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1.  Randomized Controlled Trial of Acitretin Versus Placebo in Patients at High Risk for Basal Cell or Squamous Cell Carcinoma of the Skin (North Central Cancer Treatment Group Study 969251) 
Cancer  2011;118(8):2128-2137.
BACKGROUND
Chemoprevention with systemic retinoids has demonstrated promise in decreasing the incidence of new primary nonmelanoma skin cancers (NMSCs) in immunocompromised post-transplantation recipients. There is limited evidence for the use of systemic retinoids in the nontransplantation patient. To the authors’ knowledge, this is the first randomized controlled trial to assess the efficacy of acitretin as a chemopreventive agent in nontransplantation patients at high risk for NMSC.
METHODS
The study was designed as a prospective, randomized, double-blind, placebo-controlled clinical trial. To test the possible skin cancer-preventing effect of a 2-year treatment with acitretin, 70 nontransplantation patients aged ≥18 years who had a history of ≥2 NMSCs within 5 years of trial onset were randomized to receive either placebo or acitretin 25 mg orally 5 days per week. The primary outcome measure was the rate of new NMSC development.
RESULTS
Seventy patients were randomized to receive either acitretin alone (N = 35) or placebo (N = 35). During the 2-year treatment period, the patients who received acitretin did not have a statistically significant reduction in the rate of new primary NMSCs (odds ratio, 0.41; 95% confidence interval, 0.15–1.13; 54% vs 74%; P = .13). However, using the incidence of new NMSC, the time to new NMSC, and total NMSC counts, an umbrella test indicated a significant trend that favored the use of acitretin (chi-square statistic, 3.94; P = .047). The patients who received acitretin reported significantly more mucositis and skin toxicities compared with the patients who received placebo.
CONCLUSIONS
Although there was not a statistically significant benefit observed with the use of acitretin, this may have been the result of low statistical power.
doi:10.1002/cncr.26374
PMCID: PMC3365547  PMID: 21882176
acitretin; chemoprevention; basal cell carcinoma; squamous cell carcinoma; clinical trials
2.  Personalizing Aspirin Use for Targeted Breast Cancer Chemoprevention Among Postmenopausal Women 
Mayo Clinic proceedings  2015;91(1):71-80.
Objective
To better understand the potential risk/benefit ratio for targeted chemoprevention, we evaluated the association of aspirin and other NSAIDs with incidence of postmenopausal breast cancer for risk subgroups defined by selected non-modifiable or difficult-to-modify breast cancer risk factors.
Patients and Methods
Postmenopausal women with no history of cancer on July 1, 1992 (N=26,580) were prospectively followed through December 31, 2005 for breast cancer incidence (N=1581). Risk subgroups were defined on family history of breast cancer, age at menarche, age at menopause, parity/age at first live birth, history of benign breast disease, and body mass index (BMI). Hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for other breast cancer risk factors were estimated using Cox models.
Results
Aspirin use was associated with a lower incidence of breast cancer for women with family history of breast cancer (HR=0.62 for 6+ per week vs. never use; 95%CI 0.41-0.93) and personal history of benign breast disease (HR=0.69; 95%CI 0.50-0.95), but not for women in higher risk subgroups for age at menarche, age at menopause, parity/age at first live birth or BMI. In contrast, inverse associations with aspirin use were observed in all lower risk subgroups. NSAID use had no association with breast cancer incidence.
Conclusion
Based on their increased risk of breast cancer, postmenopausal women with a family history of breast cancer or a history of benign breast disease could potentially be targeted for aspirin chemoprevention studies. Future studies are needed to confirm these findings.
doi:10.1016/j.mayocp.2015.10.018
PMCID: PMC4807132  PMID: 26678006
3.  Tumor Budding in Colorectal Carcinoma: Confirmation of Prognostic Significance and Histologic Cutoff in a Population-based Cohort 
Tumor budding in colorectal carcinoma has been associated with poor outcome in multiple studies, but the absence of an established histologic cutoff for “high” tumor budding, heterogeneity in study populations and varying methods for assessing tumor budding have hindered widespread incorporation of this parameter in clinical reports. We used an established scoring system in a population-based cohort to determine a histologic cutoff for “high” tumor budding and confirm its prognostic significance. We retrieved hematoxylin and eosin-stained sections from 553 incident colorectal carcinoma cases. Each case was previously characterized for select molecular alterations and survival data. Interobserver agreement was assessed between two GI pathologists and a group of four general surgical pathologists. High budding (≥10 tumor buds in a 20× objective field) was present in 32% of cases, low budding in 46% and no budding in 22%. High tumor budding was associated with advanced pathologic stage (p<0.001), microsatellite stability (p=0.005), KRAS mutation (p=0.010) and on multivariate analysis with a greater than two times risk of cancer-specific death (HR=2.57 (1.27, 5.19)). After multivariate adjustment, via penalized smoothing splines, we found increasing tumor bud counts from 5 upward to be associated with an increasingly shortened cancer-specific survival. By this method, a tumor bud count of 10 corresponded to approximately 2.5 times risk of cancer –specific death. The interobserver agreement was good with weighted kappa of 0.70 for two GI pathologists over 121 random cases and 0.72 between all six pathologists for 20 random cases. Using an established method to assess budding on routine histologic stains, we have shown a cutoff of 10 for high tumor budding is independently associated with a significantly worse prognosis. The reproducibility data provide support for the routine widespread implementation of tumor budding in clinical reports.
