TPS10632 Background: CRC is a leading cause of cancer-related mortality; CRC screening has been shown to reduce mortality through detection of early-stage disease, yet adherence to recommended screening remains suboptimal. Shield is a methylation partitioning cell-free DNA (mp-cfDNA) blood-based test indicated for CRC screening in average-risk adults age 45 years or older. This test achieved 83% sensitivity for CRC and 90% specificity for advanced neoplasia in a prospective, observational study that enrolled over 20,000 patients (ECLIPSE), and became the first blood-based screening test approved by the FDA as a primary CRC screening option in July 2024. SOLAR is an FDA-mandated, post-approval study to evaluate longitudinal performance of the blood-based mp-cfDNA test in the intended use population. Methods: SOLAR (NCT06880055) is an observational, prospective study supplemented with real-world data to evaluate the mp-cfDNA test following a second round of CRC screening. Patients will receive an initial mp-cfDNA test (Shield, Guardant Health, Palo Alto, CA) at baseline (T0). Deidentified healthcare claims data will be collected to assess overall health and any development of disease at 1 and 2 years following the baseline test (T1 and T2, respectively). Patients with a negative screening result at T0 will receive a screening colonoscopy alongside a blood draw approximately 3 years after baseline screening (T3). Patients with a positive result at T0 will be recommended to receive diagnostic colonoscopy. Individuals aged 45-81 years at average-risk for CRC are eligible for the trial. Individuals who have a personal/family history of CRC or are at high risk for CRC are excluded. Those with a positive result from any of the following CRC screening tests are also excluded: fecal occult blood test or fecal immunochemical test within the last 12 months, multi-target stool DNA test within the last 36 months, mp-cfDNA test within the last 36 months, or another CRC screening method within the last six months. Primary outcome is the performance of the mp-cfDNA test at T3, including sensitivity for CRC or advanced adenoma detection and specificity for advanced neoplasia detection. Enrollment began July 2025. There are currently 29 active study sites across the US. Clinical trial information: NCT06880055 .

10550 Background: Blood-based multi-cancer detection (MCD) tests hold promise for early cancer detection. MCD tests should demonstrate high specificity, clinically meaningful sensitivity, and provide information to guide clinical diagnostic evaluation. Methods: We developed an MCD test that leverages a next-generation sequencing epigenomics hybrid capture assay (Shield) to measure DNA methylation in regions differentially methylated across solid tumor cancers. We then implemented a two-step classification algorithm. First, a regression model (multi-cancer classifier) was trained to distinguish cancer from non-cancer samples at 98% target specificity. Next, a cancer signal of origin (CSO) model was trained to categorize 10 solid tumors (Table 1) in samples predicted to be cancer. The test was evaluated in a blinded case-control cohort of plasma samples (3mL; Streck) from adults with treatment naïve cancer, or who were self-reported cancer free with 1 year of follow-up (NCT05334069). Results: Final evaluable dataset was 962 participants (excludes 31 (3.1%) that failed quality control). Median age was 62 years (range: 40-78). 55% were female. Self-reported race was 81% White. Observed specificity was 98.6% (436/442). Sensitivity for the 10 cancer types included in the CSO model was 59.7% (224/375) and was 55.7% (263/472) overall when incorporating 4 solid tumor types not included in the CSO model. Primary or secondary CSO prediction was 92% accurate for the cancer types included (Table 1). Conclusions: In this cohort, this MCD test shows 59.7% sensitivity, 98.6% specificity, and 92% primary or secondary CSO accuracy for the cancer types included. Integrating an MCD test with an FDA approved blood-based CRC screening test may increase the MCD clinical value in the intended use population, which should be studied further. A version of this MCD test is being studied in a prospective, interventional study evaluating MCD testing feasibility. Overall and per cancer sensitivity and CSO accuracy results. Overall Sensitivity % Sensitivity Stage I/II, % Sensitivity Stage III/IV, % Primary or Secondary CSO Accuracy, % All Samples, 472 56% 31% 81% - Cancers included in CSO caller, 375 60% 35% 84% 92% Bladder, 13 62% 44% 100% 75% Breast, 86 45% 17% 88% 97% Colorectal, 41 83% 53% 100% 91% Esophageal-Stomach, 25 96% 100% 95% 96% Hepatocellular, 16 94% 100% 92% 67% Lung, 57 67% 41% 93% 97% Ovarian, 20 70% 80% 67% 100% Pancreas, 59 68% 50% 96% 93% Prostate, 59 21% 3% 41% 92% Cancers not included in CSO caller, 97 40% 18% 65% Endometrial, 29 38% 12% 75% Head & Neck, 15 80% 100% 63% Kidney, 44 34% 0% 71% Melanoma, 9 11% 0% 20%

