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AbstractDespite advances in acute myeloid leukemia (AML) treatment, significant unmet medical needs remain. Surrogate end points for overall survival can accelerate the approval of novel therapies. Measurable residual disease (MRD) is a promising surrogate end point candidate, providing a sensitive and quantitative assessment of disease burden. Numerous studies have demonstrated that negative MRD status—across diverse methodologies, assessment timepoints and thresholds, patient subgroups, and clinical settings—independently predicts improved survival. Although MRD can inform therapeutic decisions at the patient level, its formal integration as a primary surrogate end point in regulatory frameworks for clinical trials requires rigorous validation. MRD Partnership and Alliance in AML Clinical Treatment (MPAACT) is a research consortium among industry and academic leaders. MPAACT actively engages with regulatory agencies, health technology assessment bodies, technology vendors, and patient groups to establish a pathway for validating MRD as a surrogate end point in AML clinical trials. For the current article, the authors reviewed the status of MRD assessment, its use in recent clinical trials, current MRD assessment methodologies, standardization, regulatory guidance, statistical approaches, and patient access considerations necessary for MRD to become a surrogate clinical trial end point. The extensive collaboration between MPAACT, global industry, and academic partners—including data sharing and resource integration—underscores the collective commitment to advancing AML therapies. Establishing MRD as a surrogate end point could accelerate the development and approval of innovative treatments, ultimately improving patient outcomes.

LBA3509 Background: Systemic inflammation has been implicated in colon cancer progression. We examined whether intake of a proinflammatory diet is associated with survival among patients (pts) with stage III colon cancer. Methods: This prospective cohort study was nested within a randomized phase III trial of adjuvant therapy in pts with stage III colon cancer who had undergone curative-intent resection. EDIP score – a validated tool to classify the inflammatory nature of diets – was derived as a cumulative exposure using data from food-frequency questionnaires completed within 6 weeks of randomization and 14-16 months (mo) after randomization. Cox proportional hazards regression was used to assess the associations of EDIP with disease-free survival (DFS) and overall survival (OS). Results: Of 1625 included pts, the mean (SD) age was 60.9 (10.5) years (yrs). Compared to pts in the lowest EDIP quintile, pts in the highest quintile (a more inflammatory diet) were younger (58.7 ± 10.8 vs 61.3 ± 9.5 yrs old) and more likely to be female (64.0% vs 48.9%) and have worse performance status (ECOG 1-2: 35.7% vs 19.4%). Pts in the highest quintile were less likely to be White (76.6% vs 92.0 %) and more likely to be Black (15.4% vs 3.7%). Baseline aspirin use, assigned chemotherapy (3 mo vs 6 mo), and assigned pharmacotherapy (celecoxib vs placebo) were not significantly different across EDIP quintiles. Compared with pts in the lowest EDIP quintile, pts in the highest quintile had significantly worse OS (multivariable hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.26-2.77, P trend =0.01), but not DFS (HR 1.36, 95% CI 0.99-1.86, P trend =0.22). Diet and physical activity jointly influenced OS. Those with lower EDIP scores (quintiles 1-4, 80% of the study population) and higher physical activity (≥9 MET-h/wk) had the best OS (HR 0.37, 95% CI 0.25-0.53) compared with pts in the highest EDIP quintile (20% of the study population) and lower physical activity (<9 MET-h/wk) ( P interaction <0.001). The association between higher EDIP and OS was consistent when analyzed by celecoxib and placebo treatment arms ( P interaction 0.54). The relationship between EDIP and OS did not differ significantly according to aspirin use, with HR 1.60 (95% CI 0.71-3.60) among aspirin users and HR 2.01 (95% CI 1.27-3.16) among aspirin non-users ( P interaction 0.06). Conclusions: Our findings suggest that greater intake of a proinflammatory dietary pattern is associated with worse OS in pts with stage III colon cancer. Regular physical activity may attenuate the association, and further investigation of diet and physical activity intervention is warranted. Support: U10CA180821, U10CA180882, U24CA196171, U10CA180863, CCS 707213, UG1CA233234, U10CA180820, U10CA180868, U10CA180888; https://acknowledgments.alliancefound.org. Pfizer; ClinicalTrials.gov Identifier: NCT01150045.

