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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.

Inflammation plays a major role in colon carcinogenesis. Endogenously produced specialized proresolving lipid mediators (SPMs) play a central role in inflammation and tissue homeostasis, and have been implicated in carcinogenesis. We studied the associations of plasma levels of two SPMs [lipoxin A4 (LXA4 ) and resolvin D1(RvD1)] with risk for recurrent adenoma. In this pilot study, we used data and biosamples from an adenoma chemoprevention study investigating the effects of aspirin and/or folic acid on the occurrence of colorectal adenomas. In the parent study, 1121 participants with a recent adenoma were randomized to study agents to be taken until the next surveillance colonoscopy about 3 years later. In this pilot study, LXA4 and RvD1 from samples taken near the end of study treatment were measured in a randomly selected sub-set of 200 participants. Commercially available ELISA kits to assay the analytes were validated using a metabololipidomic LC-MS/MS assay. Poisson regression with a robust error variance was used to calculate risk ratios and 95% confidence intervals. Plasma LXA4 and RvD1 were not associated with the risk of adenoma occurrence. LXA4 at the end of study follow-up was 32% (P = 0.01) proportionately higher in women compared to men. A similar non-significant trend toward higher levels among women was observed for RvD1. Our preliminary findings provided no evidence that plasma LXA4 or RvD1 are associated with reduced risk of colorectal adenoma occurrence, but suggest LXA4 may differ among men and women. Future studies focusing on SPM's local effects and levels in the colon are needed.

Colorectal cancer (CRC) is one of the most common malignancies in the United States. Every 3 years, the American Cancer Society provides an update of CRC incidence, survival, and mortality rates and trends. Incidence data through 2013 were provided by the Surveillance, Epidemiology, and End Results program, the National Program of Cancer Registries, and the North American Association of Central Cancer Registries. Mortality data through 2014 were provided by the National Center for Health Statistics. CRC incidence rates are highest in Alaska Natives and blacks and lowest in Asian/Pacific Islanders, and they are 30% to 40% higher in men than in women. Recent temporal patterns are generally similar by race and sex, but differ by age. Between 2000 and 2013, incidence rates in adults aged ≥50 years declined by 32%, with the drop largest for distal tumors in people aged ≥65 years (incidence rate ratio [IRR], 0.50; 95% confidence interval [95% CI], 0.48-0.52) and smallest for rectal tumors in ages 50 to 64 years (male IRR, 0.91; 95% CI, 0.85-0.96; female IRR, 1.00; 95% CI, 0.93-1.08). Overall CRC incidence in individuals ages ≥50 years declined from 2009 to 2013 in every state except Arkansas, with the decrease exceeding 5% annually in 7 states; however, rectal tumor incidence in those ages 50 to 64 years was stable in most states. Among adults aged

Key Points Question What is the increase in the colorectal cancer incidence rate from 49 to 50 years of age when large segments of the population begin average-risk screening? Findings This cross-sectional analysis of colorectal cancer incidence rates in 1-year age increments (30-60 years) from 2000 to 2015 in the Surveillance, Epidemiology, and End Results 18 registries found an incidence rate increase of 46.1% from 49 to 50 years of age. A total of 92.9% of the cases of colorectal cancer diagnosed at 50 years of age were invasive (beyond in situ stage). Meaning Steep incidence increases from 49 to 50 years of age are consistent with preexisting colorectal cancers diagnosed via screening uptake, supporting the presence of a large undetected preclinical case burden in patients younger than 50 years that is not reflected in observed Surveillance, Epidemiology, and End Results incidence rates., Importance Early-onset colorectal cancer incidence rates among patients aged 45 to 49 years have been considered much lower compared with the rates among patients aged 50 to 54 years, prompting debate about earlier screening benefits at 45 years. However, the observed incidence rates in the Surveillance, Epidemiology, and End Results (SEER) registries may underestimate colorectal cancer case burdens in those younger than 50 years compared with those older than 50 years because average-risk screening is generally not performed to detect preclinical cases of colorectal cancer. Finding steep incidence increases of invasive stage (beyond in situ) cases of colorectal cancer from age 49 to 50 years would be consistent with high rates of preexisting, undetected cancers in younger patients ultimately receiving a diagnosis of colorectal cancer after undergoing screening at 50 years. Objective To assess the preclinical burden of colorectal cancer by analyzing its incidence in 1-year age increments, focusing on the transition between ages 49 and 50 years. Design, Setting, and Participants Data from the SEER 18 registries, representing 28% of the US population, were used to conduct a cross-sectional study of colorectal cancer incidence rates from January 1, 2000, to December 31, 2015, in 1-year age increments (ages 30-60 years) stratified by US region (South, West, Northeast, and Midwest), sex, race, disease stage, and tumor location. Statistical analysis was conducted from November 1, 2018, to December 15, 2019. Main Outcomes and Measures Incidence rates of colorectal cancer. Results A total of 170 434 cases of colorectal cancer were analyzed among 165 160 patients (92 247 men [55.9%]; mean [SD] age, 51.6 [6.7] years). Steep increases in the incidence of colorectal cancer in the SEER 18 registries were found from 49 to 50 years of age (46.1% increase: 34.9 [95% CI, 34.1-35.8] to 51.0 [95% CI, 50.0-52.1] per 100 000 population). Steep rate increases from 49 to 50 years of age were also seen in all US regions, men and women, white and black populations, and in colon and rectal cancers. The rate ratio incidence increase in the SEER 18 registries from 49 to 50 years of age (1.46 [95% CI, 1.43-1.51]) was significantly higher than earlier 1-year age transitions. Steep rate increases in the SEER 18 registries were found from 49 to 50 years of age in localized-stage (75.9% increase: 11.2 [95% CI, 10.7-11.7] to 19.7 [95% CI, 19.0-20.3] per 100 000) and regional-stage (30.3% increase: 13.2 [95% CI, 12.7-13.8] to 17.2 [95% CI, 16.7-17.8] per 100 000) colorectal cancers. A total of 8799 of the 9474 cases (92.9%) of colorectal cancer in the SEER 18 registries from 2000 to 2015 that were diagnosed among individuals aged 50 years were invasive. Conclusions and Relevance Steep incidence increases between 49 and 50 years of age are consistent with previously undetected colorectal cancers diagnosed via screening uptake at 50 years. These cancers are not reflected in observed rates of colorectal cancer in the SEER registries among individuals younger than 50 years. Hence, using observed incidence rates from 45 to 49 years of age alone to assess potential outcomes of earlier screening may underestimate cancer prevention benefits., This cross-sectional study uses data from the Surveillance, Epidemiology, and End Results registries to assess the preclinical burden of colorectal cancer by analyzing its incidence in 1-year age increments, focusing on the transition between 49 and 50 years of age.