OBJECTIVES:Although U.S. Preventive Services Task Force (USPSTF) recommended CRC screenings are effective; patient reluctance reduces adherence. Most cost-effectiveness models assume perfect adherence, yet one-third of eligible individuals aren't current with CRC screening. Our study assesses the cost-effectiveness of Shield, an FDA-approved blood-based CRC screening test, using real-world adherence. METHODS:The CAN-SCREEN (Colorectal cANcer SCReening Economics and adherENce) model, a validated discrete-event simulation, evaluated clinical and economic outcomes of CRC screening under real-world adherence scenarios. We compared the Shield blood-based test administered every 3 years to no screening, considering it cost-effective if the incremental cost-effectiveness ratio (ICER) was under $100,000 per quality-adjusted life-year (QALY) gained. RESULTS:Shield increased QALYs by 154 and raised costs by $7.5 million per 1,000 individuals, with an ICER of $48,662 per QALY, meeting the $100,000/QALY threshold. Shield remained cost-effective up to a unit cost of $3,241 (at $100,000/QALY) and $4,942 (at $150,000/QALY). Sensitivity analyses confirmed cost-effectiveness with lower adherence to diagnostic colonoscopy (56.1%) and annual screenings. CONCLUSION:The CAN-SCREEN model shows that Shield is cost-effective compared to no screening. Including real-world adherence improves accuracy in assessing screening strategies. Shield's noninvasive approach offers a promising, cost-effective way to increase adherence and reduce CRC mortality.

AIM:Insufficient adherence to colorectal cancer (CRC) screening impedes individual and population health benefits, with about one-third of individuals non-adherent to available screening options. The impact of poor adherence is inadequately considered in most health economics models, limiting the evaluation of real-world population-level screening outcomes. This study introduces the CAN-SCREEN (Colorectal cANcer SCReening Economics and adherENce) model, utilizing real-world adherence scenarios to assess the effectiveness of a blood-based test (BBT) compared to existing strategies. MATERIALS AND METHODS:The CAN-SCREEN model evaluates various CRC screening strategies per 1,000 screened individuals for ages 45-75. Adherence is modeled in two ways: (1) full adherence and (2) longitudinally declining adherence. BBT performance is based on recent pivotal trial data while existing strategies are informed using literature. The full adherence model is calibrated using previously published Cancer Intervention and Surveillance Modeling Network (CISNET) models. Outcomes, including life-years gained (LYG), CRC cases averted, CRC deaths averted, and colonoscopies, are compared to no screening. RESULTS:Longitudinal adherence modeling reveals differences in the relative ordering of health outcomes and resource utilization, as measured by the number of colonoscopies performed per 1,000, between screening modalities. BBT outperforms the fecal immunochemical test (FIT) and the multitarget stool DNA (mtsDNA) test with more CRC deaths averted (13) compared to FIT and mtsDNA (7, 11), more CRC cases averted (27 vs. 16, 22) and higher LYG (214 vs. 157, 199). BBT yields fewer CRC deaths averted compared to colonoscopy (13, 15) but requires fewer colonoscopies (1,053 vs. 1,928). LIMITATIONS:Due to limited data, the CAN-SCREEN model with longitudinal adherence leverages evidence-informed assumptions for the natural history and real-world longitudinal adherence to screening. CONCLUSIONS:The CAN-SCREEN model demonstrates that amongst non-invasive CRC screening strategies, those with higher adherence yield more favorable health outcomes as measured by CRC deaths averted, CRC cases averted, and LYG.

