Samadder, N. Jewel

Purpose: Neuroendocrine neoplasms (NENs) are increasingly recognized to have a hereditary predilection, yet the prevalence and clinical relevance of pathogenic germline variants (PGVs) in unselected patients with NEN remain poorly defined. This prospective, multicenter study aimed to evaluate the prevalence and clinical utility of PGVs through universal multigene panel testing in a diverse cohort of patients with NENs. Patients and Methods: Between 2018 and 2024, we enrolled unselected patients with NENs from 3 Mayo Clinic Cancer Centers. Germline genetic testing was performed using a next-generation sequencing panel of up to 84 cancer predisposition genes. Patients were not selected based on age, disease stage, ethnicity, or family history. Variants were classified as PGVs, variants of uncertain significance (VUS), or negative. Clinical and demographic data were analyzed descriptively. Results: Among 88 patients, PGVs were identified in 15.9% (n=14), most frequently in high- or moderate-penetrance genes including MEN1 , CHEK2 , MITF , and MUTYH . PGVs were most commonly found in pancreatic NENs [n=12/55 (21.8%)], followed by small bowel NENs [n=2/20 (10%)], with no PGVs detected in lung NENs. Mismatch repair (MMR) gene alterations were identified in 5.7% of patients, including 1 MLH1 PGV and 4 MSH2/MSH6 VUS, 2 of which demonstrated MMR deficiency by protein testing. VUS were reported in 34.1% of patients. Notably, 35.7% of PGV-positive patients did not meet current NCCN or ACMG testing criteria, and 53.9% had PGVs in genes outside of cancer-specific guideline recommendations. Conclusions: Universal germline testing in unselected patients with NEN identified clinically relevant PGVs in over 15% of cases. These findings support broader genetic testing approaches to guide treatment, enhance familial risk assessment, and inform cascade testing—regardless of traditional clinical selection criteria.

Abstract Globally, gastric adenocarcinoma is the fourth leading cause of cancer mortality and a major cancer disparity in the United States. Chemoprevention strategies are lacking for high-risk individuals with gastric premalignant conditions (GPMC). Curcumin, the principal curcuminoid in turmeric, exerts immunomodulatory effects in the epithelium and against Helicobacter pylori, and studies suggest chemoprevention potential. We conducted a double-blind, phase IIa randomized controlled trial in high-risk populations in Puerto Rico and Honduras. We investigated the utility of a bioavailable formulation of curcumin (Meriva) among individuals with H. pylori–negative GPMC, specifically, multifocal atrophic gastritis (MAG) or gastric intestinal metaplasia (GIM). Patients were 1:1 randomized to 1,000 mg Meriva daily or placebo for a 6-month intervention with endoscopy at baseline and 6 months. Outcomes included assessment of epithelial cytokine and chemokine levels, histology, and DNA damage as assessed by γ-H2AX phosphorylation IHC. Of the 110 subjects screened, 50 participants were randomized, and 48 completed the trial. A significant reduction in gastric mucosal IL1β levels from baseline in the gastric body, the primary endpoint, was observed in the Meriva group (P = 0.032). Changes in epithelial IL8, TNFα, and inducible protein 10 levels and gastric mucosal histology and DNA damage (secondary endpoints) were similar between arms. Curcumin (Meriva) was safe, well-tolerated, and showed potential as a curcuminoid chemoprevention agent in H. pylori–negative patients with GPMC. A potential reduction in gastric inflammation as measured by gastric mucosal IL1β levels was observed. Further studies are warranted, including studies in H. pylori–positive individuals, based upon the curcuminoid direct effects on H. pylori. Prevention Relevance: Gastric adenocarcinoma is a leading cause of cancer mortality worldwide. Chemoprevention candidates for GPMCs are limited. This randomized phase IIa trial evaluated a bioavailable curcumin formulation in high-risk individuals with MAG and GIM. The results support further study of curcuminoids for gastric cancer risk reduction. See related Spotlight, p. 387 See related article by Morgan et al., p. 391