Background Current recommendations of The US Preventive Services Task Force (USPSTF) on colorectal cancer (CRC) screening strategies are based on models that assume 100% adherence to screening. Since adherence can largely affect the outcomes of a screening modality, we aimed to assess the comparative effectiveness of CRC screening strategies under published rates of actual adherence. Methods We developed an individual-level simulation model and validated it against landmark trials and USPSTF models. Then we assessed the effectiveness of colonoscopy (COL), flexible sigmoidoscopy (FS), high-sensitivity guaiac fecal occult blood test (HS-gFOBT), fecal immunochemical test (FIT), multitarget stool DNA test (FIT-DNA), computed tomography colonography (CTC), and methylated SEPT9 DNA test (SEPT9) in reducing CRC incidence and mortality. For each strategy, we also estimated the incremental life-years gained, number of colonoscopies, and adverse events. Results Assuming 100% adherence, FIT-DNA, FIT, HS-gFOBT, and SEPT9 averted 58 to 59 CRC cases and 28 CRC deaths; COL and CTC strategies 56 cases and 27 deaths, while FS averted 39 cases and 19 deaths per 1,000 individuals. Life-years gained were similar across FIT-DNA, FIT, HS-gFOBT, SEPT9, CTC, and COL strategies. The total number of colonoscopies was highest with COL (3,567), followed by SEPT9 (3,231), HS-gFOBT (2,584), FIT-DNA (2,079), FIT (2,067), CTC (1,691) and FS (1,538) strategies. Assuming actual adherence, SEPT9 averted 54 CRC cases and 26 CRC deaths, followed by COL with 49 cases and 24 deaths, and FIT-DNA, FIT, CTC and HS-gFOBT with approximately 36 to 41 cases and 18 to 21 deaths averted per 1000 individuals screened. Life-years gained reflected the effectiveness of each strategy in reducing CRC cases and deaths. Conclusions Adherence is a key factor in determining the effectiveness of CRC screening and strategies with higher expected adherence rates have the potential to reduce cancer incidence and mortality. Key messages Adherence has a substantial impact on screening outcomes, such as cancer incidence and mortality, and may influence selection of optimal screening strategies. Strategies with higher expected adherence rates can lead to clinically meaningful benefits compared to strategies that may have better one-time sensitivity and/or specificity.

Current recommendations of The US Preventive Services Task Force (USPSTF) on colorectal cancer (CRC) screening strategies are based on models that assume 100% adherence. Since adherence can have a large effect on screening outcomes, we aimed to compare the effectiveness of CRC screening strategies under reported adherence rates at the population level. We developed and validated a microsimulation model to assess the effectiveness of colonoscopy (COL), flexible sigmoidoscopy (FS), high‐sensitivity guaiac fecal occult blood‐test (HS‐gFOBT), fecal immunochemical test (FIT), multitarget stool DNA test (FIT‐DNA), computed tomography colonography (CTC), and methylated SEPT9 DNA test (SEPT9) in terms of CRC incidence and mortality, incremental life years gained (LYG), number of colonoscopies, and adverse events for men and women 50 years or older over their lifetime. We assessed outcomes under 100% adherence rates and reported adherence rates. We also performed sensitivity analyses to evaluate the impact of varying adherence levels on CRC outcomes. Assuming 100% adherence, FIT‐DNA, FIT, HS‐gFOBT, and SEPT9 averted 42‐45 CRC cases and 25‐26 CRC deaths, COL 46 cases and 26 deaths, CTC 39 cases and 23 deaths, FS 32 cases and 19 deaths per 1000 individuals. Assuming reported adherence, SEPT9 averted 37 CRC cases and 23 CRC deaths, COL 34 cases and 20 deaths, FIT‐DNA, FIT, CTC and HS‐gFOBT 16‐25 cases and 10‐16 deaths per 1000 individuals. LYG reflected the effectiveness of each strategy in reducing CRC cases and deaths. Adverse events were more common for COL (3.7 per 1000 screened) and annual SEPT9 (3.4 per 1000 screened), and proportional to the number of colonoscopies. Among the screening strategies recommended by USPSTF, colonoscopy results in the largest benefit when we account for adherence. Adherence rates higher than 65%‐70% would be required for any stool or blood‐based screening modality to match the benefits of colonoscopy., Although adherence to colorectal cancer screening has a substantial impact on clinical outcomes, estimating the magnitude of this impact has been challenging. This study provides a quantitative analysis of the extent to which differences in adherence rates affect clinical outcomes of different screening strategies. We found that higher adherence can lead to meaningful benefits when compared to strategies with better one‐time sensitivity and/or specificity, but lower adherence rates. This is relevant for optimizing screening strategies when considering other factors in addition to test performance, such as access to screening and patient behavior.

Cancer is fundamentally a genetic disease caused by mutational or epigenetic alterations in DNA. There has been a remarkable expansion of the molecular understanding of colonic carcinogenesis in the last 30 years and that understanding is changing many aspects of colorectal cancer care. It is becoming increasingly clear that there are genetic subsets of colorectal cancer that have different risk factors, prognosis, and response to treatment. This article provides a general update on colorectal cancer and highlights the ways that genetics is changing clinical care.

Persons with a family history (FH) of colorectal cancer (CRC) or adenomas that are not due to known hereditary syndromes have an increased risk for CRC. An understanding of these risks, screening recommendations, and screening behaviors can inform strategies for reducing the CRC burden in these families. A comprehensive review of the literature published within the past 10 years has been performed to assess what is known about cancer risk, screening guidelines, adherence and barriers to screening, and effective interventions in persons with an FH of CRC and to identify FH tools used to identify these individuals and inform care. Existing data show that having 1 affected first-degree relative (FDR) increases the CRC risk 2-fold, and the risk increases with multiple affected FDRs and a younger age at diagnosis. There is variability in screening recommendations across consensus guidelines. Screening adherence is

Individuals diagnosed with colorectal cancer (CRC) are at risk of developing a metachronous CRC. We examined the associations between personal, tumour-related and lifestyle risk factors, and risk of metachronous CRC. A total of 7,863 participants with incident colon or rectal cancer who were recruited in the USA, Canada and Australia to the Colon Cancer Family Registry during 1997-2012, except those identified as high-risk, for example, Lynch syndrome, were followed up approximately every 5 years. We estimated the risk of metachronous CRC, defined as the first new primary CRC following an interval of at least one year after the initial CRC diagnosis. Observation time started at the age at diagnosis of the initial CRC and ended at the age at diagnosis of the metachronous CRC, last contact or death whichever occurred earliest, or were censored at the age at diagnosis of any metachronous colorectal adenoma. Cox regression was used to derive hazard ratios (HRs) and 95% confidence intervals (CIs). During a mean follow-up of 6.6 years, 142 (1.81%) metachronous CRCs were diagnosed (mean age at diagnosis 59.8; incidence 2.7/1,000 person-years). An increased risk of metachronous CRC was associated with the presence of a synchronous CRC (HR = 2.73; 95% CI: 1.30-5.72) and the location of cancer in the proximal colon at initial diagnosis (compared with distal colon or rectum, HR = 4.16; 95% CI: 2.80-6.18). The presence of a synchronous CRC and the location of the initial CRC might be useful for deciding the intensity of surveillance colonoscopy for individuals diagnosed with CRC.

Background: Visceral adiposity is a risk factor for colorectal adenomas, and aspirin is an established chemopreventive agent. Evidence from clinical trials suggests the effectiveness of aspirin at preventing cardiovascular disease and cancer may require higher doses for higher body weight. Methods: Body mass index, body surface area, fat-free mass, and fat mass were calculated from baseline height and weight in 1,121 participants of the Aspirin/Folate Polyp Prevention Study, a double-blind, placebo-controlled, 3 × 2 factorial randomized clinical trial of low-dose (81 mg/day) or high-dose (325 mg/day) aspirin and/or 1 mg/day folic acid to prevent metachronous colorectal adenomas. Participants were treated during a surveillance colonoscopy interval of approximately 3 years. Risk ratios (RR) with 95% confidence intervals (CI) for any colorectal neoplasia and high-risk adenoma (HRA, advanced or ≥3 adenomas) were estimated from log-linear regression. Results: We did not find evidence to suggest aspirin dose-response differed by body composition measurements, including weight alone. Among those weighing ≥ 80 kg, treatment effects for low-dose aspirin (RR for colorectal neoplasia, 0.75; 95% CI, 0.60–0.94; RR for HRA, 0.52; 95% CI, 0.31–0.86) and high-dose aspirin (RR for colorectal neoplasia, 0.88; 95% CI, 0.72–1.08; RR for HRA, 0.68; 95% CI, 0.43–1.09) were not meaningfully different than for those weighing 70–79 kg or Conclusions: Measurements of body composition calculated from height and weight did not modify aspirin treatment effects for colorectal adenoma prevention. Impact: Aspirin dosing strategies accounting for body weight suggested in previous trials of colorectal cancer may not apply to adenomas.