doi:10.1097/PAS.0000000000000504
PMCID: PMC4567920  PMID: 26200097
4.  Tumor eosinophil infiltration and improved survival of colorectal cancer patients: Iowa Women’s Health Study 
The role of the innate immune response in colorectal cancer is understudied. We examined the survival of colorectal cancer patients in relation to eosinophils, innate immune cells, infiltrating the tumor. Tissue microarrays were constructed from paraffin-embedded tumor tissues collected between 1986–2002 from 441 post-menopausal women diagnosed with colorectal cancer in the Iowa Women’s Health Study. Tissue microarrays were stained with an eosinophil peroxidase antibody. Eosinophils in epithelial and stromal tissues within the tumor (called epithelial and stromal eosinophils, hereafter) were counted and scored into 3 and 4 categories, respectively. In addition, the degree of eosinophil degranulation (across epithelial and stromal tissues combined) was quantified and similarly categorized. We used Cox regression to estimate the hazard ratios and 95% confidence interval for all-cause and colorectal cancer death during five-year follow-up after diagnosis and during follow-up through 2011 (“total follow-up”). The hazard ratios associated with eosinophil scores were adjusted for age of diagnosis, SEER stage, tumor grade, body mass, and smoking history. High tumor stromal eosinophil score was inversely correlated with age and stage, and was associated with a decreased risk for all-cause and colorectal cancer death: hazard ratios (95% confidence intervals) were 0.61 (0.36–1.02; P-trend =0.02) and 0.48 (0.24–0.93; P-trend =0.01), respectively, during the five-year follow-up for the highest versus lowest category. The inverse associations also existed for total follow-up for all-cause and colorectal cancer death for the highest versus lowest stromal eosinophil score: hazard ratios (95% confidence intervals) were 0.72 (0.48–1.08; P-trend =0.04) and 0.61 (0.34–1.12; P-trend =0.04), respectively. Further adjustment for treatment, comorbidities, additional lifestyle factors, tumor location or molecular markers did not markedly change the associations, while adjustment for cytotoxic T-cells slightly attenuated all associations. The infiltration of tumors with eosinophils, especially in stromal tissue, may be an important prognostic factor in colorectal cancer.
doi:10.1038/modpathol.2016.42
PMCID: PMC4848192  PMID: 26916075
5.  Aspirin Prevents Colorectal Cancer by Normalizing EGFR Expression 
EBioMedicine  2015;2(5):447-455.
Background
Aspirin intake reduces the risk of colorectal cancer (CRC), but the molecular underpinnings remain elusive. Epidermal growth factor receptor (EGFR), which is overexpressed in about 80% of CRC cases, is implicated in the etiology of CRC. Here, we investigated whether aspirin can prevent CRC by normalizing EGFR expression.
Methods
Immunohistochemistry staining was performed on paraffin-embedded tissue sections from normal colon mucosa, adenomatous polyps from FAP patients who were classified as regular aspirin users or nonusers. The interplay between cyclooxygenase-2 (COX-2) and EGFR was studied in primary intestinal epithelial cells isolated from ApcMin mice, immortalized normal human colon epithelial cells (HCEC) as well as murine embryonic fibroblasts (MEFs).
Results
Immunohistochemistry staining results established that EGFR overexpression is an early event in colorectal tumorigenesis, which can be greatly attenuated by regular use of aspirin. Importantly, EGFR and COX-2 were co-overexpressed and co-localized with each other in FAP patients. Further mechanistic studies revealed that COX-2 overexpression triggers the activation of the c-Jun-dependent transcription factor, activator protein-1 (AP-1), which binds to the Egfr promoter. Binding facilitates the cellular accumulation of EGFR and lowers the threshold required for pre-neoplastic cells to undergo transformation.
Conclusion
Aspirin might exert its chemopreventive activity against CRC, at least partially, by normalizing EGFR expression in gastrointestinal precancerous lesions.
doi:10.1016/j.ebiom.2015.03.019
PMCID: PMC4469241  PMID: 26097892
colorectal cancer; familial adenomatous polyposis; epidermal growth factor receptor; cyclooxygenase-2
6.  Association between body mass index and mortality for colorectal cancer survivors: overall and by tumor molecular phenotype 
Background
Microsatellite instability (MSI) and BRAF-mutation status are associated with colorectal cancer survival whereas the role of body mass index (BMI) is less clear. We evaluated the association between BMI and colorectal cancer survival, overall and by strata of MSI, BRAF-mutation, sex, and other factors.
Methods
This study included 5,615 men and women diagnosed with invasive colorectal cancer who were followed for mortality (maximum: 14.7 years; mean: 5.9 years). Pre-diagnosis BMI was derived from self-reported weight approximately 1-year before diagnosis and height. Tumor MSI and BRAF-mutation status were available for 4,131 and 4,414 persons, respectively. Multivariable hazard ratios (HR) and 95% confidence intervals (CIs) were estimated from delayed-entry Cox proportional hazards models.
Results
In multivariable models, high pre-diagnosis BMI was associated with higher risk of all-cause mortality in both sexes (per 5-kg/m2, HR = 1.10; 95% CI = 1.06 to 1.15), with similar associations stratified by sex (p-interaction: 0.41), colon vs rectum (p-interaction: 0.86), MSI status (p-interaction: 0.84), and BRAF-mutation status (p-interaction: 0.28). In joint models, with MS-stable/MSI-low and normal BMI as the reference group, risk of death was higher for MS-stable/MSI-low and obese BMI (HR: 1.32; p-value: 0.0002), not statistically significantly lower for MSI-high and normal BMI (HR: 0.86; p-value: 0.29), and approximately the same for MSI-high and obese BMI (HR: 1.00; p-value: 0.98).
Conclusions
High pre-diagnosis BMI was associated with increased mortality; this association was consistent across participant subgroups, including strata of tumor molecular phenotype.
Impact
High BMI may attenuate the survival benefit otherwise observed with MSI-high tumors.
doi:10.1158/1055-9965.EPI-15-0094
PMCID: PMC4526409  PMID: 26038390
obesity; microsatellite instability; survival; BRAF mutation; colon cancer
7.  Metformin Does not Reduce Markers of Cell Proliferation in Esophageal Tissues of Patients with Barrett's Esophagus 
Background & Aims
Obesity is associated with neoplasia, possibly via insulin-mediated cell pathways that affect cell proliferation. Metformin has been proposed to protect against obesity-associated cancers by decreasing serum insulin. We conducted a randomized, double-blind, placebo-controlled, phase 2 study of patients with Barrett's Esophagus (BE) to assess the effect of metformin on phosphorylated S6 kinase (pS6K1) -- a biomarker of insulin pathway activation.
