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Background and Aims Identification and resection of successful targets, i.e., T1 N0M0 pancreatic ductal adenocarcinoma (PDAC) and high-grade precursors during surveillance of high-risk individuals (HRIs) confers improved survival. Late-stage PDACs refer to T2-4 N0M0 and nodal or distant metastatic PDAC stages diagnosed during the follow-up phase of HRI surveillance. This study aimed to quantify late-stage PDACs during HRI surveillance and identify associated clinicoradiologic factors. Methods A systematic search (PROSPERO:CRD42018117189) from Cochrane Library, Embase, Google Scholar, Medline, PubMed, Scopus, and Web of Science was last performed on April 18, 2021. Only original HRI surveillance manuscripts which specified follow-up strategies were included, while studies with only baseline information were excluded. Cumulative incidences of advanced neoplasia: high-grade precursors and all PDACs, and surveillance-detected/interval late-stage PDACs were calculated through random-effects model. Incidence of late-stage PDACs underwent metaregression to identify association with HRI clinicoradiologic features. Publication bias was assessed through the Funnel plot and Egger’s Regression line. Results Thirteen original surveillance studies included 2169 HRIs followed over 7302.72 patient-years. Cumulative incidence of advanced neoplasia and late-stage PDACs was 3.3 [95% CI:0.6-7.4] and 1.7 [95% CI:0.2-4.0] per 1000 patient-years, respectively. Late-stage PDACs lacked significant association with surveillance imaging, baseline pancreatic morphology, study location, genetic background, gender, or age. Limited information on diagnostic error, symptoms, timing of presentation, lesion site, and surveillance adherence precluded formal meta-analysis. Conclusion A sizable proportion of late-stage PDACs were detected during follow-up. Their incidence lacked association with baseline clinicoradiologic features. Further causal investigation of stage-based outcomes is warranted for overall improvement in HRI surveillance.

Approximately 35% of patients with colorectal cancer (CRC) have a family history of the disease attributed to genetic factors, common exposures, or both. Some families with a history of CRC carry genetic variants that cause CRC with high or moderate penetrance, but these account for only 5% to 10% of CRC cases. Most families with a history of CRC and/or adenomas do not carry genetic variants associated with cancer syndromes; this is called common familial CRC. Our understanding of familial predisposition to CRC and cancer syndromes has increased rapidly due to advances in next-generation sequencing technologies. As a result, there has been a shift from genetic testing for specific inherited cancer syndromes based on clinical criteria alone, to simultaneous testing of multiple genes for cancer-associated variants. We summarize current knowledge of common familial CRC, provide an update on syndromes associated with CRC (including the nonpolyposis and polyposis types), and review current recommendations for CRC screening and surveillance. We also provide an approach to genetic evaluation and testing in clinical practice. Determination of CRC risk based on family cancer history and results of genetic testing can provide a personalized approach to cancer screening and prevention, with optimal use of colonoscopy to effectively decrease CRC incidence and mortality.

Background & Aims There is substantial interest in liquid biopsy approaches for cancer early detection among subjects at risk, using multi-marker panels. CA19-9 is an established circulating biomarker for pancreatic cancer; however, its relevance for pancreatic cancer early detection or for monitoring subjects at risk has not been established. Methods CA19-9 levels were assessed in blinded sera from 175 subjects collected up to 5 years before diagnosis of pancreatic cancer and from 875 matched controls from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. For comparison of performance, CA19-9 was assayed in blinded independent sets of samples collected at diagnosis from 129 subjects with resectable pancreatic cancer and 275 controls (100 healthy subjects; 50 with chronic pancreatitis; and 125 with noncancerous pancreatic cysts). The complementary value of 2 additional protein markers, TIMP1 and LRG1, was determined. Results In the PLCO cohort, levels of CA19-9 increased exponentially starting at 2 years before diagnosis with sensitivities reaching 60% at 99% specificity within 0 to 6 months before diagnosis for all cases and 50% at 99% specificity for cases diagnosed with early-stage disease. Performance was comparable for distinguishing newly diagnosed cases with resectable pancreatic cancer from healthy controls (64% sensitivity at 99% specificity). Comparison of resectable pancreatic cancer cases to subjects with chronic pancreatitis yielded 46% sensitivity at 99% specificity and for subjects with noncancerous cysts, 30% sensitivity at 99% specificity. For prediagnostic cases below cutoff value for CA19-9, the combination with LRG1 and TIMP1 yielded an increment of 13.2% in sensitivity at 99% specificity (P = .031) in identifying cases diagnosed within 1 year of blood collection. Conclusion CA19-9 can serve as an anchor marker for pancreatic cancer early detection applications.