Calcium supplementation (1,200 mg/day) did not significantly reduce colorectal adenomas in our recent randomized, controlled trial (Vitamin D/Calcium Polyp Prevention Study, VCPPS, 2004-2013) in contrast to our previous trial (Calcium Polyp Prevention Study, CPPS, 1988-1996). To reconcile these findings, we identified participant characteristics that differed between the study populations and modified the effect of calcium supplementation on adenomas or high-risk findings (advanced or multiple adenomas). Compared to the CPPS, more participants in the VCPPS were obese (body mass index (BMI) ≥30 kg/m2 ; 37.5% vs. 24.4%) and fewer had normal BMI (BMI

The NCCN Guidelines for Colorectal Cancer (CRC) Screening outline various screening modalities as well as recommended screening strategies for individuals at average or increased-risk of developing sporadic CRC. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize 2018 updates to the NCCN Guidelines, with a primary focus on modalities used to screen individuals at average-risk for CRC.

Although widely recommended, Lynch syndrome (LS) testing with tumor microsatellite instability (MSI) and/or immunohistochemistry (IHC) is infrequently performed in early-onset colorectal cancer (CRC), and CRC generally. Reasons are poorly understood. Hence, we conducted a national survey focusing on gastroenterologists, as they are frequently first to diagnose CRC, assessing testing barriers and which specialist is felt responsible for ordering MSI/IHC. Additionally, we assessed factors influencing timing of MSI/IHC ordering; testing on colonoscopy biopsy, opposed to post-operative surgical specimens, assists decisions on preoperative germline genetic testing and extent of colonic resection (ECR).A 21-question web-based survey was distributed through an American College of Gastroenterology email listing.In total 509 completed the survey. 442 confirmed gastroenterologists were analyzed. Only 33.4% felt gastroenterologists were responsible for MSI/IHC ordering; pathologists were believed most responsible (38.6%). Cost, unfamiliarity interpreting results and unavailable genetic counseling most commonly prevented routine ordering (33.3%, 29.2%, 24.9%, respectively). In multivariable analysis, non-academic and rural settings were associated with cost and genetic counseling barriers. Only 46.1% felt MSI/IHC should always be performed on colonoscopy biopsy. Guideline familiarity predicted whether respondents felt surgical resection should be delayed until results returned given potential effect on ECR decisions.Inconsistencies in who is felt should order MSI/IHC may lead to diffusion of responsibility, preventing consistent testing, including preoperatively. Assuring institutional universal testing protocols are in place, with focus on timing of testing, can optimize care. Strategies addressing cost barriers and genomic service availability in rural and non-academic settings can enhance testing. Greater emphasis on guideline familiarity is required.

Colorectal cancer incidence has been rapidly rising in those under the age of 50 over the last 20 years. This paper will review the epidemiology, clinicopathologic, molecular features, proposed risk factors, and prevention/treatment approach for early onset CRC (EOCRC) patients. EOCRC appears to have a different spectrum of clinical, pathologic, and molecular presentation compared to CRC diagnosed in older individuals. EOCRCs are disproportionately located in the distal colon; these patients tend to present with symptoms, and there is a longer interval between symptoms and diagnosis. There may be a distinct molecular signature, including progression through the microsatellite and chromosomal stable (MACS) pathway and LINE-1 hypomethylation for a subset of EOCRCs. The majority of EOCRCs are sporadic without clear risk factors that would have made the patient eligible for earlier screening. There is an acute need for educational efforts aimed at both providers and patients to raise awareness about CRC in the young. Improving adherence to screening in young patients eligible for screening and emphasizing early evaluation of symptoms are important steps to decreasing the burden of CRC in younger patients. Modeling and empiric data are needed to determine whether our current screening approach should be modified and whether causation and treatment options may be different in a molecular subset EOCRCs.

Individuals whose families meet the Amsterdam II clinical criteria for hereditary non-polyposis colorectal cancer are recommended to be referred for genetic counseling and to have colonoscopic screening every 1-2 years. To assess the uptake and knowledge of guideline-based genetic counseling and colonoscopic screening in unaffected members of families who meet Amsterdam II criteria and their treating endoscopists.Participants in the Family Health Promotion Project who met the Amsterdam II criteria were surveyed regarding their knowledge of risk-appropriate guidelines for genetic counseling and colonoscopy screening. Endoscopy/pathology reports were obtained from patients screened during the study to determine the follow-up recommendations made by their endoscopists. Survey responses were compared using Fisher's Exact and the χ(2) test. Concordance in participant/provider-reported surveillance interval was assessed using the kappa statistic.Of the 165 participants, the majority (98%) agreed that genetics and family history are important predictors of CRC, and 63% had heard of genetic testing for CRC, although only 31% reported being advised to undergo genetic counseling by their doctor, and only 7% had undergone genetic testing. Only 26% of participants reported that they thought they should have colonoscopy every 1-2 years and 30% of endoscopists for these participants recommended 1-2-year follow-up colonoscopy. There was a 65% concordance (weighted kappa 0.42, 95% CI 0.24-0.61) between endoscopist recommendations and participant reports regarding screening intervals.A minority of individuals meeting Amsterdam II criteria in this series have had genetic testing and reported accurate knowledge of risk-appropriate screening, and only a small percentage of their endoscopists provided them with the appropriate screening recommendations. There was moderate concordance between endoscopist recommendations and participant knowledge suggesting that future educational interventions need to target both health-care providers and their patients.

Background: The CpG island methylator phenotype (CIMP) is a major molecular pathway in colorectal cancer. Approximately 25% to 60% of CIMP tumors are microsatellite unstable (MSI-H) due to DNA hypermethylation of the MLH1 gene promoter. Our aim was to determine if the distributions of clinicopathologic factors in CIMP-positive tumors with MLH1 DNA methylation differed from those in CIMP-positive tumors without DNA methylation of MLH1. Methods: We assessed the associations between age, sex, tumor-site, MSI status BRAF and KRAS mutations, and family colorectal cancer history with MLH1 methylation status in a large population-based sample of CIMP-positive colorectal cancers defined by a 5-marker panel using unconditional logistic regression to assess the odds of MLH1 methylation by study variables. Results: Subjects with CIMP-positive tumors without MLH1 methylation were significantly younger, more likely to be male, and more likely to have distal colon or rectal primaries and the MSI-L phenotype. CIMP-positive MLH1-unmethylated tumors were significantly less likely than CIMP-positive MLH1-methylated tumors to harbor a BRAF V600E mutation and significantly more likely to harbor a KRAS mutation. MLH1 methylation was associated with significantly better overall survival (HR, 0.50; 95% confidence interval, 0.31–0.82). Conclusions: These data suggest that MLH1 methylation in CIMP-positive tumors is not a completely random event and implies that there are environmental or genetic determinants that modify the probability that MLH1 will become methylated during CIMP pathogenesis. Impact: MLH1 DNA methylation status should be taken into account in etiologic studies. Cancer Epidemiol Biomarkers Prev; 25(1); 68–75. ©2015 AACR.