Abstract Purpose: Familial adenomatous polyposis (FAP) confers a significant risk of colorectal/duodenal cancer. Encapsulated rapamycin (eRapa) has demonstrated promise as FAP chemoprevention in early clinical studies. Patients and Methods: Thirty patients with FAP enrolled to three dosing regimens of eRapa (0.5 mg): cohort 1—every other day, cohort 2—daily every other week, or cohort 3—daily. The primary endpoints were safety/tolerability, pharmacokinetics, and percentage change from baseline (PCFB) in colorectal polyp burden (CPB) at 6 months. Secondary endpoints included PCFB total (TPB) and duodenal (DPB) polyp burden and change in International Society for Gastrointestinal Hereditary Tumors stage and Spigelman score at 6 and 12 months. Results: Twenty nine of thirty patients (97%) completed the 12-month study with predictable bioavailability. Low-grade adverse events were frequent but most pronounced in daily dosing. Two patients discontinued treatment related to toxicity. Cohort 1 had the largest decrease median PCFB CPB, DPB, and TPB at 6 months: −39.4 % (IQR, 108.9; P = 0.28), −33.33 % (IQR, 90; P = 0.04), and −38.6 % (IQR, 88.5; P = 0.26), respectively. At 12 months, cohort 2 had the largest decrease median PCFB CPB and TPB: −29.3 % (IQR, 67.6; P = 0.37) and −26.3 % (IQR, 49.5; P = 0.29), respectively. Intermittent dosing cohorts (1 and 2) reduced DPB at 6 months (P = 0.04) and improved TPB at 12 months (P = 0.05) compared with daily dosing. Conclusions: eRapa was safe, tolerable, and showed preliminary efficacy for FAP chemoprevention. The 0.5 mg daily every-other-week schedule will be evaluated in an upcoming phase III trial.

93 Background: Colorectal cancer (CRC) is the 4th most common cancer among men and women and roughly 2-4% of all CRCs occur in patients with a diagnosis of Lynch syndrome (LS), an autosomal dominant condition found to be the most common cause of hereditary CRC with estimated lifetime risk of developing CRC between 50-80%. LS results from mutations in one or more of 5 genes: MLH1, MSH2, MSH6, PMS2, and EPCAM, which lead to a deficiency in DNA mismatch repair ( dMMR ). Current guidelines suggest testing every CRC for microsatellite instability ( MSI ) or MMR gene expression using immunohistochemistry (IHC) to identify LS-related CRC. QuantCRC is a prognostic AI model that identifies important histological features of CRC and provides a recurrence prediction estimate useful for treatment decisions. It uses computational image analysis to extract quantitative features from digitized H&E stained pathology slides such as tumor grade, tumor-infiltrating lymphocytes, and other morphometric parameters. 4 It has been verified and validated in Aiforia (AI for image analysis) Platform using whole slide images and against reviews by independent pathologists from 8 hospitals. Our study sought to use QuantCRC to identify histological differences between those with MSI (confirmed LS), sporadic MSI , and microsatellite stability (MSS ) CRC to better help clinicians identify which patients would benefit from additional testing. Methods: We conducted a retrospective cohort study of patients with CRC whose pathology was analyzed at Mayo Clinic Arizona. Tumor characteristics were analyzed by QuantCRC and Receiver Operating Characteristic (ROC) curve analysis using Area Under the Curve (AUC) was used to see if QuantCRC could distinguish CRCs with MSI or LS. Results: Of the total 5132 patients with CRC, 1101 (21.5%) samples were MSI/dMMR with 468 (42.5%) of those having confirmed LS. The study had roughly equal parts men and there were more women with non-LS MSI (59%) than with LS or microsatellite stability. The QuantCRC model’s ROC analysis revealed an AUC of 0.83 for predicting MSI/dMMR among all patients with a sensitivity of 0.75 and a specificity of 0.79. AUC for predicting LS among all patients was 0.76 and of predicting LS among MSI/dMMR was 0.64. Conclusions: The QuantCRC model was useful in predicting MSI/dMMR status among all patients with CRC. It can be a helpful clinical tool when assessing which patients may benefit from additional genetic or IHC testing, especially in lower resource areas where molecular testing may be difficult to access or expensive relative to an H&E slide.