BACKGROUND: Small, randomized trials of patients with cervical artery dissection showed conflicting results regarding optimal stroke prevention strategies. We aimed to compare outcomes in patients with cervical artery dissection treated with antiplatelets versus anticoagulation. METHODS: This is a multicenter observational retrospective international study (16 countries, 63 sites) that included patients with cervical artery dissection without major trauma. The exposure was antithrombotic treatment type (anticoagulation versus antiplatelets), and outcomes were subsequent ischemic stroke and major hemorrhage (intracranial or extracranial hemorrhage). We used adjusted Cox regression with inverse probability of treatment weighting to determine associations between anticoagulation and study outcomes within 30 and 180 days. The main analysis used an as-treated crossover approach and only included outcomes occurring with the above treatments. RESULTS: The study included 3636 patients (402 [11.1%] received exclusively anticoagulation and 2453 [67.5%] received exclusively antiplatelets). By day 180, there were 162 new ischemic strokes (4.4%) and 28 major hemorrhages (0.8%); 87.0% of ischemic strokes occurred by day 30. In adjusted Cox regression with inverse probability of treatment weighting, compared with antiplatelet therapy, anticoagulation was associated with a nonsignificantly lower risk of subsequent ischemic stroke by day 30 (adjusted hazard ratio [HR], 0.71 [95% CI, 0.45–1.12]; P =0.145) and by day 180 (adjusted HR, 0.80 [95% CI, 0.28–2.24]; P =0.670). Anticoagulation therapy was not associated with a higher risk of major hemorrhage by day 30 (adjusted HR, 1.39 [95% CI, 0.35–5.45]; P =0.637) but was by day 180 (adjusted HR, 5.56 [95% CI, 1.53–20.13]; P =0.009). In interaction analyses, patients with occlusive dissection had significantly lower ischemic stroke risk with anticoagulation (adjusted HR, 0.40 [95% CI, 0.18–0.88]; P interaction =0.009). CONCLUSIONS: Our study does not rule out the benefit of anticoagulation in reducing ischemic stroke risk, particularly in patients with occlusive dissection. If anticoagulation is chosen, it seems reasonable to switch to antiplatelet therapy before 180 days to lower the risk of major bleeding. Large prospective studies are needed to validate our findings.

ABSTRACT Intratumor heterogeneity arises from ongoing somatic evolution complicating cancer diagnosis, prognosis, and treatment. Here we present TEATIME (es t imating e volution a ry events t hrough s i ngle-ti m epoint s e quencing), a novel computational framework that models tumors as mixtures of two competing cell populations: an ancestral clone with baseline fitness and a derived subclone with elevated fitness. Using cross-sectional bulk sequencing data, TEATIME estimates mutation rates, timing of subclone emergence, relative fitness, and number of generations of growth. To quantify intratumor fitness asymmetries, we introduce a novel metric—fitness diversity—which captures the imbalance between competing cell populations and serves as a measure of functional intratumor heterogeneity. Applying TEATIME to 33 tumor types from The Cancer Genome Atlas, we revealed divergent as well as convergent evolutionary patterns. Notably, we found that immune-hot microenvironments constraint subclonal expansion and limit fitness diversity. Moreover, we detected temporal dependencies in mutation acquisition, where early driver mutations in ancestral clones epistatically shape the fitness landscape, predisposing specific subclones to selective advantages. These findings underscore the importance of intratumor competition and tumor-microenvironment interactions in shaping evolutionary trajectories, driving intratumor heterogeneity. Lastly, we demonstrate that TEATIME-derived evolutionary parameters and fitness diversity offer novel prognostic insights across multiple cancer types.