Aspirin has been shown to protect against colorectal neoplasms; however, the optimal chemopreventive dose and underlying mechanisms are unclear. We aimed to study the relationship between prostanoid metabolites and aspirin's effect on adenoma occurrence. We used data from the Aspirin/Folate Polyp Prevention Study, in which 1,121 participants with a recent adenoma were randomized to placebo or two doses of aspirin (81 or 325 mg/d) to be taken until the next surveillance colonoscopy, anticipated about 3 years later. Urinary metabolites of prostanoids (PGE-M, PGI-M, and dTxB2) were measured using liquid chromatography/mass spectrometry or GC/NICI-MS in 876 participants near the end of treatment follow-up. Poisson regression with a robust error variance was used to calculate relative risks and 95% confidence intervals. PGE-M, PGI-M, and dTxB2 levels were 28%, 37%, and 60% proportionately lower, respectively, in individuals who took 325 mg of aspirin compared with individuals who took placebo (all P < 0.001). Similarly, among individuals who took 81 mg of aspirin, PGE-M, PGI-M, and dTxB2 were, respectively, 18%, 30%, and 57% proportionally lower compared with placebo (all P < 0.005). None of the metabolites or their ratios were statistically significantly associated with the risk of adenoma occurrence. The effect of aspirin in reducing adenoma risk was independent of prostanoid levels. Aspirin use is associated with lower levels of urinary prostanoid metabolites. However, our findings do not support the hypothesis that these metabolites are associated with adenoma occurrence, suggesting that COX-dependent mechanisms may not completely explain the chemopreventive effect of aspirin on colorectal neoplasms. Cancer Prev Res; 8(11); 1061–8. ©2015 AACR.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Colorectal Cancer Screening provide recommendations for selecting individuals for colorectal cancer screening, and for evaluation and follow-up of colon polyps. These NCCN Guidelines Insights summarize major discussion points of the 2015 NCCN Colorectal Cancer Screening panel meeting. Major discussion topics this year were the state of evidence for CT colonography and stool DNA testing, bowel preparation procedures for colonoscopy, and guidelines for patients with a positive family history of colorectal cancer.

Background: Approximately 10% to 20% of colorectal cancers exhibit somatic mutations in the phosphoinositide-3-kinase, catalytic, alpha polypeptide gene (PIK3CA). We evaluated the relationship of PIK3CA mutation status in colorectal cancer with race/ethnicity, colorectal cancer survival, and other patient and tumor factors. Methods: This study comprised 377 racial/ethnic minorities with incident invasive colorectal cancer, enrolled in the Colon Cancer Family Registry via population-based cancer registries. Tumor specimens were tested for PIK3CA mutations in exon 9 and 20 hotspots, BRAF p.V600E mutations, and DNA mismatch repair (MMR). In logistic regression models, we evaluated the association between PIK3CA mutation status and race/ethnicity, overall, and by mutation site. Using Cox regression, we evaluated the association between PIK3CA mutation status and survival after colorectal cancer diagnosis. Results: PIK3CA mutations were detected in 42 cases (11%), with a similar prevalence across racial/ethnic groups. Individuals with PIK3CA-mutated colorectal cancer were significantly more likely than those with PIK3CA-wildtype disease to have proximal colon cancer, MMR-deficient tumors, and a germline MMR mutation (P ≤ 0.01). There was no evidence for an association between PIK3CA and overall survival (HR, 0.77; 95% confidence interval, 0.43–1.39). Conclusions: The prevalence of PIK3CA mutation status in colorectal cancer does not differ according to race/ethnicity, but may vary according to other relevant clinicopathologic and etiologic factors, including germline MMR mutation status, tumor MMR status, and tumor site. Impact: These findings underscore the importance of PIK3CA mutation status in colorectal cancer epidemiology and provide evidence that the prevalence of such mutations is similar across several racial/ethnic groups. Cancer Epidemiol Biomarkers Prev; 24(7); 1046–51. ©2015 AACR.

Background An accurate system for tracking of colonoscopy quality and surveillance intervals could improve the effectiveness and cost-effectiveness of colorectal cancer (CRC) screening and surveillance. The purpose of this study was to create and test such a system across multiple institutions utilizing natural language processing (NLP). Methods From 42,569 colonoscopies with pathology records from 13 centers, we randomly sampled 750 paired reports. We trained (n=250) and tested (n=500) an NLP-based program with 19 measurements that encompass colonoscopy quality measures and surveillance interval determination, using blinded, paired, annotated expert manual review as the reference standard. The remaining 41,819 nonannotated documents were processed through the NLP system without manual review to assess performance consistency. The primary outcome was system accuracy across the 19 measures. Results A total of 176 (23.5%) documents with 252 (1.8%) discrepant content points resulted from paired annotation. Error rate within the 500 test documents was 31.2% for NLP and 25.4% for the paired annotators (P=0.001). At the content point level within the test set, the error rate was 3.5% for NLP and 1.9% for the paired annotators (P=0.04). When eight vaguely worded documents were removed, 125 of 492 (25.4%) were incorrect by NLP and 104 of 492 (21.1%) by the initial annotator (P=0.07). Rates of pathologic findings calculated from NLP were similar to those calculated by annotation for the majority of measurements. Test set accuracy was 99.6% for CRC, 95% for advanced adenoma, 94.6% for nonadvanced adenoma, 99.8% for advanced sessile serrated polyps, 99.2% for nonadvanced sessile serrated polyps, 96.8% for large hyperplastic polyps, and 96.0% for small hyperplastic polyps. Lesion location showed high accuracy (87.0-99.8%). Accuracy for number of adenomas was 92%. Conclusions NLP can accurately report adenoma detection rate and the components for determining guideline-adherent colonoscopy surveillance intervals across multiple sites that utilize different methods for reporting colonoscopy findings.

Background Colorectal cancer (CRC) is largely preventable by finding and removing adenomas, but many people have not been screened, especially the uninsured with low income. Purpose To establish a statewide infrastructure to ensure that low-income Coloradans receive colonoscopy for CRC screening and diagnostic evaluation. Design In 2006, a statewide program to provide free colonoscopy to uninsured Coloradans was developed as a partnership between the University of Colorado Cancer Center and Colorado safety-net clinics. Funded by excise tax revenues, the Colorado Colorectal Screening Program (CCSP) successfully embedded screening into primary care, providing patient navigation support and reimbursement that allowed primary care providers to refer patients for colonoscopy. Setting/participants More than 50 safety-net clinics joined the CCSP to provide colonoscopies to uninsured Coloradans with low income, aged ≥50 years or Main outcome measures Process and clinical outcomes included people screened, show rates, patient satisfaction, and quality measures, such as adenoma detection rate, bowel cleansing quality, and timeliness of care. Program costs and benefits were estimated. The 2013 analysis was completed using 2006−2012 data on 13,252 of 13,774 people receiving colonoscopy. Results In 2006−2012, the CCSP screened 13,774 people, with 38% minorities and 39% men. Patient navigators ensured >90% of those referred attended their colonoscopy. Adenomas were removed from 27% of patients and 1% had cancers diagnosed. Total direct medical services cost was $998/person receiving colonoscopy. About 325 fewer future incident CRCs were predicted due to adenoma removal, projecting substantial future cost savings. Conclusions The CCSP, a successful community clinic/academic partnership provides cost-effective CRC screening and prevention services to low-income uninsured Coloradans and establishes the infrastructure to support screening low-income Coloradans as Affordable Care Act reforms provide payer coverage for them.

Background: The CpG island methylator phenotype (CIMP) represents a subset of colorectal cancers characterized by widespread aberrant DNA hypermethylation at select CpG islands. The risk factors and environmental exposures contributing to etiologic heterogeneity between CIMP and non-CIMP tumors are not known. Methods: We measured the CIMP status of 3,119 primary population-based colorectal cancer tumors from the multinational Colon Cancer Family Registry. Etiologic heterogeneity was assessed by a case–case study comparing risk factor frequency of colorectal cancer cases with CIMP and non-CIMP tumors using logistic regression to estimate the case–case odds ratio (ccOR). Results: We found associations between tumor CIMP status and MSI-H (ccOR = 7.6), BRAF V600E mutation (ccOR = 59.8), proximal tumor site (ccOR = 9; all P < 0.0001), female sex [ccOR = 1.8; 95% confidence interval (CI), 1.5–2.1], older age (ccOR = 4.0 comparing over 70 years vs. under 50; 95% CI, 3.0–5.5), and family history of CRC (ccOR = 0.6; 95% CI, 0.5–0.7). While use of NSAIDs varied by tumor CIMP status for both males and females (P = 0.0001 and P = 0.02, respectively), use of multivitamin or calcium supplements did not. Only for female colorectal cancer was CIMP status associated with increased pack-years of smoking (Ptrend < 0.001) and body mass index (BMI; Ptrend = 0.03). Conclusions: The frequency of several colorectal cancer risk factors varied by CIMP status, and the associations of smoking and obesity with tumor subtype were evident only for females. Impact: Differences in the associations of a unique DNA methylation–based subgroup of colorectal cancer with important lifestyle and environmental exposures increase understanding of the molecular pathologic epidemiology of this heavily methylated subset of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 512–9. ©2015 AACR.