Background Colorectal cancer is the third most diagnosed cancer in adults in the United States. Early detection could prevent more than 90% of colorectal cancer-related deaths, yet more than one third of the screening-eligible population is not up to date with screening despite multiple available tests. A blood-based test has the potential to improve screening adherence, detect colorectal cancer earlier, and reduce colorectal cancer-related mortality.Methods We assessed the performance characteristics of a cell-free DNA (cfDNA) blood-based test in a population eligible for colorectal cancer screening. The coprimary outcomes were sensitivity for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions) relative to screening colonoscopy. The secondary outcome was sensitivity to detect advanced precancerous lesions.Results The clinical validation cohort included 10,258 persons, 7861 of whom met eligibility criteria and were evaluable. A total of 83.1% of the participants with colorectal cancer detected by colonoscopy had a positive cfDNA test and 16.9% had a negative test, which indicates a sensitivity of the cfDNA test for detection of colorectal cancer of 83.1% (95% confidence interval [CI], 72.2 to 90.3). Sensitivity for stage I, II, or III colorectal cancer was 87.5% (95% CI, 75.3 to 94.1), and sensitivity for advanced precancerous lesions was 13.2% (95% CI, 11.3 to 15.3). A total of 89.6% of the participants without any advanced colorectal neoplasia (colorectal cancer or advanced precancerous lesions) identified on colonoscopy had a negative cfDNA blood-based test, whereas 10.4% had a positive cfDNA blood-based test, which indicates a specificity for any advanced neoplasia of 89.6% (95% CI, 88.8 to 90.3). Specificity for negative colonoscopy (no colorectal cancer, advanced precancerous lesions, or nonadvanced precancerous lesions) was 89.9% (95% CI, 89.0 to 90.7).Conclusions In an average-risk screening population, this cfDNA blood-based test had 83% sensitivity for colorectal cancer, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions. (Funded by Guardant Health; ECLIPSE ClinicalTrials.gov number, NCT04136002.) In a cohort at average risk for colorectal cancer, a cell-free DNA blood-based test had 83% sensitivity for colorectal cancer, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions.

What if a simple blood draw taken during a routine visit to the doctor for a check-up or a flu shot could allow us to identify specific cancers at an early stage, when they are the most treatable? What if blood tests could help the cancer care team improve patient care at every step of the patient’s journey—from detection to treatment selection to response and recurrence monitoring?

Perspective on This Article from A Randomized Controlled Trial of Celecoxib to Prevent Recurrence of Nonmuscle-Invasive Bladder Cancer

Introduction: Poor adherence to colorectal cancer (CRC) screening significantly hinders individual and population health benefits. Barriers for the available screening options lead to approximately 1/3 of people not being up to date. The impact of poor adherence is not adequately considered in leading health economics models, limiting the ability to evaluate population level real-world screening benefits and harms. We developed and validated a discrete-event simulation (DES) model with real-world adherence to evaluate the effectiveness of a blood-based screening test relative to existing screening strategies. Methods: The CAN-SCREEN (Colorectal cANcer SCReening Economics and adherENce) model evaluated the performance of different CRC screening strategies per 1,000 screened individuals beginning at age 45. Adherence was modeled as: 1) assumed 100% adherence, and 2) longitudinal using a decline model calibrated to real world one-time adherence and population-level cumulative adherence from the National Health Interview Survey (NHIS). Performance for currently available strategies were derived from the literature. Blood-based test performance was per recently reported data (ECLIPSE NCT#04136002; Guardant Health, USA). The 100% adherence model was calibrated with previous CISNET published models (2021). Life-years gained (LYG), CRC deaths averted, and number of colonoscopies were compared to a no screening cohort. Results: Modeling longitudinal adherence to reflect real-world utilization yields differences in health outcomes and resource utilization between screening modalities (Table 1). Blood based testing is comparable to colonoscopy for LYG (217, 255) and CRC deaths averted (15,15) while leading to fewer colonoscopies over the modeled time period (820, 1996) and is superior to stool-based testing. A blood-based test strategy modeled with real world adherence demonstrated a favorable CRC stage shift, with 83% of CRC diagnoses at stage I – III vs 76% in colonoscopy and 78-81% in stool-based testing. Conclusion: The CAN-SCREEN model demonstrates that CRC screening strategies integrating test performance with high adherence yield more favorable health outcomes. Existing models assuming 100% adherence are limited in the ability to accurately predict population level health outcomes. Incorporating the blood test, that maximizes adherence due to its ease of use, as an additional strategy could avert additional deaths and reduce the number of colonoscopies performed. Table 1. - Colorectal cANcer SCReening Economics and adherENce (CAN-SCREEN) Results for Four Colorectal Cancer (CRC) Screening Strategies from Age 45 per 1,000 Simulated Individuals Screened as Compared to No Screening CRC Screening Strategy 100% Adherence Longitudinal Real-World Adherence Life Years Gained CRC Deaths Averted Number of colonoscopies Life Years Gained CRC Deaths Averted Number of colonoscopies Colonoscopy 360 26 4209 255 15 1996 FIT stool based test 319 24 1682 126 7 127 mtsDNA stool based test 295 22 1655 173 12 676 Blood-Based Test 247 20 986 217 15 820