Methods
Seventy-four subjects with BE (mean age 58.7 years; 58 men [78%0; 52 with BE>2 cm [70%] were recruited through 8 participating organizations of the Cancer Prevention Network. Participants were randomly assigned to groups given metformin daily (increasing to 2000 mg/day by week 4; n=38) or placebo (n=36) for 12 weeks. Biopsy specimens were collected at baseline and at week 12 via esophagogastroduodenoscopy. We calculated and compared percent changes in median levels of pS6K1 between subjects given metformin vs placebo as the primary endpoint.
Results
The percent change in median level of pS6K1 did not differ significantly between groups (1.4% among subjects given metformin vs – 14.7% among subjects given placebo; 1-sided P=.80). Metformin was associated with an almost significant reduction in serum levels of insulin (median −4.7% among subjects given metformin vs 23.6% increase among those given placebo, P=.08) as well as in homeostatic model assessments of insulin resistance (median −7.2% among subjects given metformin vs 38% increase among those given placebo, P=.06). Metformin had no effects on cell proliferation (based on assays for KI67) or apoptosis (based on levels of caspase 3).
Conclusions
In a chemoprevention trial of patients with BE, daily administration of metformin for 12 weeks, compared with placebo, did not cause major reductions in esophageal levels of pS6K1. Although metformin reduced serum levels of insulin and insulin resistance, it did not discernibly alter epithelial proliferation or apoptosis in esophageal tissues. These findings do not support metformin as a chemopreventive agent for BE-associated carcinogenesis.
doi:10.1016/j.cgh.2014.08.040
PMCID: PMC4362887  PMID: 25218668
HOMA-IR; diabetes drug; cancer development; tumorigenesis
8.  Associations between Environmental Exposures and Incident Colorectal Cancer by ESR2 Protein Expression Level in a Population-Based Cohort of Older Women 
Background
Cigarette smoking (smoking), hormone therapy (MHT), and folate intake (folate) are each thought to influence colorectal cancer (CRC) risk, but the underlying molecular mechanisms remain incompletely defined. Expression of estrogen receptor beta (ESR2) has been associated with CRC stage and survival.
Methods
In this prospective cohort study, we examined smoking, MHT, and folate -associated CRC risks by ESR2 protein expression level among participants in the Iowa Women’s Health Study (IWHS). Self-reported exposure variables were assessed at baseline. Archived, paraffin-embedded CRC tissue specimens were collected and evaluated for ESR2 protein expression by immunohistochemistry. Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs) for associations between smoking, MHT, or folate and ESR2-defined CRC subtypes.
Results
Informative environmental exposure and protein expression data were available for 491 incident CRC cases. Positive associations between ESR2-low and -high tumors and several smoking-related variables were noted, most prominently with average number of cigarettes per day (RR = 4.24; 95% CI = 1.81–9.91 for ESR2-low and RR=2.15; 95%CI=1.05–4.41 for ESR2-high for ≥40 cigarettes compared to non-smokers). For MHT, a statistically significant association with ESR2-low tumors was observed with longer duration of exposure (RR = 0.54; 95% CI = 0.26–1.13 for > 5 years compared to never use). No associations were found for folate.
Conclusions
In this study, smoking and MHT were associated with ESR2 expression patterns.
Impact
These data support possible heterogeneous effects from smoking and MHT on ERβ-related pathways of colorectal carcinogenesis in older women.
doi:10.1158/1055-9965.EPI-14-0756
PMCID: PMC4383694  PMID: 25650184
9.  Circulating Prostaglandin Biosynthesis in Colorectal Cancer and Potential Clinical Significance 
EBioMedicine  2015;2(2):165-171.
Background
Colorectal cancer (CRC) represents the third leading cause of cancer-related death in the United States. Lack of reliable biomarkers remains a critical issue for early detection of CRC. In this study, we investigated the potential predictive values of circulating prostaglandin (PG) biosynthesis in CRC risk.
Methods
Profiles of circulating PG biosynthesis and platelet counts were determined in healthy subjects (n = 16), familial adenomatous polyposis (FAP) patients who were classified as regular aspirin users (n = 14) or nonusers (n = 24), and CRC patients with (n = 18) or without FAP history (n = 20). Immunohistochemistry staining was performed on biopsy samples.
Results
Analysis of circulating PG biosynthesis unexpectedly revealed that CRC progression is accompanied by a pronounced elevation of circulating thromboxane A2 (TXA2) levels. When a circulating TXA2 level of 1000 pg/mL was selected as a practical cutoff point, 95% of CRC patients were successfully identified. Further study suggested that the TXA2 pathway is constitutively activated during colorectal tumorigenesis and required for anchorage-independent growth of colon cancer cells.
Conclusions
This study established the importance of the TXA2 pathway in CRC pathophysiology, and laid the groundwork for introducing a TXA2-targeting strategy to CRC prevention, early detection and management.
doi:10.1016/j.ebiom.2014.12.004
PMCID: PMC4347518  PMID: 25750933
colorectal cancer; familial adenomatous polyposis; thromboxane A2
10.  Association Between Molecular Subtypes of Colorectal Cancer and Patient Survival 
Gastroenterology  2014;148(1):77-87.e2.
Background and Aims.
Colorectal cancer (CRC) is a heterogeneous disease that can develop via several pathways. Different CRC subtypes, identified based on tumor markers, have been proposed to reflect these pathways. We evaluated the significance of these previously proposed classifications to survival.
Methods.
Participants in the population-based Seattle Colon Cancer Family Registry were diagnosed with invasive CRC from 1998 through 2007 in western Washington State (n=2706), and followed for survival through 2012. Tumor samples were collected from 2050 participants and classified into 5 subtypes based on combinations of tumor markers: type 1 (microsatellite instability [MSI] high, CpG island methylator phenotype [CIMP] positive, positive for BRAF mutation, negative for KRAS mutation); type 2 (microsatellite stable [MSS] or MSI-low, CIMP-positive, positive for BRAF mutation, negative for KRAS mutation); type 3 (MSS or MSI-low, non-CIMP, negative for BRAF mutation, positive for KRAS mutation); type 4 (MSS or MSI-low, non-CIMP, negative for mutations in BRAF and KRAS); and type 5 (MSI-high, non-CIMP, negative for mutations in BRAF and KRAS). Multiple imputation was used to impute tumor markers for those missing data on 1-3 markers. We used Cox regression to estimate hazard ratios (HR) and 95% confidence intervals (CI) for associations of subtypes with disease-specific and overall mortality, adjusting for age, sex, body mass, diagnosis year, and smoking history.