Background: Total ankle arthroplasty (TAA) using patient-specific instrumentation (PSI) has increased in popularity with evidence for decreased operative duration, fluoroscopy usage, and increased implant placement accuracy. To date, no comparisons have verified the accuracy of PSI in vivo using preoperative and postoperative weightbearing computed tomography (WBCT). Our study aims to supplement the literature by quantifying the accuracy and precision of PSI-guided implant positioning using WBCT. The primary study outcome is to identify positioning deviations in degrees or millimeters in any plane for talus and tibial PSI-guided resections and subsequent implant placement. Secondary outcomes were correlation and regression analyses performed to identify variables that correlate to resection or implant placement deviation, as well as comparison to existing radiography-based PSI techniques. Methods: This was a single-surgeon, single-implant consecutive patient retrospective study where preoperative and postoperative WBCTs were obtained. TAA was performed by the senior author with the same low-profile implant for all cases. Talus and tibial resection analysis was performed in computer-automated fashion on postoperative segmented WBCTs and is described as 3 possible deviations from plan (cut height in millimeters, sagittal slope, varus/valgus deviation). Overall deformity in this group was not severe. Implant placement factors independent of PSI guides are described as center-of-mass translations (mm) and axial rotation (degrees). Desired accuracy for the PSI system was within ±2 mm or ±2 degrees of the preoperative plan. Statistical analysis of data collected included Student t test and linear regression analyses. Results: Thirty patients were included. Four talus implants were excluded per intraoperative surgeon discretion (deviation from PSI plan, use of conventional instruments). All postoperative tibial measurements were within the desired limits, except for mediolateral center of mass positioning ( P = .003) and slope ( P = .013). Two of six talar parameters also diverged from preoperative measurements: axial rotation ( P = .015) and anteroposterior positioning ( P = .002). In addition, no correlations exceeding r = 0.5 were noted between preoperative deformity measurements and postoperative positioning. Conclusion: For the 26 ankles that did not require an intraoperative deviation from PSI plan and/or use of conventional instruments, total ankle replacement performed with PSI using WBCT results in component placement with relatively little deviation from the preoperative plan. In addition, the lack of correlation between preoperative deformity and implant placement suggests that the magnitude of preoperative deformity in this group was not associated with the accuracy of PSI-guided component positioning. Level of Evidence: Level III, retrospective cohort study.

e19554 Background: Adding daratumumab to standard multiple myeloma (MM) regimens improves response rates and clinical outcomes. Systematic reviews (meta-analyses) allow further evaluation of its effectiveness in MM patients with high-risk cytogenetic factors but are limited by model assumptions. his study addresses these limitations using a novel synthetic individual patient data (SynIPD) generation algorithm to enable a more robust analysis. Methods: Advances in AI have enabled the creation of synthetic data that mimics the statistical properties of real patient data, empowering aggregated analyses of clinical trials. This study focuses on newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) patients with high-risk cytogenetic profiles. Six studies were included: ALCYONE, CASSIOPEIA, and MAIA for NDMM, and CANDOR, CASTOR, and POLLUX for RRMM. Large language models extracted clinical evidence, and SynIPD was generated, incorporating cytogenetic profiles. Random-effects meta-analyses were conducted, and results were compared with pooled analyses using synthetic data. Results: Synthetic data were generated for three studies for NDMM (ALCYONE, CASSIOPEIA, MAIA) and three studies for RRMM (CANDOR, CASTOR, POLLUX). The generated hazard ratios (HRs) for each study closely aligned with reported HRs for high-risk patients, with a maximum relative error of less than 2%. By pooling these datasets, we obtained synthetic datasets for NDMM and RRMM patients. Stratified Cox regression analyses yielded HRs (95% confidence interval) of 0.764 (0.529-1.104) for NDMM and 0.431 (0.294-0.613) for RRMM. Random-effects meta-analyses showed HRs (95% confidence interval) of 0.764 (0.529-1.104) for NDMM and 0.425 (0.287-0.621) for RRMM. Compared with traditional meta-analysis techniques, the synthetic data approach provides additional clinical insights that were not available in the original publications. For instance, the clinical results for the three NDMM studies are summarized as KM curves in Figure 1, which were not reported in the original studies. Conclusions: Our results suggest that the addition of daratumumab to standard regimens improves PFS for RRMM patients with high-risk cytogenetic factors, although its benefit for NDMM patients is not statistically significant. Pooling synthetic data enhances the robustness of conventional meta-analysis outcomes. The identification of HRs and corresponding confidence intervals through SynIPD improves the credibility of our proposed method, offering a reliable approach to evaluating the efficacy of daratumumab in high-risk patients. Since SynIPD includes individual covariate information, it provides deep clinical insights beyond merely enhancing meta-analysis. In other words, any statistical results derived from the original IPD can be effectively approximated using SynIPD.