TPS1602 Background: Implementation of asymptomatic cancer screening has yielded positive impacts on global cancer mortality rates. However, significant screening adherence gaps exist. A blood-based multi-cancer screening test with clinically significant performance in cancers where early detection and intervention can save lives, can address adherence gaps, especially by reducing access barriers inherent to current screening options. Effective evaluation of such a test in screen relevant populations requires studies designed to enroll individuals across multiple cancer types, taking into account prevalence rates for the cancers being evaluated, allowing for overlapping screen-eligible populations, and ensuring representation of individuals from diverse ethnicities and geographies. Methods: SHIELD (Screening for High Frequency Malignant Disease; NCT# 05117840) is a prospective, observational, multi-center basket study ongoing in the United States and Europe uniquely designed to recruit individuals across multiple cancer types. The study’s primary objective is to evaluate the performance of a blood-based multi-cancer screening test (GuardantLUNAR-2, Guardant Health, USA) to detect cancer in screen-relevant individuals as compared to the reference standard cancer screening modality. The study will recruit eligible individuals into multiple separate cohorts with specified pathways for cancer screening. Within each cohort, eligible individuals consent to whole blood collection within 90-days of the standard of care screening method. Clinical diagnoses, including the diagnosis of cancer, are made per standard of care. Primary outcomes are sensitivity, specificity, negative predictive value, and positive predictive value of the test as compared to the standard of care screening modality. Secondary outcome is the number of screen-detected cancers, early- (stage I/II) and late-stage (stage III/IV), per 1000 screened individuals. Follow-up continues for 24 months with outcomes collected at one and two-years to investigate the possibility of incidental non-screen relevant cancer cases and interval screen-relevant cancer cases that had not reached clinical threshold for detection at initial screening. Additional cancer specific follow-up is designed per cohort. The first cohort to enroll screen-eligible individuals, cohort A, is focused on those who meet guideline criteria for lung cancer screening with low dose CT. Additional cancer-risk cohorts will begin enrolling as the study expands and are designated cohort B, C, etc. Cohort A: Eligibility criteria are aligned with lung cancer screening guidelines – age 50-80 years with > 20 pack-year smoking history who are current smokers or have quit < 15 years prior, without a cancer history, preinvasive lung lesions, or current treatment for pneumonia. Cohort A enrollment, targeting 9,000 subjects over 24 months at up to 120 global sites, began in January 2022. Clinical trial information: NCT05117840.

556 Background: Homologous recombination and repair (HRR) deficiency (HRD) is characterized by genomic instability associated with dysfunction in BRCA1/2 or other HRR genes. Patients with breast cancer harboring an HRD phenotype with or without HRR mutations have derived clinical benefit from PARPi therapy. We have previously shown that GuardantINFINITY, a novel genomic and epigenomic liquid biopsy assay, can identify HRR SNVs, indels, rearrangements, copy number loss, reversions, and BRCA1 promoter methylation for patient selection and resistance monitoring, a major challenge for PARPi treatment. Here, we present a method of predicting HRD status by cfDNA using GuardantINFINITY in patients with advanced breast cancer. Methods: We developed a probabilistic genomic model to predict HRD status, inferred from genome-wide somatic SNV, indel, and CNV signatures indicative of BRCA1/2 deficiency, including large-scale state transitions (LST), whole-genome tumor loss of heterozygosity (LOH), telomeric allelic imbalance (TAI). A second probabilistic model, based on targeted measurements of genomic and epigenetic changes was learned from a subset of clinical samples to enhance the genomic model. The model was trained and tested on a cohort of over 12,000 GuardantOMNI and GuardantINFINITY clinical breast cancer samples to assess the sensitivity of accurately detecting deficiency in select HRR-genes ( BRCA1/2, PALB2, RAD51D). The aggregated predictive model was validated on an independent cohort of breast cancer samples. Results: The model based on genomic and epigenetic signals identified HRR-gene deficiency in a breast cancer cohort with a estimated 95% LoD of 22.5% tumor fraction and an AUC of 0.75 across all tumor fractions, an improvement in sensitivity over when only the genomic model is used (AUC of 0.7, 95% LoD of 28%). Specificity remained high for both models (100%, n = 83) in cancer free samples. Application of this model in a cohort of 1,101 patients with unselected breast cancer identified 390 patients with an HRD phenotype, of whom 192 patients had a known HRR-gene mutation. Of the 201 patients with a known pathogenic mutation in an HRR gene, 49 also had co-occurring LoH in the same gene, indicating biallelic loss. Conclusions: In this analysis, we demonstrate that a probabilistic model of genomic and methylation predictors can detect HRD status in patients with breast cancer from cfDNA using GuardantINFINITY. Additional analytical and clinical studies to further evaluate this model are ongoing. With HRD prediction, GuardantINFINITY provides a comprehensive minimally-invasive solution for PARPi and DNA damage treatment selection, longitudinal monitoring, and an exploratory platform for investigating epigenetic signals that may underpin resistance.

