activity at least that often (vs. once a month or less), the HRs for DFS and OS were 0.82 [95% confidence interval (CI), 0.69–0.99] and 0.76 (95% CI, 0.63–0.93), respectively. There was no evidence of material effect modification in these associations by patient or tumor attributes, except that physical activity was more strongly inversely associated with OS in patients with stage T3 versus T4 tumors (Pinteraction = 0.03). Conclusions: These findings suggest that higher physical activity around the time of colon cancer diagnosis may be associated with more favorable colon cancer outcomes. Impact: Our findings support further research on whether colon cancer survival may be enhanced by physical activity. Cancer Epidemiol Biomarkers Prev; 27(6); 696–703. ©2018 AACR.

Reproductive factors and risk of colorectal polyps in a colonoscopy-based study in western Washington State

BackgroundOral contraceptives (OC) are associated with a decreased risk of colorectal cancers; however, a recent study reported an increased risk of small colorectal adenomas associated with OC use. To determine if these results were replicable in a different study population, we investigated the relationship between OC use and other reproductive factors and risk of colorectal polyps in a case–control study in western Washington.MethodsStudy participants were 24–79-year-old female enrollees at an integrated health care system in western Washington who were diagnosed as having adenomas (n = 299), serrated polyps (n = 337), both types of polyps (n = 105) or as polyp-free controls (n = 615) through an index colonoscopy and completed a structured interview to collect reproductive history information. Multivariable polytomous logistic regression was used to compare case groups to controls and to each other; odds ratios (OR) and 95% confidence intervals were estimated.ResultsThere was no association between OC use, duration of use, or recency of use and the risk of either adenomas or serrated polyps [adjusted OR for OC ever use (95% CI) 0.85 (0.58–1.23) and 0.96 (0.66–1.40), respectively], and associations did not differ by lesion severity within the adenoma or serrated pathways. Further, no associations were observed between other reproductive factors and risk of colorectal polyp subtypes.ConclusionsOur results suggest that reproductive factors, including OC use, are not associated with early colorectal cancer precursor lesions.

Abstract PR-03: A prospective study of systemic markers of inflammation and risk of esophageal adenocarcinoma in a Barrett's esophagus cohort

Background : A sustained increase in incidence of and mortality from esophageal adenocarcinoma (EA) has been observed over the past four decades in many developed countries. Persons diagnosed with Barrett9s esophagus (BE), a metaplastic condition that confers a 30- to 100-fold increase in EA risk, are typically followed in a surveillance program involving periodic endoscopy with biopsies, with relatively few progressing to EA. No medical, surgical or lifestyle interventions have been proven to safely lower risk of EA. Recently studies have shown that prediagnostic serum inflammation markers may be predictive of cancers of the breast, colon, lung and prostate, but their role in predicting EA is unknown. Methods : We investigated whether elevated serum markers of chronic inflammation, including C-reactive protein (CRP), Interleukin-6 (IL-6) and surface tumor necrosis factor receptors I and II (sTNF-RI & sTNF-RII) could predict progression to EA in a cohort of 411 BE patients followed prospectively. Participants underwent periodic endoscopy with multiple biopsies, personal interview and blood draw. Levels of CRP, IL-6 and sTNF receptors were measured in stored plasma samples using high-sensitivity nephelometry, ELISA and multiplex assay, respectively. For most individuals, two measurements were available - at baseline and the first follow up visit. Their mean was used as the primary predictor. CRP measurements over 10 mg/L were considered to be indicative of acute inflammation and were excluded from the analysis. Adjusted Hazard ratios (HR) were estimated using Cox proportional hazards regression. Results : Median age of the cohort was 61.2 years and 81.3% were males. Median plasma concentrations of all markers were higher among cases (n=56) than among non-cases (CRP 2.65 vs. 1.85 mg/L; IL-6 1.94 vs. 1.87 pg/ml; sTNF-RI 1753 vs. 1378 pg/ml; sTNF-RII 6296 vs. 5337 pg/ml). The main analyses focused on 397 persons with at least 5 months of follow-up (median 78.6 months, 33,635 person-months), in whom 45 developed EA. Elevated CRP was significantly associated with an increased risk of EA after adjustment for age and gender. With CRP modeled as a continuous variable, the HR comparing the 75th%tile vs. 25th%tile was 1.62 (p-trend=0.01; 95% CI 1.12–2.34). Further adjustment for the effects of waist-to-hip ratio, smoking and NSAIDS intake attenuated the association only slightly. Although we found that persons with IL-6 levels above the median had a two-fold increased risk for EA (HR 1.95; 95% CI 1.03–3.72), we did not observe evidence of a trend with increasing concentrations. Increased sTNF receptor levels were not associated with EA risk and we did not observe any trend with increasing sTNF concentrations. Conclusions : Prediagnostic plasma CRP concentrations are predictive of neoplastic progression to cancer in persons with BE. Although there is some suggestion of increased risk with IL-6, there was no significant trend with increasing concentrations. We did not observe any association between levels of sTNF receptors with EA risk. These data support the hypothesis that inflammation may play a significant role in EA development among BE patients, and suggest that serum CRP may be useful in identifying persons at higher risk of progression to cancer. Continued follow-up of this and other larger cohorts is needed to further evaluate CRP and potentially IL-6 as tools for clinical risk stratification among BE patients. Citation Information: Cancer Prev Res 2011;4(10 Suppl):PR-03.