The sessile serrated polyp (SSP), also known as sessile serrated adenoma, is the evil twin among the colorectal cancer precursors. As will be described, these lesions have multiple aliases (serrated adenoma, serrated polyp, or serrated lesion among others), they hang out in a bad neighborhood (the poorly prepped right colon), they hide behind a mask of mucus, they are difficult for witnesses (pathologists) to identify, they are difficult for police (endoscopists) to find, they are difficult to permanently remove from the society (high incomplete resection rate), they can be impulsive (progress rapidly to colorectal cancer (CRC)), and enforcers (gastroenterologists) do not know how best to control them (uncertain surveillance recommendations). There is no wonder that there is a need to understand these lesions well, learn how best to prevent the colonic mucosa from going down this errant path or, if that fails, detect these deviants and eradicate them from the colonic society. These lesions should be on endoscopists' most wanted list.

Summary Background Familial occurrence is common in colorectal cancer (CRC), but whether this increased familial risk differs by colonic subsite of the index patients CRC is not well understood. Aim To quantify the risk of CRC in first-degree (FDR), second-degree (SDR) and first cousin (FC) relatives of individuals with CRC, stratified by subsite in the colorectum and age at diagnosis. Methods Colorectal cancers diagnosed between 1980 and 2010 were identified from the Utah Cancer Registry and linked to pedigrees from the Utah Population Database. Age and gender-matched CRC-free controls were selected to form the comparison group for determining CRC risk in relatives using Cox regression analysis. Results Of the 18 208 index patients diagnosed with CRC, 6584 (36.2%) were located in the proximal colon, 5986 (32.9%) in the distal colon and 5638 (31%) in the rectum. The elevated risk of CRC in relatives was similar in analysis stratified for CRC colorectal subsites in the index cases. FDR had similarly elevated risk of all site CRC, whether the index patient had cancer in the proximal colon [hazards ratio (HR): 1.85; 95% CI: 1.70–2.02], distal colon (HR: 1.90; 95% CI: 1.73–2.08) or rectum (HR: 1.83; 95% CI: 1.66–2.02) compared to relatives of controls. This risk was consistently greater for FDR when cases developed CRC below the age of 60 years. Conclusions Relatives of CRC patients have a similarly elevated risk of CRC regardless of colonic tumour subsite in the index patient, and it is greatest for relatives of younger age index cases.

BACKGROUND In 2016, the Microsimulation Screening Analysis‐Colon (MISCAN‐Colon) model was used to inform the US Preventive Services Task Force colorectal cancer (CRC) screening guidelines. In this study, 1 of 2 microsimulation analyses to inform the update of the American Cancer Society CRC screening guideline, the authors re‐evaluated the optimal screening strategies in light of the increase in CRC diagnosed in young adults. METHODS The authors adjusted the MISCAN‐Colon model to reflect the higher CRC incidence in young adults, who were assumed to carry forward escalated disease risk as they age. Life‐years gained (LYG; benefit), the number of colonoscopies (COL; burden) and the ratios of incremental burden to benefit (efficiency ratio [ER] = ΔCOL/ΔLYG) were projected for different screening strategies. Strategies differed with respect to test modality, ages to start (40 years, 45 years, and 50 years) and ages to stop (75 years, 80 years, and 85 years) screening, and screening intervals (depending on screening modality). The authors then determined the model‐recommended strategies in a similar way as was done for the US Preventive Services Task Force, using ER thresholds in accordance with the previously accepted ER of 39. RESULTS Because of the higher CRC incidence, model‐predicted LYG from screening increased compared with the previous analyses. Consequently, the balance of burden to benefit of screening improved and now 10‐yearly colonoscopy screening starting at age 45 years resulted in an ER of 32. Other recommended strategies included fecal immunochemical testing annually, flexible sigmoidoscopy screening every 5 years, and computed tomographic colonography every 5 years. CONCLUSIONS This decision‐analysis suggests that in light of the increase in CRC incidence among young adults, screening may be offered earlier than has previously been recommended. Cancer 2018;124:2964‐73. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society., Colorectal cancer incidence has been increasing since the mid‐1990s in adults aged

Colorectal cancer (CRC) is one of the most common malignancies in the United States. Every 3 years, the American Cancer Society provides an update of CRC incidence, survival, and mortality rates and trends. Incidence data through 2013 were provided by the Surveillance, Epidemiology, and End Results program, the National Program of Cancer Registries, and the North American Association of Central Cancer Registries. Mortality data through 2014 were provided by the National Center for Health Statistics. CRC incidence rates are highest in Alaska Natives and blacks and lowest in Asian/Pacific Islanders, and they are 30% to 40% higher in men than in women. Recent temporal patterns are generally similar by race and sex, but differ by age. Between 2000 and 2013, incidence rates in adults aged ≥50 years declined by 32%, with the drop largest for distal tumors in people aged ≥65 years (incidence rate ratio [IRR], 0.50; 95% confidence interval [95% CI], 0.48-0.52) and smallest for rectal tumors in ages 50 to 64 years (male IRR, 0.91; 95% CI, 0.85-0.96; female IRR, 1.00; 95% CI, 0.93-1.08). Overall CRC incidence in individuals ages ≥50 years declined from 2009 to 2013 in every state except Arkansas, with the decrease exceeding 5% annually in 7 states; however, rectal tumor incidence in those ages 50 to 64 years was stable in most states. Among adults aged50 years, CRC incidence rates increased by 22% from 2000 to 2013, driven solely by tumors in the distal colon (IRR, 1.24; 95% CI, 1.13-1.35) and rectum (IRR, 1.22; 95% CI, 1.13-1.31). Similar to incidence patterns, CRC death rates decreased by 34% among individuals aged ≥50 years during 2000 through 2014, but increased by 13% in those aged50 years. Progress against CRC can be accelerated by increasing initiation of screening at age 50 years (average risk) or earlier (eg, family history of CRC/advanced adenomas) and eliminating disparities in high-quality treatment. In addition, research is needed to elucidate causes for increasing CRC in young adults. CA Cancer J Clin 2017. © 2017 American Cancer Society. CA Cancer J Clin 2017;67:177-193. © 2017 American Cancer Society.

Purpose Prior studies suggest cigarette smoking is associated with 1.5- to twofold increased risk of colorectal adenomas and possibly a higher risk of serrated polyps. Further clarification of risk differences between adenomas and serrated polyps is needed with regard to co-occurrence and polyp location. Methods We conducted a combined analysis of conventional adenoma and serrated polyp occurrence using individual-level data from 2,915 patients participating in three colonoscopy-based clinical trials. All participants had ≥1 adenomas removed at baseline and were followed for up to 4 years. Smoking habits and other lifestyle factors were collected at baseline using questionnaires. We used generalized linear regression to estimate risk ratios and 95 % confidence intervals. Results Smokers were at slightly increased risk of adenomas compared to never smokers [current: RR 1.29 (95 % CI 1.11–1.49) and former: RR 1.18 (1.05–1.32)]. Smoking was associated with greater risk of serrated polyps [current: RR 2.01 (1.66–2.44); former: RR 1.42 (1.20–1.68)], particularly in the left colorectum. Associations between current smoking and occurrence of serrated polyps only [RR 2.33 (1.76–3.07)] and both adenomas and serrated polyps [RR 2.27 (1.68–3.06)] were more pronounced than for adenomas only [RR 1.31 (1.08–1.58)]. Results were similar for other smoking variables and did not differ by gender or for advanced adenomas. Conclusions Cigarette smoking has only a weak association with adenomas, but is associated with a significantly increased risk of serrated polyps, particularly in the left colorectum. Since a minority of left-sided serrated polyps is thought to have malignant potential, the role of smoking in initiation phases of carcinogenesis is uncertain.