Background: Previous gastrointestinal (GI) outcomes of nonsteroidal anti-inflammatory drug (NSAID) trials have focused on upper GI events, although recent evidence suggests NSAID-related lower GI effects are important and clinically relevant.Objective: We assessed the long-term GI adverse event (AE) profile of celecoxib in a nonarthritis population. The aim of this post hoc analysis was to determine the incidence of serious GI AEs, using a new Clinically Significant Upper and/or Lower GI Events end point.Methods: Patients from 2 colorectal adenoma recurrence studies were included. Patients received celecoxib 200 mg/400 mg BID, 400 mg once daily, or placebo over 3 years. The analysis measured noninferiority, using a prespecified definition of noninferiority. Celecoxib was predefined to be noninferior to placebo if the upper limit of the 95% CI for the hazard ratio (HR) with celecoxib was <1.25, at any dose, compared with the placebo (calculated using the Cox proportional hazards model).Results: A total of 3588 patients were included; in the primary analysis, the HR for celecoxib (any dose) compared with placebo was 1.22(95% CI: 0.69-2.18; P = 0.4948). In the secondary dose analyses, the HR associated with a 400-mg daily dose, compared with placebo, was 1.04 (95% CI: 0.55-1.96; P = 0.9149); for 800 mg/d, the HR was 1.79 (95% CI: 0.82-3.89; P = 0.1427). In a third covariate analysis, low-dose aspirin use (HR = 2.33; 95% CI: 1.33-4.08) and age years (HR = 1.82; 95% CI, 1.05-3.15) was suggested to have a statistically significant association with increased risk of GI AEs. Study limitations include retrospective evaluation and small sample size of patients with GI AEs.Conclusions: The noninferiority of celecoxib to placebo was not established because the HR for the time to the first Clinically Significant Upper and/or Lower GI Event was greater than the prespecified upper limit of 95% CI for noninferiority. In addition, HRs associated with daily doses of 400 or 800 mg celecoxib compared with placebo were not significant. However, a significantly increased risk of clinically significant upper and/or lower GI events was observed in low-dose

Abstract Significant morbidity and expense result from frequent recurrences of nonmuscle-invasive bladder cancer (NMIBC) after standard treatment, and carcinoma in situ (Tis) is a poor prognostic factor. Predicated on observational and preclinical data strongly supporting cyclooxygenase-2 (COX-2) in the pathogenesis, and the activity of COX-2 inhibitors, in bladder cancer, we conducted a randomized, double-blind, placebo-controlled trial to determine whether celecoxib could reduce the time-to-recurrence (TTR) in NMIBC patients at high risk for recurrence. A total of 146 patients were randomized to celecoxib (200 mg) or placebo orally twice daily for at least 12 months. The average treatment duration was 1.25 years. Primary intent-to-treat analysis revealed celecoxib did not statistically significantly prolong TTR compared with placebo (P = 0.17, log rank) with a median follow-up of 2.49 years. The recurrence-free rate at 12 months with celecoxib was 88% (95% CI: 0.81–0.96) versus 78% (95% CI: 0.69–0.89) with placebo. After controlling for covariates with Cox regression analysis, recurrence rates did not differ between the two study arms (HR = 0.69; 95% CI: 0.37–1.29). However, celecoxib had a marginally significant effect on reducing metachronous recurrences (vs. placebo) with HR of 0.56 (95% CI: 0.3–1.06; P = 0.075). Celecoxib was well tolerated, with similar adverse events and quality-of-life in both arms. Our clinical trial results do not show a clinical benefit for celecoxib in preventing NMIBC recurrence but further investigation of COX-2 inhibitors in this setting is warranted. Cancer Prev Res; 4(10); 1580–9. ©2011 AACR.