Results.
Compared to participants with type 4 tumors (the most predominant), participants with type 2 tumors had the highest disease-specific mortality (HR=2.20, 95% CI: 1.47-3.31); subjects with type 3 tumors also had higher disease-specific mortality (HR=1.32, 95% CI: 1.07-1.63). Subjects with type 5 tumors had the lowest disease-specific mortality (HR=0.30, 95% CI: 0.14-0.66). Associations with overall mortality were similar to those with disease-specific mortality.
Conclusions.
Based on a large, population-based study, CRC subtypes, defined by proposed etiologic pathways, are associated with marked differences in survival. These findings indicate the clinical importance of studies into the molecular heterogeneity of CRC.
doi:10.1053/j.gastro.2014.09.038
PMCID: PMC4274235  PMID: 25280443
oncogene; methylation; serrated colorectal cancer; prognostic factor
11.  Chemoprevention of colorectal cancer in individuals with previous colorectal neoplasia: systematic review and network meta-analysis 
The BMJ  2016;355:i6188.
Objective To assess the comparative efficacy and safety of candidate agents (low and high dose aspirin, non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), calcium, vitamin D, folic acid, alone or in combination) for prevention of advanced metachronous neoplasia (that is, occurring at different times after resection of initial neoplasia) in individuals with previous colorectal neoplasia, through a systematic review and network meta-analysis.
Data sources Medline, Embase, Web of Science, from inception to 15 October 2015; clinical trial registries.
Study selection Randomized controlled trials in adults with previous colorectal neoplasia, treated with candidate chemoprevention agents, and compared with placebo or another candidate agent. Primary efficacy outcome was risk of advanced metachronous neoplasia; safety outcome was serious adverse events.
Data extraction Two investigators identified studies and abstracted data. A Bayesian network meta-analysis was performed and relative ranking of agents was assessed with surface under the cumulative ranking (SUCRA) probabilities (ranging from 1, indicating that the treatment has a high likelihood to be best, to 0, indicating the treatment has a high likelihood to be worst). Quality of evidence was appraised with GRADE criteria.
Results 15 randomized controlled trials (12 234 patients) comparing 10 different strategies were included. Compared with placebo, non-aspirin NSAIDs were ranked best for preventing advanced metachronous neoplasia (odds ratio 0.37, 95% credible interval 0.24 to 0.53; SUCRA=0.98; high quality evidence), followed by low-dose aspirin (0.71, 0.41 to 1.23; SUCRA=0.67; low quality evidence). Low dose aspirin, however, was ranked the safest among chemoprevention agents (0.78, 0.43 to 1.38; SUCRA=0.84), whereas non-aspirin NSAIDs (1.23, 0.95 to 1.64; SUCRA=0.26) were ranked low for safety. High dose aspirin was comparable with low dose aspirin in efficacy (1.12, 0.59 to 2.10; SUCRA=0.58) but had an inferior safety profile (SUCRA=0.51). Efficacy of agents for reducing metachronous colorectal cancer could not be estimated.
Conclusions Among individuals with previous colorectal neoplasia, non-aspirin NSAIDs are the most effective agents for the prevention of advanced metachronous neoplasia, whereas low dose aspirin has the most favorable risk:benefit profile.
Registration PROSPERO (CRD42015029598).
doi:10.1136/bmj.i6188
PMCID: PMC5137632  PMID: 27919915
13.  Accuracy of urea breath test in Helicobacter pylori infection: Meta-analysis 
AIM: To quantitatively summarize and appraise the available evidence of urea breath test (UBT) use to diagnose Helicobacter pylori (H. pylori) infection in patients with dyspepsia and provide pooled diagnostic accuracy measures.
METHODS: We searched MEDLINE, EMBASE, Cochrane library and other databases for studies addressing the value of UBT in the diagnosis of H. pylori infection. We included cross-sectional studies that evaluated the diagnostic accuracy of UBT in adult patients with dyspeptic symptoms. Risk of bias was assessed using QUADAS (Quality Assessment of Diagnostic Accuracy Studies)-2 tool. Diagnostic accuracy measures were pooled using the random-effects model. Subgroup analysis was conducted by UBT type (13C vs 14C) and by measurement technique (Infrared spectrometry vs Isotope Ratio Mass Spectrometry).
RESULTS: Out of 1380 studies identified, only 23 met the eligibility criteria. Fourteen studies (61%) evaluated 13C UBT and 9 studies (39%) evaluated 14C UBT. There was significant variation in the type of reference standard tests used across studies.Pooled sensitivity was 0.96 (95%CI: 0.95-0.97) andpooled specificity was 0.93 (95%CI: 0.91-0.94). Likelihood ratio for a positive test was 12 and for a negative test was 0.05 with an area under thecurve of 0.985. Meta-analyses were associated with a significant statistical heterogeneity that remained unexplained after subgroup analysis. The included studies had a moderate risk of bias.
CONCLUSION: UBT has high diagnostic accuracy for detecting H. pylori infection in patients with dyspepsia. The reliability of diagnostic meta-analytic estimates however is limited by significant heterogeneity.
doi:10.3748/wjg.v21.i4.1305
PMCID: PMC4306177  PMID: 25632206
Helicobacter pylori; Dyspepsia; Breath tests; Urea/analysis; Diagnosis; Sensitivity; Specificity; Gastritis; Positive predictive value; Negative predictive value
14.  Cigarette Smoking and Colorectal Cancer Risk by KRAS Mutation Status Among Older Women 
OBJECTIVES
Existing data support a modest association between cigarette smoking and incident colorectal cancer (CRC) overall. In this study, we evaluated associations between cigarette smoking and CRC risk stratified by KRAS mutation status, using data and tissue resources from the Iowa Women’s Health Study (IWHS).