3520 Background: Recent analyses highlight nonhierarchical outcomes using the 8 th Edition AJCC staging system for CC. For instance, the 5-year survival rate for stages I and IIIa patients (pts) closely align. Additionally, tumor deposits (TDs) have been established as significant prognostic indicators. The AJCCCCEP commissioned this study to develop an updated pathological staging system for CC focused specifically on pts without distant metastasis (M0), while retaining the existing stage IV classification. Methods: Individual patient data (IPD) from pts diagnosed with cc (2010- 2017) in the NCDB were divided into training (70%) and internal validation (30%) datasets. External validation used IPD from clinical trials. The primary endpoint was overall survival (OS). Risk classification development for M0 pts incorporated ungrouped data on pathologic T categories, the number of involved regional lymph nodes (LN+), and TD counts. Recursive partitioning and regression tree analyses were applied to construct hierarchical staging levels. Pre-specified criteria required survival probabilities to be consecutive and show clear separations using Kaplan-Meier (KM) estimates with pairwise log-rank test P of < 0.005 for the training and < 0.05 for validation analyses. Results: Data from 281,997 pts (median age 67 years, 50% male, 81% white, 55% T3, 19% T4, 44% N+, 26% M+, and 11% with ≥1 TD) were analyzed, with a median follow-up of 7.3 years. The updated staging system (Table) met pre-specified criteria, with all observed pairwise P < 0.0001 in the development and internal validation sets. KM OS curves displayed a hierarchical separation across all sub-levels after the 1 st year of diagnosis. Consistent results were seen in pts treated with adjuvant chemotherapy in 4 trials (all pair-wise P < 0.0001). Conclusions: The proposed pathological staging system for M0 pts fulfills pre-specified criteria for hierarchical risk stratification, validated both internally and externally, and provides an evidence-based update. Pending review process, the AJCCCCEP will recommend that these changes be made to the Version 9 staging protocol for colon cancer to improve prognostication for CC pts. Stage T, # of LN+, # of TD M % of pts 1y OS (CI), % 3y OS (CI), % 5y OS (CI), % I T1, 0, 0 0 5 96 (95-97) 91 (90-92) 84 (83-86) IIa T2, 0, 0 0 10 95 (94-95) 88 (88-89) 80 (79-81) IIb T1, 0, 1+T1, 1+, 0T2, 0, 1+T2, 1-4, 0T3, 0, 0 0 27 93 (92-93) 84 (84-85) 75 (75-76) IIIa T1, 1+, 1+T2, 1-4, 1+T2, 5+, 0T3, 0, 1+T3, 1-4, 0 0 14 92 (91-92) 80 (80-81) 71 (70-72) IIIb T2, 5+, 1+T3, 1-4, 1+T3, 5+, 0T4a, 0-4, 0T4b, 0-2, 0 0 13 86 (86-87) 69 (68-70) 58 (57-59) IIIc T3, 5+, 1+T4a, 0-4, 1+T4a, 5+, anyT4b, 0-2, 1+T4b, 3+, any 0 5 78 (77-80) 53 (51-54) 40 (38-41) IVa Any 1a 19 59 (58-60) 28 (28-29) 17 (16-18) IVb Any 1b 7 43 (42-44) 14 (13-14) 6 (6-7) CI: 95% confidence internal; Peritoneum involvement data were not available before 2018 in NCDB. Thus, IVa/b were based on 7 th Edition.