OBJECTIVES:Celecoxib is approved as an adjunctive chemopreventive agent in adults with familial adenomatous polyposis (FAP). Its safety and efficacy for colorectal polyps in children is unknown. We evaluated the short-term (3 months) safety and preliminary efficacy of celecoxib in children with FAP.METHODS:This was a phase I, dose-escalation trial, with three successive cohorts of six children. Children of ages 10-14 years with APC gene mutations and/or adenomas with a family history of FAP were studied at M.D. Anderson Cancer Center and the Cleveland Clinic. Colonoscopy was performed at baseline and month 3. Random assignment was in a 2:1 generic:placebo ratio, escalating from cohort 1 (4 mg/kg/day) to cohort 2 (8 mg/kg/day) to cohort 3 (16 mg/kg/day). Adherence and adverse event (AE) monitoring was conducted at 2-week intervals during drug administration. Safety profile, difference in number, and percent change in colorectal polyps were compared among the four treatments (placebo and the three dose-escalation groups).RESULTS:Eighteen subjects completed drug dosing and both colonoscopies. Median age was 12.3 years (56% female). No clinically meaningful differences in AEs were seen between placebo subjects and subjects at any of the three celecoxib doses. Median polyp count at baseline was 31. There was a 39.1% increase in the number of polyps in placebo subjects at month 3, whereas in the highest dose celecoxib group, 16 mg/kg/day, a 44.2% reduction was seen (P=0.01).CONCLUSIONS:Celecoxib at a dose of 16 mg/kg/day, corresponding to the adult dose of 400 mg BID, is safe, well tolerated, and significantly reduced the number of colorectal polyps in children with FAP.

B32 Background: In a randomized trial, the cyclooxygenase-2 inhibitor celecoxib reduced, in a dose-dependent manner, the occurrence of newly detected colorectal adenomas but was associated with an increase in cardiovascular events. Genetic variants in the cytochrome P450 2C9 (CYP2C9) enzyme, particularly the I359L allele, are associated with impaired metabolism of celecoxib and may influence dose-related response or toxicity. Methods: In the Adenoma Prevention with Celecoxib trial, 2,035 participants with a history of prior adenoma were randomized to placebo, 200 mg, or 400 mg of celecoxib twice daily. We genotyped 1660 participants for the I359L as well as R144C variant alleles of CYP2C9; 1497 patients underwent evaluation with at least one follow-up colonoscopy at 1 and 3 years for the occurrence of newly detected adenomas. Results: Compared with placebo, celecoxib treatment at either the twice-daily 200 mg and 400 mg dose was associated with an overall lower three-year cumulative incidence of adenoma among participants with either wild-type or variant genotypes (≥ one R144C or I359L allele). However, the additional benefit of the higher dose was observed primarily among those with I359 genotypes. Among 183 participants with I359L genotypes, treatment with the 400 mg dose was significantly associated with reduced adenoma incidence compared with the 200 mg dose (RR 0.54; 95% CI, 0.31-0.92; p=0.02). In contrast, treatment with the 400 mg dose was not associated with a significantly greater reduction in adenoma incidence compared with the 200 mg dose among the 318 participants with R144C genotypes (RR 0.93; 95% CI, 0.64-1.36; p=0.72) or the 996 participants with wild-type genotypes (RR 0.88; 95% CI, 0.71-1.11; p=0.28). Among participants with I359L genotypes, the three-year cumulative incidence of investigator-reported, treatment-emergent, cardiovascular events was 4.4% for placebo, 3.4% for 200 mg, and 13.3% for 400 mg. The cumulative incidence of cardiovascular events was 3.9% for placebo, 2.8% for 200 mg, and 9.4% for 400 mg among participants with R144C genotypes and 5.7% for placebo, 9.6% for 200 mg, and 8.1% for 400 mg among participants with wild-type genotypes. Conclusions: Chemoprevention with celecoxib appears to be modified by genetic variation in its metabolism. Individuals with CYP2C9 variant I359L genotypes may benefit differentially according to celecoxib dose.