METHODS
The IWHS is a population-based cohort study of cancer incidence among 41,836 randomly selected Iowa women, ages 55–69 years of age at enrollment (1986). Exposure data, including cigarette smoking, were obtained by self-report at baseline. Incident CRCs (n = 1,233) were ascertained by annual linkage with the Iowa Cancer Registry. Archived tissue specimens from CRC cases recorded through 2002 were recently requested for molecular epidemiology investigations. Tumor KRAS mutation status was determined by direct sequencing of exon 2, with informative results in 507/555 (91%) available CRC cases (342 mutation negative and 165 mutation positive). Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs) for associations between cigarette smoking variables and KRAS-defined CRC subtypes.
RESULTS
Multiple smoking variables were associated with increased risk for KRAS mutation-negative tumors, including age at initiation (P = 0.02), average number of cigarettes per day (P = 0.01), cumulative pack-years (P = 0.05), and induction period (P = 0.04), with the highest point estimate observed for women who smoked ≥ 40 cigarettes per day on average (RR = 2.38; 95% CI = 1.25–4.51; compared with never smokers). Further consideration of CRC subsite suggested that cigarette smoking may be a stronger risk factor for KRAS mutation-negative tumors located in the proximal colon than in the distal colorectum. None of the smoking variables were significantly associated with KRAS mutation-positive CRCs (overall or stratified by anatomic subsite).
CONCLUSIONS
Data from this prospective study of older women demonstrate differential associations between cigarette smoking and CRC subtypes defined by KRAS mutation status, and are consistent with the hypothesis that smoking adversely affects the serrated pathway of colorectal carcinogenesis.
doi:10.1038/ajg.2012.21
PMCID: PMC3588167  PMID: 22349355
15.  Associations Between Colorectal Cancer Molecular Markers and Pathways With Clinicopathologic Features in Older Women 
Gastroenterology  2013;145(2):348-356.e2.
BACKGROUND & AIMS
Colorectal tumors have a large degree of molecular heterogeneity. Three integrated pathways of carcinogenesis (ie, traditional, alternate, and serrated) have been proposed, based on specific combinations of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in BRAF and KRAS. We used resources from the population-based Iowa Women’s Health Study (n = 41,836) to associate markers of colorectal tumors, integrated pathways, and clinical and pathology characteristics, including survival times.
METHODS
We assessed archived specimens from 732 incident colorectal tumors and characterized them as microsatellite stable (MSS), MSI high or MSI low, CIMP high or CIMP low, CIMP negative, and positive or negative for BRAF and/or KRAS mutations. Informative marker data were collected from 563 tumors (77%), which were assigned to the following integrated pathways: traditional (MSS, CIMP negative, BRAF mutation negative, and KRAS mutation negative; n = 170), alternate (MSS, CIMP low, BRAF mutation negative, and KRAS mutation positive; n = 58), serrated (any MSI, CIMP high, BRAF mutation positive, and KRAS mutation negative; n = 142), or unassigned (n = 193). Multivariable-adjusted Cox proportional hazards regression models were used to assess the associations of interest.
RESULTS
Patients’ mean age (P = .03) and tumors’ anatomic subsite (P = .0001) and grade (P = .0001) were significantly associated with integrated pathway assignment. Colorectal cancer (CRC) mortality was not associated with the traditional, alternate, or serrated pathways, but was associated with a subset of pathway-unassigned tumors (MSS or MSI low, CIMP negative, BRAF mutation negative, and KRAS mutation positive) (n = 96 cases; relative risk = 1.76; 95% confidence interval, 1.07–2.89, compared with the traditional pathway).
CONCLUSIONS
We identified clinical and pathology features associated with molecularly defined CRC subtypes. However, additional studies are needed to determine how these features might influence prognosis.
doi:10.1053/j.gastro.2013.05.001
PMCID: PMC3772766  PMID: 23665275
Molecular Epidemiology; Colon Cancer; Prognostic Factor; Integrated Pathways
16.  Patient and Tumor Characteristics and BRAF and KRAS Mutations in Colon Cancer, NCCTG/Alliance N0147 
Background
KRAS and BRAF V600E mutations are important predictive and prognostic markers, respectively, in colon cancer, but little is known about patient and clinical factors associated with them.
Methods
Two thousand three hundred twenty-six of 3397 patients in the N0147 phase III adjuvant trial for stage III colon cancer completed a patient questionnaire. Primary tumors were assessed for KRAS and BRAF V600E mutations and defective mismatch repair (dMMR) status. Logistic regression models and categorical data analysis were used to identify associations of patient and tumor characteristics with mutation status. All statistical tests were two-sided.
Results
KRAS (35%) and BRAF V600E (14%) mutations were nearly mutually exclusive. KRAS mutations were more likely to be present in patients without a family history of colon cancer and never smokers. Tumors with KRAS mutations were less likely to have dMMR (odds ratio [OR] = 0.21; 95% confidence interval [CI] = 0.15 to 0.31; P < .001) and high-grade histology (OR = 0.73; 95% CI = 0.59 to 0.92; P < .001) but were more often right-sided. Among KRAS-mutated tumors, those with a Gly13Asp mutation tended to have dMMR and high-grade histology. Tumors with BRAF V600E mutations were more likely to be seen in patients who were aged 70 years or older (OR = 3.33; 95% CI = 2.50 to 4.42; P < .001) and current or former smokers (OR = 1.64; 95% CI = 1.26 to 2.14; P < .001) but less likely in non-whites and men. Tumors with BRAF V600E mutations were more likely to be right-sided and to have four or more positive lymph nodes, high-grade histology, and dMMR.
Conclusions
Specific patient and tumor characteristics are associated with KRAS and BRAF V600E mutations.
doi:10.1093/jnci/dju106
PMCID: PMC4110470  PMID: 24925349
17.  Associations Between Cigarette Smoking Status and Colon Cancer Prognosis Among Participants in North Central Cancer Treatment Group Phase III Trial N0147 
Journal of Clinical Oncology  2013;31(16):2016-2023.