3504 Background: Among patients with resected node-positive colon cancer, nearly 30% will relapse despite standard adjuvant chemotherapy. Analysis of molecular residual disease (MRD) using circulating tumor DNA (ctDNA) may enable risk stratification for tumor recurrence and inform adjuvant treatment decisions. Methods: Postsurgical ctDNA was analyzed in patients with stage III colon carcinoma who participated in a phase 3 trial of adjuvant FOLFOX alone or combined with cetuximab (n = 3084) [NCCTG N0147]. We utilized a tissue-free epigenomic assay for ctDNA detection (Guardant Reveal) with sampling prior to start of adjuvant therapy. Among ctDNA positives, epigenomic tumor fraction (TF) was estimated and ctDNA genotyping was done with Guardant360 (panel of 739 genes). Median follow-up was 6.1 years (yr). Study endpoints included time-to-recurrence (TTR), disease-free survival (DFS) and overall survival (OS) analyzed by Kaplan–Meier method. Multivariable Cox proportional hazards models were used to assess prognostic utility of ctDNA status adjusting for confounders. Interaction between ctDNA and clinicopathological features were assessed. Results: Among 2260 patients with evaluable ctDNA data, 461 (20.4%) were ctDNA positive.Tumors were significantly associated with higher T, N stage, BRAF V600E , high grade, obstruction/perforation, and worse performance status. Positive vs negative ctDNA was significantly associated with shorter TTR (hazard ratio [HR] 4.33, 95% confidence interval [CI] 3.65-5.13, P < 0.0001), poorer DFS (HR 3.74, CI 3.18-4.39, P < 0.0001] and OS (HR 3.17, CI 2.63-3.83, P < 0.0001), adjusting for covariates and tissue MMR, KRAS and BRAF V600E . ctDNA positive vs negative patients had 3y DFS of 36.4% (95%CI 32.2-41.2%) vs 82.5% (95% CI 80.0-84.4%), respectively. Adverse prognosis was consistent across subgroups (all P < 0.05), with stronger detrimental effects for positive ctDNA in N1 (vs. N2), T1/2 (vs T3 or 4), and mismatch repair deficient tumors [interaction P = 0.0002 to 0.041). Among patients with positive ctDNA, TF in those who recurred/died within 3 yr was double of those who remained recurrence-free ( P = 0.0001). High vs. low ctDNA TF ( > vs ≤ median) further stratified TTR (HR 1.48, CI 1.17-1.88, P = 0.0011), DFS (HR 1.52, CI 1.21-1.92, P = 0.0004) and OS (HR 1.58, CI 1.21-2.07, P = 0.0009), adjusting for confounders. ctDNA positive cases, . Analyses of ctDNA detection by site of recurrence, ctDNA clearance, and genomic variant detection are ongoing. Conclusions: In the largest study evaluating tissue-free epigenomic-based MRD detection, we demonstrate a robust prognostic utility of postsurgical ctDNA. Tumor fraction provided further patient stratification and analysis is ongoing to identify a subgroup based on TF that may be unlikely to clear ctDNA despite adjuvant chemotherapy.

TPS3634 Background: For patients with oligometastatic colorectal cancer (CRC), aggressive local therapy of isolated metastases, particularly in the liver, has been associated with long-term progression-free and overall survival (OS) primarily based on retrospective evidence. However, in patients with limited metastatic CRC that is deemed inoperable or those with additional disease outside of the liver or lungs, the role of local ablative therapies, including microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), to render patients disease free is less clear. Despite the long history of treating oligometastatic CRC with local therapy, which is largely provider biased, questions remain regarding the benefit of extending the paradigm of metastatic directed therapy to patients with more extensive disease. This trial seeks to use a pragmatic multimodality approach that mirrors the current clinical dilemma. This study is designed to evaluate the safety and efficacy of adding total ablative therapy (TAT) of all sites of disease to standard of care systemic treatment in those with limited metastatic CRC. Methods: A022101/NRG-GI009 is a National Clinical Trials Network randomized phase III study planned to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable) without peritoneal metastasis or liver-only disease on baseline imaging. Patients receive first-line systemic therapy for 12-39 weeks. Patients with ≤4 sites of metastatic disease following initial systemic therapy that are amenable to any combination of surgical resection, MWA, and/or SBRT are then randomized 1:1, stratified by number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and presence of metastatic disease outside the liver/lungs in at least 1 site. Patients in Arm 1 will receive TAT consisting of treatment of all metastatic sites with SBRT, MWA, and/or surgical resection followed by standard of care systemic therapy. Patients in Arm 2 will continue with standard of care systemic therapy alone. The primary endpoint is OS. Secondary endpoints include event-free survival, treatment-related toxicities, and local recurrence with exploratory biomarker analyses. The study needs 346 evaluable patients combined in the 2 arms to demonstrate an improvement in OS with a hazard ratio of 0.7 to provide 80% power with a one-sided alpha of 5%. The trial utilizes a group sequential design with two interim analyses (25% and 50% of events) for futility. The trial activated in January 2023 and recruitment is ongoing. Support: U10CA180821, U10CA180882; https://acknowledgments.alliancefound.org. U10CA180820 (ECOG-ACRIN); U10CA180868 (NRG); U10CA180888 (SWOG); Clinical trial information: NCT05673148 .