Adequate serum 25-hydroxyvitamin D concentrations, [25(OH)D], are required for optimal bone health, and low levels are associated with chronic diseases.We investigated whether 41 candidate single nucleotide polymorphisms (SNPs) in vitamin D and calcium pathway genes (GC, DHCR7, CYP2R1, CYP27B1, CYP24A1, VDR, and CASR) are associated with [25(OH)D] or modify the increase in [25(OH)D] from vitamin D3 supplementation.Baseline and year 1 [25(OH)D] measurements from a randomized controlled trial conducted at 11 clinical centers in the United States.A total of 1787 healthy non-Hispanic white participants aged 45-75 years.Vitamin D3 (1000 IU/d), calcium carbonate (1200 mg/d elemental), both, or placebo.Genotype main effects and interactions with vitamin D3 treatment estimated using multiple linear regression.The baseline serum [25(OH)D] was 25.4 ± 8.7 ng/mL (mean ± SD). Associations with baseline levels were discovered for SNPs in CYP24A1 (rs2209314, rs2762939) and confirmed for SNPs in GC and CYP2R1. After 1 year, [25(OH)D] increased on average by 6.1 ± 8.9 ng/mL on vitamin D3 treatment and decreased by 1.1 ± 8.4 ng/mL on placebo. The increase in [25(OH)D] due to vitamin D3 supplementation was modified by genotypes at rs10766197 near CYP2R1, rs6013897 near CYP24A1, and rs7968585 near VDR.The increase in [25(OH)D] attributable to vitamin D3 supplementation may vary according to common genetic differences in vitamin D 25-hydroxylase (CYP2R1), 24-hydroxylase (CYP24A1), and the vitamin D receptor (VDR) genes. These findings have implications for achieving optimal vitamin D status and potentially for vitamin D-related health outcomes.

Background: Individuals with a family history of colorectal cancer in first-degree relatives have an elevated risk of developing colorectal cancer themselves, particularly colorectal cancer exhibiting high microsatellite instability (MSI-high). Given that MSI-high colorectal cancer is associated with a favorable prognosis, it is plausible that having a family history of colorectal cancer could, in turn, be favorably associated with colorectal cancer survival. Methods: This study comprised N = 4,284 incident colorectal cancer cases enrolled in the Colon Cancer Family Registry via population-based cancer registries. Using Cox proportional hazards regression, we evaluated the association between family history and both overall and disease-specific survival, accounting for MSI status and tumor site via stratified analyses and statistical adjustment. Results: There was no evidence of association between family history and overall [hazard ratio (HR), 0.92; 95% confidence interval (CI), 0.79–1.08] or disease-specific survival (HR, 1.03; 95% CI, 0.85–1.24) for all cases combined, after adjustment for MSI status or tumor site. Only for rectal cancer cases was colorectal cancer family history modestly associated with more favorable overall survival (HR, 0.75; 95% CI, 0.56–0.99). Conclusions: Although individuals with a family history of colorectal cancer were more likely to have MSI-high tumors than those with nonfamilial disease, this did not translate to a survival benefit. Impact: Overall, there is no evidence that family history of colorectal cancer is associated with colorectal cancer survival; however, specific mechanisms underlying family history may have prognostic impact and merit further study. Cancer Epidemiol Biomarkers Prev; 23(8); 1700–4. ©2014 AACR.

Background: Individuals with a strong family history of colorectal cancer have significant risk for colorectal cancer, although adherence to colonoscopy screening in these groups remains low. This study assessed whether a tailored telephone counseling intervention can increase adherence to colonoscopy in members of high-risk families in a randomized, controlled trial. Methods: Eligible participants were recruited from two national cancer registries if they had a first-degree relative with colorectal cancer under age 60 or multiple affected family members, which included families that met the Amsterdam criteria for hereditary non-polyposis colon cancer (HNPCC), and if they were due for colonoscopy within 24 months. Participants were randomized to receive a tailored telephone intervention grounded in behavioral theory or a mailed packet with general information about screening. Colonoscopy status was assessed through follow-up surveys and endoscopy reports. Cox proportional hazards models were used to assess intervention effect. Results: Of the 632 participants (ages 25–80), 60% were female, the majority were White, non-Hispanic, educated, and had health insurance. Colonoscopy adherence increased 11 percentage points in the tailored telephone intervention group, compared with no significant change in the mailed group. The telephone intervention was associated with a 32% increase in screening adherence compared with the mailed intervention (HR, 1.32; P = 0.01). Conclusions: A tailored telephone intervention can effectively increase colonoscopy adherence in high-risk persons. This intervention has the potential for broad dissemination to healthcare organizations or other high-risk populations. Impact: Increasing adherence to colonoscopy among persons with increased colorectal cancer risk could effectively reduce incidence and mortality from this disease. Cancer Epidemiol Biomarkers Prev; 23(4); 601–10. ©2014 AACR.

There is consensus internationally that research participants should be offered the opportunity to receive clinically relevant genetic information identified through research, but there is little empirical peer-reviewed work documenting this process. We report the experience of conducting genetic research with nearly 35,000 participants in the Colon Cancer Family Registry, based in the USA, Canada, Australia, and New Zealand. Investigators from six multinational sites provided information about disclosure protocols, implementation, and uptake of genetic results and made suggestions to inform practice. Across 5 of the 6 registry sites, 1,634 participants in families with mismatch repair or MutYH gene mutations have been offered results. Participant uptake ranged from 56 to 86 %. Researchers faced significant challenges in the effort to return results. We offer suggestions in five key areas: (1) planning for the disclosure process, (2) participant information, (3) autonomy of participants, (4) monitoring scientific progress, and (5) involvement of stakeholders. Despite increasing discussion of the importance of returning incidental findings from genetic research, this paper highlights the considerable diversity, challenges, and costs faced in practice when returning expected findings with established utility and validity. We argue that more work is needed to ensure that genetic results in research are optimally managed.

The adenoma detection rate (ADR) in screening colonoscopy is higher than original cost-effectiveness models estimated. Future colorectal cancer (CRC) risk is decreased once the ADR is 20%, but it is unclear how much additional protection is provided with higher ADRs. We modeled the impact of a high ADR on future CRC risk and surveillance colonoscopy burden.We created three hypothetical scenarios for 100,000 average-risk individuals undergoing screening colonoscopy at age 50: (i) 20% ADR with 30% future CRC risk reduction; (ii) 50% ADR with 30% future CRC risk reduction; and (iii) 50% ADR with 50% future CRC risk reduction. After colonoscopy, patients could have high-risk or low-risk adenomas, or no adenomas.When the ADR increases from 20% to 50% but no additional CRC cases are prevented, future CRC risk for each group is still reduced, because lower-risk patients migrate into apparently higher-risk groups (the Will Rogers phenomenon). Future risk is further reduced if a 50% ADR leads to greater protection from CRC. However, despite the reductions in group-specific and overall future CRC risk, 34,635 additional surveillance colonoscopies are performed before the cohort is 60 years old when the ADR is 50% compared with 20%.If current surveillance practices continue along with high ADRs, screening colonoscopy may not remain cost-effective.