Purpose
By using data from North Central Cancer Treatment Group Phase III Trial N0147, a randomized adjuvant trial of patients with stage III colon cancer, we assessed the relationship between smoking and cancer outcomes, disease-free survival (DFS), and time to recurrence (TTR), accounting for heterogeneity by patient and tumor characteristics.
Patients and Methods
Before random assignment to infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or FOLFOX plus cetuximab, 1,968 participants completed a questionnaire on smoking history and other risk factors. Cox models assessed the association between smoking history and the primary trial outcome of DFS (ie, time to recurrence or death), as well as TTR, adjusting for other clinical and patient factors. The median follow-up was 3.5 years among patients who did not experience events.
Results
Compared with never-smokers, ever smokers experienced significantly shorter DFS (3-year DFS proportion: 70% v 74%; hazard ratio [HR], 1.21; 95% CI, 1.02 to 1.42). This association persisted after multivariate adjustment (HR, 1.23; 95% CI, 1.02 to 1.49). There was significant interaction in this association by BRAF mutation status (P = .03): smoking was associated with shorter DFS in patients with BRAF wild-type (HR, 1.36; 95% CI, 1.11 to 1.66) but not BRAF mutated (HR, 0.80; 95% CI, 0.50 to 1.29) colon cancer. Smoking was more strongly associated with poorer DFS in those with KRAS mutated versus KRAS wild-type colon cancer (HR, 1.50 [95% CI, 1.12 to 2.00] v HR, 1.09 [95% CI, 0.85 to 1.39]), although interaction by KRAS mutation status was not statistically significant (P = .07). Associations were comparable in analyses of TTR.
Conclusion
Overall, smoking was significantly associated with shorter DFS and TTR in patients with colon cancer. These adverse relationships were most evident in patients with BRAF wild-type or KRAS mutated colon cancer.
doi:10.1200/JCO.2012.46.2457
PMCID: PMC3661936  PMID: 23547084
18.  Young-Onset Colorectal Cancer in Patients With No Known Genetic Predisposition 
Medicine  2008;87(5):259-263.
Early recognition of colorectal cancer (CRC) in young patients without known genetic predisposition is a challenge, and clinicopathologic features at time of presentation are not well described. We conducted the current study to review these features in a large population of patients with young-onset CRC (initial diagnosis at age ≤50 yr without established risk factors).
We reviewed the records of all patients aged 50 years or younger diagnosed with a primary CRC at our institution between 1976 and 2002. Patients with inflammatory bowel disease, polyposis syndromes, or a known genetic predisposition for CRC were excluded. Data regarding clinical and pathologic features at time of initial presentation were abstracted by trained personnel.
We identified 1025 patients, 585 male. Mean age at presentation was 42.4 years (standard deviation 6.4). Eight hundred eighty-six (86%) patients were symptomatic at time of diagnosis. Clinical features in symptomatic patients included rectal bleeding (51%), change in bowel habits (18%), abdominal pain (32%), weight loss (13%), nausea/vomiting (7%), melena (2%), and other (26%). Evaluation of asymptomatic patients was pursued with findings of anemia (14%), positive fecal occult blood test (7%), abdominal mass (2%), mass on digital rectal exam (2%), and other (80%). Site of primary tumor was colonic in 51% and rectal in 49%. Synchronous malignant lesions were noted in 1%. Mucinous and signet cell histology was seen in 11% and 2%, respectively. Tumor grade distribution was grade 1 (2%), grade 2 (54%), grade 3 (34%), and grade 4 (7%). The stage distribution was stage I (13%), stage II (21%), stage III (32%), and stage IV (34%).
To our knowledge, the current study is the largest cohort of young-onset CRC patients with no known genetic predisposition for disease. Most patients were symptomatic, had left-colon or rectal cancers and presented with more advanced stage disease. Our findings should promote increased awareness and the aggressive pursuit of symptoms in otherwise young, low-risk patients, as these symptoms may represent an underlying colorectal malignancy.
doi:10.1097/MD.0b013e3181881354
PMCID: PMC4437192  PMID: 18794708
19.  Randomized Phase II Trial of Sulindac for Lung Cancer Chemoprevention 
Introduction
Sulindac represents a promising candidate agent for lung cancer chemoprevention, but clinical trial data have not been previously reported. We conducted a randomized, phase II chemoprevention trial involving current or former cigarette smokers (≥ 30 pack-years) utilizing the multi-center, inter-disciplinary infrastructure of the Cancer Prevention Network (CPN).
Methods
At least 1 bronchial dysplastic lesion identified by fluorescence bronchoscopy was required for randomization. Intervention assignments were sulindac 150 mg bid or an identical placebo bid for six months. Trial endpoints included changes in histologic grade of dysplasia (per-participant as primary endpoint and per lesion as secondary endpoint), number of dysplastic lesions (per-participant), and Ki67 labeling index.
Results
Slower than anticipated recruitment led to trial closure after randomizing participants (n = 31 and n = 30 in the sulindac and placebo arms, respectively). Pre- and post-intervention fluorescence bronchoscopy data were available for 53/61 (87%) randomized, eligible participants. The median (range) of dysplastic lesions at baseline was 2 (1-12) in the sulindac arm and 2 (1-7) in the placebo arm. Change in dysplasia was categorized as regression:stable:progression for 15:3:8 (58%:12%:31%) subjects in the sulindac arm and 15:2:10 (56%:7%:37%) subjects in the placebo arm; these distributions were not statistically different (p=0.85). Median Ki67 expression (% cells stained positive) was significantly reduced in both the placebo (30 versus 5; p = 0.0005) and sulindac (30 versus 10; p = 0.0003) arms, but the difference between arms was not statistically significant (p = 0.92).
Conclusions
Data from this multi-center, phase II squamous cell lung cancer chemoprevention trial do not demonstrate sufficient benefits from sulindac 150 mg bid for 6 months to warrant additional phase III testing. Investigation of pathway-focused agents is necessary for lung cancer chemoprevention.
doi:10.1016/j.lungcan.2012.11.011
PMCID: PMC3566344  PMID: 23261228
lung cancer; chemoprevention; phase II clinical trial; sulindac; NSAIDs
20.  Aspirin Prevents Colorectal Cancer by Normalizing EGFR Expression 
EBioMedicine  2015;2(5):447-455.