817 Background: Universal germline sequencing is increasingly utilized in practice, but existing evidence and guidelines are based on studies in predominantly white populations. This study aims to compare the prevalence of genetic alterations in white vs underrepresented minority (URM) populations and assess incremental findings discovered with universal testing beyond current guidelines. Methods: This prospective, multicenter study analyzed genetic alterations in white and URM cohorts with primary GI malignancies receiving care at Mayo Clinic cancer centers between April 2018 and April 2025. Patients underwent germline sequencing using a next-generation sequencing (NGS) platform targeting over 80 genes. We compared the distribution of results between white and URM populations. Concordance with NCCN testing guidelines and incremental findings were assessed. Results: A total of 1128 patients were studied, of which 758 were white and 370 were URM, (47.6% Hispanic, 22.7% Black, 13.8% Asian, 10.5% American Indian, 0.8% Pacific Islander, and 6.8% other). Pathogenic variants (PGV) were more common in the white population (16.1% vs 9.2% P < 0.001). Variants of uncertain significance (VUS) were more common in the URM population (53.2 vs 43.5%, P<0.001). A total of 156 patients were found to have a PGV. PGVs outside primary cancer genes were more common in white patients (57.4% vs. 32.4%; p=0.0241). Incremental findings from universal testing were higher in white patients (66.4% vs 35.3%; p=0.0011). Conclusions: This study reveals a significant difference in the prevalence of PGV and VUS between white and URM patients with primary GI malignancies. The higher rate of PGVs in white patients and VUS in URM patients highlights potential inequities in both detection and interpretation of genetic results. These findings emphasize the need for broader representation in genetic databases to ensure equitable access to precision oncology. Screening guidelines met by patients with PGV. White (N=122) URM (N=34) Total (N=156) p value Did they meet NCCN testing guidelines for their primary cancer? 0.0991 Yes 87 (71.3%) 29 (85.3%) 116 (74.4%) No 35 (28.7%) 5 (14.7%) 40 (25.6%) Was the PGV outside of the primary genes recommended for their primary cancer? 0.0241 Yes 70 (57.4%) 11 (32.4%) 81 (51.9%) No 47 (38.5%) 22 (64.7%) 69 (44.2%) Incremental Finding 0.0011 Yes 81 (66.4%) 12 (35.3%) 93 (59.6%) No 41 (33.6%) 22 (64.7%) 63 (40.4%)

BACKGROUND: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disorder that increases risk for premature coronary artery disease and has accessible and effective interventions. The Dutch lipid clinic network is currently the most used diagnostic criterion; however, genetic sequencing provides a definitive diagnosis of FH. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify individuals who were genotype positive for FH. METHODS: Participants were recruited from 3 geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; and Jacksonville, FL). Participants underwent Exome+ sequencing (dba Helix, San Mateo, CA) and return of results for specific genetic findings in APOB , LDLR , or PCSK9 . A chart review was performed to collect demographics, personal, and family cardiovascular history. RESULTS: At the time of the study, 84 413 participants were enrolled in the Tapestry study. Annotation and interpretation of all variants in genes for FH resulted in the identification of 419 likely pathogenic and pathogenic variants (prevalence, 0.50%), which included 116 APOB , 298 LDLR , and 5 PCSK9 . Sixty-six percent were female, the mean body mass index was 27.3, with 12.3% reporting a history of diabetes. Hypertriglyceridemia (≥150 mg/dL) was present in 39.5% and reduced HDL (<50 mg/dL) was present in 56.7% of patients. 27.5% of patients were not on cholesterol-lowering medications, and only 10% of FH carriers were at goal low-density lipoprotein cholesterol levels. A history of coronary artery disease was reported in 22.4% of the cohort. Nearly 90% of these participants were newly diagnosed carriers of FH. Only 30.8% of confirmed genetic diagnoses of FH satisfied clinical (Dutch lipid clinic network) criteria for a diagnosis. CONCLUSIONS: Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have familial hypercholesterolemia. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05212428.

Abstract Introduction There is convincing evidence that overall adiposity increases the risks of several cancers. Whether the distribution of adiposity plays a similar role is unclear. Methods We used 2-sample Mendelian randomization (MR) to examine causal relationships of 5 adiposity distribution traits (abdominal subcutaneous adipose tissue (ASAT); visceral adipose tissue (VAT); gluteofemoral adipose tissue (GFAT); liver fat; and pancreas fat) with the risks of 12 obesity-related cancers (endometrial, ovarian, breast, colorectal, pancreas, multiple myeloma, liver, kidney (renal cell), thyroid, gallbladder, esophageal adenocarcinoma, and meningioma). Results Sample size across all genome-wide association studies (GWAS) ranged from 8407 to 728 896 (median: 57 249). We found evidence that higher genetically predicted ASAT increased the risks of endometrial cancer, liver cancer, and esophageal adenocarcinoma (odds ratios (OR) and 95% confidence intervals (CI) per standard deviation (SD) higher ASAT = 1.79 (1.18 to 2.71), 3.83 (1.39 to 10.53), and 2.34 (1.15 to 4.78), respectively). Conversely, we found evidence that higher genetically predicted GFAT decreased the risks of breast cancer and meningioma (ORs and 95% CIs per SD higher genetically predicted GFAT = 0.77 (0.62 to 0.97) and 0.53 (0.32 to 0.90), respectively). We also found evidence for an effect of higher genetically predicted VAT and liver fat on increased liver cancer risk (ORs and 95% CIs per SD higher genetically predicted adiposity trait = 4.29 (1.41 to 13.07) and 4.09 (2.29 to 7.28), respectively). Discussion Our analyses provide novel insights into the relationship between adiposity distribution and cancer risk. These insights highlight the potential importance of adipose tissue distribution alongside maintaining a healthy weight for cancer prevention.