Background and Aims Lynch syndrome is associated with pathogenic variants in 4 mismatch repair (MMR) genes that increase lifetime risk of colorectal cancer. Guidelines recommend intensive colorectal cancer surveillance with colonoscopy every 1–2 years starting at age 25 years for all carriers of Lynch syndrome–associated variants, regardless of gene product. We constructed a simulation model to analyze the effects of different ages of colonoscopy initiation and surveillance intervals for each MMR gene (MLH1, MSH2, MSH6, and PMS2) on colorectal cancer incidence and mortality, quality-adjusted life-years, and cost. Methods Using published literature, we developed a Markov simulation model of Lynch syndrome progression for patients with each MMR variant. The model simulated clinical trials of Lynch syndrome carriers, varying age of colonoscopy initiation (5-year increments from 25–40 years), and surveillance intervals (1–5 years). We assessed the optimal strategy for each gene, defined as the strategy with the highest quality-adjusted life-years and incremental cost-effectiveness ratio below a $100,000 willingness-to-pay threshold. Results Optimal surveillance for patients with pathogenic variants in the MLH1 and MSH2 genes was colonoscopy starting at age 25 years, with 1- to 2-year surveillance intervals. Initiating colonoscopy at age 35 and 40 years, with 3-year intervals, was cost-effective for patients with pathogenic variants in MSH6 or PMS2, respectively. Conclusions We developed a simulation model to select optimal surveillance starting ages and intervals for patients with Lynch syndrome based on MMR variant. The model supports recommendations for intensive surveillance of patients with Lynch syndrome–associated variants in MLH1 or MSH2. However, for patients with Lynch syndrome–associated variants of MSH6 or PMS2, later initiation of surveillance at 35 and 40 years, respectively, and at 3-year intervals, can be considered.

Background & Aims Lynch syndrome is the most common hereditary colorectal cancer (CRC) syndrome. Some previous estimates of lifetime risk for CRC and endometrial cancer (EC) did not control for ascertainment and were susceptible to bias toward overestimated risk. Methods We studied 147 families with mismatch repair gene mutations (55 MLH1 , 81 MSH2 , and 11 MSH6 ) identified at 2 US cancer genetics clinics. Age-specific cumulative risks (penetrance) and hazard ratio (HR) estimates of CRC and EC risks were calculated and compared with the general population using modified segregation analysis. The likelihood for each pedigree was conditioned on the proband and first-degree relatives affected with CRC to reduce ascertainment bias and overestimation of penetrance. Results We analyzed 628 cases of CRC, diagnosed at the median ages of 42 and 47 years for men and women, respectively. The cumulative risk of CRC was 66.08% (95% confidence interval [CI], 59.47%–76.17%) for men and 42.71% (95% CI, 36.57%–52.83%) for women, with overall HRs of 148.4 and 51.1, respectively. CRC risk was highest for males with mutations in MLH1 . There were 155 cases of EC, diagnosed at a median age of 47.5 years. The cumulative risk of EC was 39.39% (95% CI, 30.78%–46.94%) with an overall HR of 39.0 (95% CI, 30.4–50.2). For women, the cumulative risk of CRC or EC was 73.42% (95% CI, 63.76%–80.54%). Conclusions Lifetime risks of CRC and EC in mismatch repair gene mutation carriers are high even after adjusting for ascertainment. These estimates are valuable for patients and providers; specialized cancer surveillance is necessary.

Background & Aims We developed and validated a model to estimate the risks of mutations in the mismatch repair (MMR) genes MLH1 , MSH2 , and MSH6 based on personal and family history of cancer. Methods Data were analyzed from 4539 probands tested for mutations in MLH1 , MSH2 , and MSH6 . A multivariable polytomous logistic regression model (PREMM 1,2,6 ) was developed to predict the overall risk of MMR gene mutations and the risk of mutation in each of the 3 genes. The discriminative ability of the model was validated in 1827 population-based colorectal cancer (CRC) cases. Results Twelve percent of the original cohort carried pathogenic mutations (204 in MLH1 , 250 in MSH2 , and 71 in MSH6 ). The PREMM 1,2,6 model incorporated the following factors from the probands and first- and second-degree relatives (odds ratio; 95% confidence intervals [CIs]): male sex (1.9; 1.5–2.4), a CRC (4.3; 3.3–5.6), multiple CRCs (13.7; 8.5–22), endometrial cancer (6.1; 4.6–8.2), and extracolonic cancers (3.3; 2.4–4.6). The areas under the receiver operating characteristic curves were 0.86 (95% CI, 0.82–0.91) for MLH1 mutation carriers, 0.87 (95% CI, 0.83–0.92) for MSH2 , and 0.81 (95% CI, 0.69–0.93) for MSH6 ; in validation, they were 0.88 for the overall cohort (95% CI, 0.86–0.90) and the population-based cases (95% CI, 0.83–0.92). Conclusions We developed the PREMM 1,2,6 model, which incorporates information on cancer history from probands and their relatives to estimate an individual's risk of mutations in the MMR genes MLH1 , MSH2 , and MSH6 . This Web-based decision making tool can be used to assess risk of hereditary CRC and guide clinical management.

Despite the advances in the selection of patients for genetic testing in Lynch syndrome at least a third of patients with Bethesda criteria and lack of MLH1 expression have sporadic tumours and should not receive genetic testing. The aim of this study is to investigate the role of the methylation analysis using MS-MLPA in the diagnosis of Lynch syndrome. MSMLPA is a novel and methodologically easy technique for quantitative measure of gene methylation. Methods. Sixty colorectal cancer (CRC) specimens with loss of MLH1 expression were selected. DNA from paraffin-embedded tumours was tested for 2 quantitative methylation detection methods: Methylight (Applied biosystems) and MS-MLPA (Methylation Specific-Multiplex Ligation Probe Amplification) (MCR Holland) calculating Methylation Ratio in MLH1. Somatic mutation in BRAF V600E was investigated from tumour DNA. Germline mutations in MLH1 were analyzed by sequentiation. Results: Correlation of quantitative results of the 2 methylation analysis techniques (Methylation and MS-MLPA) was 96.7% (p