Background
Aspirin intake reduces the risk of colorectal cancer (CRC), but the molecular underpinnings remain elusive. Epidermal growth factor receptor (EGFR), which is overexpressed in about 80% of CRC cases, is implicated in the etiology of CRC. Here, we investigated whether aspirin can prevent CRC by normalizing EGFR expression.
Methods
Immunohistochemistry staining was performed on paraffin-embedded tissue sections from normal colon mucosa, adenomatous polyps from FAP patients who were classified as regular aspirin users or nonusers. The interplay between cyclooxygenase-2 (COX-2) and EGFR was studied in primary intestinal epithelial cells isolated from ApcMin mice, immortalized normal human colon epithelial cells (HCECs) as well as murine embryonic fibroblasts (MEFs).
Results
Immunohistochemistry staining results established that EGFR overexpression is an early event in colorectal tumorigenesis, which can be greatly attenuated by regular use of aspirin. Importantly, EGFR and COX-2 were co-overexpressed and co-localized with each other in FAP patients. Further mechanistic studies revealed that COX-2 overexpression triggers the activation of the c-Jun-dependent transcription factor, activator protein-1 (AP-1), which binds to the Egfr promoter. Binding facilitates the cellular accumulation of EGFR and lowers the threshold required for pre-neoplastic cells to undergo transformation.
Conclusion
Aspirin might exert its chemopreventive activity against CRC, at least partially, by normalizing EGFR expression in gastrointestinal precancerous lesions.
Highlights
•CRC progression is accompanied by an elevation in EGFR levels, which can be attenuated by aspirin intake.•The widespread overexpression of EGFR occurs as a consequence of COX-2 activation in FAP patients.•This study revealed a functional association between COX-2 and EGFR expression during colorectal carcinogenesis.
doi:10.1016/j.ebiom.2015.03.019
PMCID: PMC4469241  PMID: 26097892
CRC, colorectal cancer; FAP, familial adenomatous polyposis; EGFR, epidermal growth factor receptor; COX-2, cyclooxygenase-2; PGs, prostaglandins; Colorectal cancer; Familial adenomatous polyposis; Epidermal growth factor receptor; Cyclooxygenase-2
21.  Sensitivity of CT Colonography for the Detection of Non-polypoid Adenomas Using Restricted Criteria in the National CT Colonography Trial 
AJR. American journal of roentgenology  2014;203(6):W614-W622.
OBJECTIVE
To determine the prevalence and sensitivity of CT Colonography (CTC) in the detection of non-polypoid adenomas using restricted criteria of height:width ratio of <50% and height elevation of ≤3mm.
MATERIAL AND METHODS
In ACRIN 6664, an institutional review board-approved, HIPAA-compliant study, a cohort of 2531 asymptomatic participants underwent CTC and screening colonoscopy. The CTC exams were interpreted by both two-dimensional and three-dimensional techniques. Non-polypoid adenomatous polyps identified by CTC or colonoscopy were retrospectively reviewed to determine which polyps met the restricted criteria. The prevalence of non-polypoid adenomas and prospective sensitivity of CTC were determined. Descriptive statistics are used to report the prevalence, size, and histology. Sensitivities for the non-polypoid (with 95% CIs) and polypoid lesions are compared with a two-sided Z test for two independent binomial proportions.
RESULTS
The retrospective review confirmed 21 non-polypoid adenomas, yielding a prevalence of 0.83% (21/2531 participants). 8 (38.1%) were advanced adenomas, many (50%, 4/8) secondary to large size (≥10mm) only. The overall per polyp sensitivity of CTC (combined 2D and 3D interpretation) for detecting non-polypoid adenomas ≥ 5mm (n=21), ≥ 6mm (n=16) and ≥10mm (n=5) were 0.76, 0.75, and 0.80, respectively, which was not statistically different from the sensitivity of detecting polypoid adenomas (p>0.37).
CONCLUSION
In this large screening population, non-polypoid adenomas had a very low prevalence (<1%), and advanced pathologic features were uncommon in polyps <10mm in diameter. The majority of non-polypoid adenomas are technically visible at CTC, with prospective sensitivities similar to polypoid adenomas using an interpretation approach combining both two-dimensional and three-dimensional review.
doi:10.2214/AJR.13.12356
PMCID: PMC4312488  PMID: 25415726
22.  Circulating Prostaglandin Biosynthesis in Colorectal Cancer and Potential Clinical Significance☆☆☆★ 
EBioMedicine  2014;2(2):165-171.
Background
Colorectal cancer (CRC) represents the third leading cause of cancer-related death in the United States. Lack of reliable biomarkers remains a critical issue for early detection of CRC. In this study, we investigated the potential predictive values of circulating prostaglandin (PG) biosynthesis in CRC risk.
Methods
Profiles of circulating PG biosynthesis and platelet counts were determined in healthy subjects (n = 16), familial adenomatous polyposis (FAP) patients who were classified as regular aspirin users (n = 14) or nonusers (n = 24), and CRC patients with (n = 18) or without FAP history (n = 20). Immunohistochemistry staining was performed on biopsy samples.
Results
Analysis of circulating PG biosynthesis unexpectedly revealed that CRC progression is accompanied by a pronounced elevation of circulating thromboxane A2 (TXA2) levels. When a circulating TXA2 level of 1000 pg/mL was selected as a practical cutoff point, 95% of CRC patients were successfully identified. Further study suggested that the TXA2 pathway is constitutively activated during colorectal tumorigenesis and required for anchorage-independent growth of colon cancer cells.
Conclusions
This study established the importance of the TXA2 pathway in CRC pathophysiology, and laid the groundwork for introducing a TXA2-targeting strategy to CRC prevention, early detection and management.