BACKGROUND & AIMS: Endoscopists do not routinely follow guidelines to survey individuals with low-risk adenomas (LRAs; 1-2 small tubular adenomas, < 1 cm) every 5-10 years for colorectal cancer; many recommend shorter surveillance intervals for these individuals. We aimed to identify the reasons that endoscopists recommend shorter surveillance intervals for some individuals with LRAs and determine whether timing affects outcomes at follow-up examinations. METHODS: We collected data from 1560 individuals (45-75 years old) who participated in a prospective chemoprevention trial (of vitamin D and calcium) from 2004 through 2008. Participants in the trial had at least 1 adenoma, detected at their index colonoscopy, and were recommended to receive follow-up colonoscopy examinations at 3 or 5 years after adenoma identification, as recommended by the endoscopist. For this analysis we collected data from only participants with LRAs. These data included characteristics of participants and endoscopists and findings from index and follow-up colonoscopies. Primary endpoints were frequency of recommending shorter (3-year) vs longer (5-year) surveillance intervals, factors associated with these recommendations, and effect on outcome, determined at the follow-up colonoscopy. RESULTS: A 3-year surveillance interval was recommended for 594 of the subjects (38.1%). Factors most significantly associated with recommendation of 3-year vs a 5-year surveillance interval included African American race (relative risk [RR] to white, 1.41; 95% confidence interval [CI], 1.14-1.75), Asian/Pacific Islander ethnicity (RR to white, 1.7; 95% CI, 1.22-2.43), detection of 2 adenomas at the index examination (RR vs 1 adenoma, 1.47; 95% CI, 1.27-1.71), more than 3 serrated polyps at the index examination (RR=2.16, 95% CI, 1.59-2.93), or index examination with fair or poor quality bowel preparation (RR vs excellent quality, 2.16; 95% CI, 1.66-2.83). Other factors that had a significant association with recommendation for a 3-year surveillance interval included family history of colorectal cancer and detection of 1-2 serrated polyps at the index examination. In comparisons of outcomes, we found no significant differences between the 3-year vs 5-year recommendation groups in proportions of subjects found to have 1 or more adenomas (38.8% vs 41.7% respectively; P = .27), advanced adenomas (7.7% vs 8.2%; P = .73) or clinically significant serrated polyps (10.0% vs 10.3%; P = .82) at the follow-up colonoscopy. CONCLUSIONS: Possibly influenced by patients' family history, race, quality of bowel preparation, or number or size of polyps, endoscopists frequently recommend 3-year surveillance intervals instead of guideline-recommended intervals of 5 years or longer for individuals with LRAs. However, at the follow-up colonoscopy, similar proportions of participants have 1 or more adenomas, advanced adenomas, or serrated polyps. These findings support the current guideline recommendations of performing follow-up examinations of individuals with LRAs at least 5 years after the index colonoscopy.

Background: Although high-risk mutations in identified major susceptibility genes (DNA mismatch repair genes and MUTYH) account for some familial aggregation of colorectal cancer, their population prevalence and the causes of the remaining familial aggregation are not known. Methods: We studied the families of 5,744 colorectal cancer cases (probands) recruited from population cancer registries in the United States, Canada, and Australia and screened probands for mutations in mismatch repair genes and MUTYH. We conducted modified segregation analyses using the cancer history of first-degree relatives, conditional on the proband's age at diagnosis. We estimated the prevalence of mutations in the identified genes, the prevalence of HR for unidentified major gene mutations, and the variance of the residual polygenic component. Results: We estimated that 1 in 279 of the population carry mutations in mismatch repair genes (MLH1 = 1 in 1,946, MSH2 = 1 in 2,841, MSH6 = 1 in 758, PMS2 = 1 in 714), 1 in 45 carry mutations in MUTYH, and 1 in 504 carry mutations associated with an average 31-fold increased risk of colorectal cancer in unidentified major genes. The estimated polygenic variance was reduced by 30% to 50% after allowing for unidentified major genes and decreased from 3.3 for age Conclusions: Unidentified major genes might explain one third to one half of the missing heritability of colorectal cancer. Impact: Our findings could aid gene discovery and development of better colorectal cancer risk prediction models. Cancer Epidemiol Biomarkers Prev; 26(3); 404–12. ©2016 AACR.

Background Lynch syndrome is an autosomal dominantly inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Previous studies have shown that MMR gene mutation carriers are at increased risk of colorectal, endometrial, and several other cancers following an initial diagnosis of colorectal cancer. We estimated cancer risks following an endometrial cancer diagnosis for women carrying MMR gene mutations. Methods We obtained data from the Colon Cancer Family Registry for a cohort of 127 women who had a diagnosis of endometrial cancer and who carried a mutation in one of four MMR genes (30 carried a mutation in MLH1, 72 in MSH2, 22 in MSH6, and 3 in PMS2). We used the Kaplan-Meier method to estimate 10- and 20-year cumulative risks for each cancer. We estimated the age-, country-, and calendar period–specific standardized incidence ratios (SIRs) for each cancer, compared with the general population. Results Following endometrial cancer, women carrying MMR gene mutations had the following 20-year risks of other cancer cancers: colorectal cancer (48%, 95% confidence interval [CI] = 35% to 62%); cancer of the kidney, renal pelvis, or ureter (11%, 95% CI = 3% to 20%); urinary bladder cancer (9%, 95% CI = 2% to 17%); and breast cancer (11%, 95% CI = 4% to 19%). Compared with the general population, these women were at statistically significantly elevated risks of colorectal cancer (SIR = 39.9, 95% CI = 27.2 to 58.3), cancer of the kidney, renal pelvis, or ureter (SIR = 28.3, 95% CI = 11.9 to 48.6), urinary bladder cancer (SIR = 24.3, 95% CI = 8.56 to 42.9), and breast cancer (SIR = 2.51, 95% CI = 1.17 to 4.14). Conclusions Women with Lynch syndrome who are diagnosed with endometrial cancer have increased risks of several cancers, including breast cancer.

Despite regular surveillance colonoscopy, the metachronous colorectal cancer risk for mismatch repair (MMR) gene mutation carriers after segmental resection for colon cancer is high and total or subtotal colectomy is the preferred option. However, if the index cancer is in the rectum, management decisions are complicated by considerations of impaired bowel function. We aimed to estimate the risk of metachronous colon cancer for MMR gene mutation carriers who underwent a proctectomy for index rectal cancer. Methods This retrospective cohort study comprised 79 carriers of germline mutation in a MMR gene (18 MLH1, 55 MSH2, 4 MSH6, and 2 PMS2) from the Colon Cancer Family Registry who had had a proctectomy for index rectal cancer. Cumulative risks of metachronous colon cancer were calculated using the Kaplan–Meier method. Results During median 9 years (range 1–32 years) of observation since the first diagnosis of rectal cancer, 21 carriers (27 %) were diagnosed with metachronous colon cancer (incidence 24.25, 95 % confidence interval [CI] 15.81–37.19 per 1,000 person-years). Cumulative risk of metachronous colon cancer was 19 % (95 % CI 9–31 %) at 10 years, 47 (95 % CI 31–68 %) at 20 years, and 69 % (95 % CI 45–89 %) at 30 years after surgical resection. The frequency of surveillance colonoscopy was 1 colonoscopy per 1.16 years (95 % CI 1.01–1.31 years). The AJCC stages of the metachronous cancers, where available, were 72 % stage I, 22 % stage II, and 6 % stage III. Conclusions Given the high metachronous colon cancer risk for MMR gene mutation carriers diagnosed with an index rectal cancer, proctocolectomy may need to be considered.