Abstract Background Being able to estimate the risk of metachronous disease in a patient with colorectal cancer (CRC) could enable risk-appropriate surveillance. The aim of this study was to develop a risk-prediction model to estimate individual 10-year risk of metachronous disease following a CRC diagnosis. Methods A population-based cohort of patients with CRC was recruited soon after diagnosis between 1997 and 2012 from the United States, Canada, and Australia. Cox regression with the least absolute shrinkage and selection operator penalization was used to identify factors that predicted the risk of a new primary CRC diagnosed at least 1 year after the initial CRC diagnosis. Potential predictors included demography, anthropometry, lifestyle factors, comorbidities, personal and family cancer history, medication use, age at diagnosis, and pathological features of the first CRC. Internal validation through bootstrapping was used to evaluate the discrimination and calibration. Results We included 6085 CRC cases; 138 (2.3%) of these cases were diagnosed with metachronous disease over a median of 12 years (IQR = 5-17 years). Metachronous CRC risk was predicted by body mass index; smoking status; level of physical activity; family history of cancer and synchronous CRC; stage, grade, histological type, and DNA mismatch repair status; and age at diagnosis of the first CRC. The model was valid with a C statistic of 0.65 (95% CI = 0.63 to 0.68) and a calibration slope of 0.873 (SD = 0.087). Conclusions Metachronous CRC can be predicted with reasonable accuracy using a prediction model that consists of clinical variables collected as part of routine practice.

Abstract Menopausal users of hormone replacement therapy (HRT) are at increased breast cancer risk and decreased colorectal cancer (CRC) risk compared with individuals who have never used HRT, but these opposing associations may differ by familial risk of breast cancer and CRC. We harmonized data from 3 cohorts and generated separate breast cancer and CRC familial risk scores based on cancer family history. We defined moderate or strong family history as a risk score of 0.4 or higher, where 0.4 was equivalent to a 50-year-old woman with 1 parent diagnosed with either breast cancer or CRC at 55 years of age. Of 24 486 women assessed, 1243 and 405 were diagnosed with incident breast cancer and CRC, respectively. For breast cancer, menopausal HRT ever use versus never use hazard ratios were 1.27 (95% CI = 1.11 to 1.45) for a breast cancer familial risk score below 0.4 and 1.01 (95% CI = 0.82 to 1.25) for a breast cancer familial risk score of 0.4 or higher (Pdifference = .08). For CRC, menopausal HRT hazard ratios were 0.63 (95% CI = 0.50 to 0.78) for a CRC familial risk score below 0.4 and 1.21 (95% CI = 0.73 to 2.00) for a CRC familial risk score of 0.4 or higher (Pdifference = .03). Associations with menopausal HRT use that apply to the general population may not hold for women at moderate or strong familial risk of these cancers.

Abstract Background: Epidemiological and laboratory-based studies have provided conflicting evidence for a role of ghrelin in colorectal cancer development. We conducted two-sample Mendelian randomization (MR) analyses to evaluate evidence for an association of circulating ghrelin and colorectal cancer risk overall and by sex, cancer subsite, and age at diagnosis. Methods: Genetic instruments proxying plasma total ghrelin levels were obtained from a recent genome-wide association study of 54,219 participants. Summary data for colorectal cancer risk were obtained from a recent meta-analysis of several genetic consortia (up to 73,673 cases and 86,854 controls). A two-sample MR approach and several sensitivity analyses were applied. Results: We found no evidence for an association of genetically predicted plasma total ghrelin levels and colorectal cancer risk (0.95, 95% confidence interval, 0.81–1.12; R2 of ghrelin genetic instruments: 4.6%), with similarly null results observed when stratified by sex, anatomical subsite, and for early-onset colorectal cancer. Conclusions: Our study suggests that plasma ghrelin levels are unlikely to have a causal relationship with overall, early-onset, and sex- and cancer subsite–stratified colorectal cancer risk. Impact: This large-scale analysis adds to the growing body of evidence that plasma total ghrelin levels are not associated with colorectal cancer risk.