Highlights
•CRC progression is associated with higher circulating TXA2 levels, which merits investigation as a predictor of CRC risk.•TXA2 pathway is constitutively activated during colorectal tumorigenesis.•TXA2 pathway is required for anchorage-independent growth of colon cancer cells.•This study lays the groundwork for introducing a TXA2-targeting strategy to CRC prevention, early detection and management.
doi:10.1016/j.ebiom.2014.12.004
PMCID: PMC4347518  PMID: 25750933
CRC, colorectal cancer; FAP, familial adenomatous polyposis; PGs, prostaglandins; TXA2, thromboxane A2; mPGES1, microsomal prostaglandin E synthase-1; TBXAS1, thromboxane A2 synthase 1; TBXA2R, thromboxane A2 receptor; Colorectal cancer; Familial adenomatous polyposis; Thromboxane A2
23.  Postmenopausal hormone therapy and colorectal cancer risk by molecularly defined subtypes among older women 
Gut  2011;61(9):1299-1305.
Background
Postmenopausal hormone (PMH) therapy may reduce colorectal cancer (CRC) risk, but existing data are inconclusive.
Objectives
To evaluate associations between PMH therapy and incident CRC, overall and by molecularly defined subtypes, in the population-based Iowa Women’s Health Study of older women.
Methods
Exposure data were collected from Iowa Women’s Health Study participants (55–69 years) at baseline (1986). Archived, paraffin-embedded tissue specimens for 553 CRC cases were collected and analysed to determine microsatellite instability (MSI-L/MSS or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive) and BRAF mutation (BRAF-wildtype or BRAF-mutated) status. Multivariable Cox regression models were fit to estimate RRs and 95% CIs.
Results
PMH therapy (ever vs never use) was inversely associated with incident CRC overall (RR=0.82; 95% CI 0.72 to 0.93), with a significantly lower risk for MSI-L/MSS tumours (RR=0.75; 95% CI 0.60 to 0.94), and borderline significantly lower risks for CIMP-negative (RR=0.79; 95% CI 0.63 to 1.01) and BRAF-wildtype (RR=0.83; 95% CI 0.66 to 1.04) tumours. For PMH therapy >5 years, the subtype-specific risk estimates for MSI-L/MSS, CIMP-negative and BRAF-wildtype tumours were: RR=0.60, 95% CI 0.40 to 0.91; RR=0.68, 95% CI 0.45 to 1.03; and RR=0.70, 95% CI 0.47 to 1.05, respectively. PMH therapy was not significantly associated with the MSI-H, CIMP-positive or BRAF-mutated CRC subtypes.
Conclusions
In this prospective cohort study, PMH therapy was inversely associated with distinct molecularly defined CRC subtypes, which may be related to differential effects from oestrogen and/or progestin on heterogeneous pathways of colorectal carcinogenesis.
doi:10.1136/gutjnl-2011-300719
PMCID: PMC3584677  PMID: 22027477
24.  Alcohol Intake and Colorectal Cancer Risk by Molecularly-Defined Subtypes in a Prospective Study of Older Women 
Increased alcohol consumption is a putative colorectal cancer (CRC) risk factor. However, existing data are less conclusive for women than men. Also, to date, relatively few studies have reported alcohol-related CRC risks based on molecularly-defined tumor subtypes. We evaluated associations between alcohol intake and incident CRC, overall and by microsatellite instability (MSI-H or MSI-L/MSS), CpG island methylator phenotype (CIMP-positive or CIMP-negative) and BRAF mutation (mutated or wild-type) status in the prospective, population-based Iowa Women's Health Study (IWHS; n = 41,836). Subjects were 55–69 years at baseline (1986) and exposure data were obtained by self-report. Incident CRCs were prospectively identified and archived, paraffin-embedded tissue specimens were collected from 732 representative cases, diagnosed through December 31, 2002. Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Among alcohol consumers, the median intake (range) was 3.4 (0.9–292.8) g/day. Compared to non-consumers, alcohol intake levels of ≤ 3.4 g/day (RR = 1.00; 95% CI = 0.86–1.15) and > 3.4 g/d (RR = 1.06; 95% CI = 0.91–1.24) were not significantly associated with overall CRC risk. Analyses based on alcohol intake levels of ≤ 30 g/d and > 30 g/d or quartile distributions yielded similar risk estimates. Null associations were also observed between each alcohol intake level and the MSI-, CIMP- or BRAF-defined CRC subtypes (p > 0.05 for each comparison). These data do not support an adverse effect from alcohol intake on CRC risk, overall or by specific molecularly-defined subtypes, among older women.
doi:10.1158/1940-6207.CAPR-11-0276
PMCID: PMC3584678  PMID: 21900595
Colorectal Cancer; Alcohol; Older Women; Cohort Study
25.  Associations Between Intake of Folate and Related Micronutrients with Molecularly Defined Colorectal Cancer Risks in the Iowa Women’s Health Study 
Nutrition and cancer  2012;64(7):899-910.
Folate and related micronturients may affect colorectal cancer (CRC) risk, but the molecular mechanism(s) remain incompletely defined. We analyzed associations between dietary folate, vitamin B6, vitamin B12 and methionine with incident CRC, overall and by microsatellite instability (MSS/MSI-L or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive), BRAF mutation (negative or positive), and KRAS mutation (negative or positive) status in the prospective, population-based Iowa Women’s Health Study (IWHS; 55–69 years at baseline; n = 41,836). Intake estimates were obtained from baseline, self-reported food frequency questionnaires. Molecular marker data were obtained for 514 incident CRC cases. Folate intake was inversely associated with overall CRC risk in age-adjusted Cox regression models, while methionine intake was inversely associated with overall CRC risk in multivariable-adjusted models (RR = 0.81; 95% CI = 0.69–0.95; p trend = 0.001 and RR = 0.72; 95% CI = 0.54–0.96; p trend = 0.03 for highest versus lowest quartiles, respectively). None of the dietary exposures were associated with MSI, CIMP, BRAF, or KRAS defined CRC subtypes. These data provide minimal support for major effects from the examined micronutrients on overall or molecularly defined CRC risks in the IWHS cohort.
doi:10.1080/01635581.2012.714833
PMCID: PMC3584680  PMID: 23061900
Colorectal Cancer; Alcohol; Older Women; Cohort Study

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