Background: Adenomatous polyps are the most common precursor to colorectal cancer, the second leading cause of cancer-related death in the United States. We sought to learn more about early events of carcinogenesis by investigating shifts in the gut microbiota of patients with adenomas. Methods: We analyzed 16S rRNA gene sequences from the fecal microbiota of patients with adenomas (n = 233) and without (n = 547). Results: Multiple taxa were significantly more abundant in patients with adenomas, including Bilophila, Desulfovibrio, proinflammatory bacteria in the genus Mogibacterium, and multiple Bacteroidetes species. Patients without adenomas had greater abundances of Veillonella, Firmicutes (Order Clostridia), and Actinobacteria (family Bifidobacteriales). Our findings were consistent with previously reported shifts in the gut microbiota of colorectal cancer patients. Importantly, the altered adenoma profile is predicted to increase primary and secondary bile acid production, as well as starch, sucrose, lipid, and phenylpropanoid metabolism. Conclusions: These data hint that increased sugar, protein, and lipid metabolism along with increased bile acid production could promote a colonic environment that supports the growth of bile-tolerant microbes such as Bilophilia and Desulfovibrio. In turn, these microbes may produce genotoxic or inflammatory metabolites such as H2S and secondary bile acids, which could play a role in catalyzing adenoma development and eventually colorectal cancer. Impact: This study suggests a plausible biological mechanism to explain the links between shifts in the microbiota and colorectal cancer. This represents a first step toward resolving the complex interactions that shape the adenoma–carcinoma sequence of colorectal cancer and may facilitate personalized therapeutics focused on the microbiota. Cancer Epidemiol Biomarkers Prev; 26(1); 85–94. ©2016 AACR.

Cancer is fundamentally a genetic disease caused by mutational or epigenetic alterations in DNA. There has been a remarkable expansion of the molecular understanding of colonic carcinogenesis in the last 30 years and that understanding is changing many aspects of colorectal cancer care. It is becoming increasingly clear that there are genetic subsets of colorectal cancer that have different risk factors, prognosis, and response to treatment. This article provides a general update on colorectal cancer and highlights the ways that genetics is changing clinical care.

Background Cyclooxygenase (COX)-2 inhibitors such as celecoxib were designed to preserve anti-inflammatory activity without inhibiting COX-1. Downregulation of COX-2 inhibits colorectal carcinogenesis. Methods The Selenium and Celecoxib Trial was a randomized, placebo-controlled trial of once-daily selenium 200 µg and celecoxib 400 mg, alone or together, for colorectal adenoma prevention. Men and women between age 40 and 80 years were eligible following colonoscopic removal of adenomas. The primary outcome was development of new adenomas. Celecoxib was suspended early because of cardiovascular toxicity in other trials. Accrual to selenium or placebo continued. Before suspension, 824 participants were randomly assigned to celecoxib or placebo, of whom 712 (86.4%) were available for analysis. All statistical tests were two-sided. Results In the placebo and celecoxib arms of 356 participants each, adenoma detection was 47.5% and 49.7% (relative risk [RR] = 1.04, 95% confidence interval [CI] = 0.90 to 1.21, P = .58), respectively, after median periods of 13.6 and 14.2 months on intervention. Among participants colonoscoped within 12 months of discontinuing intervention (n = 244), overall adenoma recurrence (RR = 0.69, 95% CI = 0.48 to 0.98, P = .04) and recurrence with advanced adenomas (RR = 0.23, 95% CI = 0.07 to 0.80, P = .02) were reduced with celecoxib. Reduction of adenoma recurrence was greatest in participants with previous advanced adenomas. Celecoxib increased risk of hypertension in participants with pre-existing cardiovascular risk factors compared with placebo (hazard ratio = 2.19, 95% CI = 1.07 to 4.50, P = .03). Conclusions Limited-duration celecoxib prevents adenoma recurrence in patients with prior high-risk adenomas, in whom strategies to minimize cardiovascular toxicity might be feasible.

Background Selenium supplementation may help to prevent colorectal cancer; as precursors of colorectal cancer, colorectal adenomas are a surrogate for colorectal cancer. Selenium supplementation may increase risk of type 2 diabetes (T2D). Methods The Selenium and Celecoxib (Sel/Cel) Trial was a randomized, placebo controlled trial of selenium 200 µg daily as selenized yeast and celecoxib 400 mg once daily, alone or together, for colorectal adenoma prevention. Men and women between age 40 and 80 years were eligible following colonoscopic removal of colorectal adenomas. The primary outcome was adenoma development. Celecoxib was suspended because of cardiovascular toxicity in other trials, but accrual continued to selenium and placebo. A total of 1621 participants were randomly assigned to selenium or placebo, of whom 1374 (84.8%) were available for analysis. All statistical tests were two-sided. Results In the respective placebo and selenium arms of 689 and 685 participants, adenoma detection after medians of 33.6 (range = 0.0-85.1 months) and 33.0 months (range = 0.0-82.6 months) were 42.8% and 44.1% (relative risk [RR] = 1.03, 95% confidence interval [CI] = 0.91 to 1.16, P = .68). In participants with baseline advanced adenomas, adenoma recurrence was reduced by 18% with selenium (RR = 0.82, 95% CI = 0.71 to 0.96, P = .01). In participants receiving selenium, the hazard ratio for new-onset T2D was 1.25 (95% CI = 0.74 to 2.11, P = .41), with a statistically significantly increased risk of selenium-associated T2D among older participants (RR = 2.21; 95% CI = 1.04 to 4.67, P = .03). Conclusions Overall, selenium did not prevent colorectal adenomas and showed only modest benefit in patients with baseline advanced adenomas. With limited benefit and similar increases in T2D to other trials, selenium is not recommended for preventing colorectal adenomas in selenium-replete individuals.

This is a focused update highlighting the most current NCCN Guidelines for diagnosis and management of Lynch syndrome. Lynch syndrome is the most common cause of hereditary colorectal cancer, usually resulting from a germline mutation in 1 of 4 DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2), or deletions in the EPCAM promoter. Patients with Lynch syndrome are at an increased lifetime risk, compared with the general population, for colorectal cancer, endometrial cancer, and other cancers, including of the stomach and ovary. As of 2016, the panel recommends screening all patients with colorectal cancer for Lynch syndrome and provides recommendations for surveillance for early detection and prevention of Lynch syndrome-associated cancers.

We conducted a systematic review and meta-analysis to identify personal, lifestyle, and tumor-related risk factors for metachronous colorectal cancer (CRC) and polyp.Relevant studies were identified by searching MEDLINE, Web of Science and Cochrane Central Register through 15 May 2016. Estimates for associations were summarized using random effects models.Fifty-five studies were included in the review. For individuals who had a CRC resection, having a synchronous polyp was a risk factor for metachronous CRC or polyp (relative risk [RR], 2.04; 95% confidence interval [CI], 1.48-2.82) and having a synchronous CRC (RR, 1.90; 95% CI, 1.25-2.91) and proximally located CRC (RR, 2.12; 95% CI, 1.24-3.64) were risk factors for metachronous CRC. For individuals who had a polypectomy, larger size (RR, 4.26; 95% CI, 2.11-8.57) or severe dysplasia of the initial polyp (RR, 5.15; 95% CI, 2.02-13.14), and having a synchronous polyp (RR, 2.52; 95% CI, 1.35-4.73) were risk factors for metachronous CRC; and a family history of CRC (RR, 1.90; 95% CI, 1.26-2.87), having a synchronous polyp (RR, 2.47; 95% CI, 1.74-3.50) and a larger size (RR, 1.49; 95% CI, 1.03-2.15) and proximal location of the initial polyp (RR, 1.20; 95% CI, 1.02-1.40) were risk factors for metachronous polyp. Meta-regression showed duration of follow-up was not a source of heterogeneity for most associations. There was no evidence that lifestyle factors were associated with metachronous CRC or polyp risk.A comprehensive list of risk factors identified for metachronous CRC or polyp may have important clinical implications.