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AbstractBackgroundColon cancer patients have inferior overall survival than a matched general population (MGP). It is unknown if physical activity is associated with a reduction in this survival disparity.MethodsData were analyzed from two National Cancer Institute–sponsored postoperative treatment trials in stage III colon cancer, Cancer and Leukemia Group B (CALGB) 89803 and 80702, with 2876 patients who self‐reported physical activity. Physical activity was converted to metabolic equivalents (MET‐hours/week). The MGP was derived from the National Center for Health Statistics and matched on age, sex, and year.ResultsIn CALGB 89803, among patients who were alive at 3 years, those with <3.0 and ≥18.0 MET‐hours/week had subsequent 3‐year overall survival rates that were −17.1% (95% confidence interval [CI], −22.4 to −11.8) and −3.5% (95% CI, −7.7 to 0.3) lower than MGP, respectively. In CALGB 80702, among patients who were alive at 3 years, those with <3.0 and ≥18.0 MET‐hours/week had subsequent 3‐year overall survival rates that were −10.8% (95% CI, −15.4 to −6.9) and −4.4% (95% CI, −7.6 to −1.6) lower than MGP, respectively. In pooled analyses, among patients who were alive and did not have tumor recurrence by year 3 (n = 1908), those with <3.0 and ≥18.0 MET‐hours/week had subsequent 3‐year overall survival rates that were −3.1% (95% CI, −6.2 to −0.3) lower and 2.9% (95% CI, 1.5–4.2) higher than MGP, respectively.ConclusionsPhysical activity is associated with an attenuation of the survival disparity between patients with stage III colon cancer participating in clinical trials and MGP. Colon cancer survivors who are physically active may achieve survival that approximates the MGP.

Objectives Black/African American (B/AA) pancreatic ductal adenocarcinoma (PDAC) patients have worse clinical outcomes than White patients and are underrepresented in genomic databases. We aimed to expand our understanding of the PDAC somatic landscape from a diverse cohort. Materials and Methods Formalin-fixed paraffin-embedded specimens from 24 surgically resected PDAC cases were collected, with self-reported race/ethnicity. Whole exome sequencing was performed on malignant and benign tissue. Bioinformatics analysis included deduction of genetic ancestry and somatic mutational analysis, with comparisons to public datasets. Results Out of 24 cases, 17 identified as B/AA race; genetic ancestry analysis confirmed proportions of Sub-Saharan African ancestry greater than 47%. The most commonly mutated genes included KRAS , TP53 , SMAD4 , and CDKN2A . Comparison of mutations in our cohort versus publicly available, predominantly White datasets showed higher mutation frequencies of ATM, RREB1, BRCA1/2, KDM6A, ARID1A, BRAF, and MYC ( P < 0.04). When cohorts were combined and analyzed by race, no mutation frequencies differences were observed, including KRAS . Conclusions Genomic analysis of PDAC tumors from B/AA and White patients demonstrate similarities in mutation frequencies. Larger studies are needed to further understand molecular characterizations across continental subpopulations. This study provides further rationale for equitable representation of diverse patients in genomic databases and clinical trials.

ABSTRACTSeveral dynamic models predict mortality and corticosteroid response in alcohol‐associated hepatitis (AH), yet no consensus exists on the most effective model. This study aimed to assess predictive models for corticosteroid response and short‐term mortality in severe AH within a global cohort. We conducted a multi‐national study of patients with severe AH treated with corticosteroids for at least 7 days, enrolled between 2009 and 2019. Dynamic models—Lille‐4, Lille‐7, trajectory of serum bilirubin (TSB), and neutrophil‐to‐lymphocyte ratio (NLR)—were used to estimate 30‐ and 90‐day mortality. Lille‐7 demonstrated the highest accuracy for both 30‐ and 90‐day mortality.

PURPOSE Newly approved drugs and combinations treating multiple myeloma (MM) have resulted in substantial improvements in patients' survival. To deliver rapid access to newer therapies, an earlier end point to expedite clinical trials is needed. Our objective was to evaluate the minimal residual disease–negative complete response (MRD-CR) as an intermediate end point for progression-free survival (PFS) and overall survival (OS) in newly diagnosed (ND) transplant-eligible (NDTE) patients, ND transplant-ineligible (NDTinE) patients, and patients with relapsed/refractory (RR) MM. PATIENTS AND METHODS Individual patient data from 20 randomized multicenter trials were collected. Eleven studies (4,773 patients) with sufficient data were analyzed to evaluate whether 9- or 12-month MRD-CR classified at a 10 –5 threshold could be reasonably likely to predict the clinical benefit of new agents regarding PFS and OS. Global odds ratio (OR) was estimated using the bivariate Plackett Copula model. Supportive evaluation included correlations of the treatment effects on MRD-CR end points and PFS/OS, evaluated by both linear regression ( R 2 weighted least squared ) and Copula ( R 2 Copula ) models. RESULTS The analysis demonstrated that both 9- and 12-month MRD-CR strongly correlated with PFS at patient level in NDTE patients, NDTinE patients, and patients with RRMM. Global ORs ranged from 3.06 to 16.24, all with 95% CIs excluding 1.0. Encouraging trial-level correlations ( R 2 , 0.61-0.70) were observed by pooling three populations and were stronger ( R 2 , 0.67-0.78) in the ND population. Similar results were observed for OS. CONCLUSION Our findings provided the support for use of MRD-CR classified at a 10 –5 threshold at either 9 or 12 months after starting of the treatment, as an intermediate end point to support accelerated approvals, in future trials in NDTE patients, NDTinE patients, and patients with RRMM.

LBA22 Background: Tumor-informed circulating tumor (ct) DNA testing is recognized as a powerful predictor of CRC recurrence. However, the benefit of systemic therapy to prevent or delay clinical recurrence in patients (pts) with molecular recurrence after curative surgery remains uncertain. Methods: Pts with CRC who had undergone curative resection of primary and/or metastatic sites + standard of care (SoC) adjuvant treatment if applicable, were enrolled in ALTAIR study if they (1) prospectively tested positive for ctDNA using a clinically validated, personalized assay (Signatera™, Natera, Inc.) within 3 months before enrollment and (2) had no recurrence on radiological (CT) imaging. Pts were randomized to receive FTD/TPI or placebo for 6 months. CT and ctDNA analyses were conducted every 2 months in the first year, every 3 months in the second year, and every 6 months in the third year. The primary endpoint was disease-free survival (DFS), with secondary endpoints including ctDNA clearance, overall survival (OS), and adverse events. The study assumed a median DFS of 8 months in the placebo group, an HR of 0.667 for the FTD/TPI group, 0.05 significance level, 0.80 power, 2-year enrollment, and 1-year follow-up, requiring 240 pts and 190 DFS events. Baseline ctDNA levels were evaluated by mean tumor molecules (MTM)/ml. Results: Between July 2020 and June 2023, 243 pts were enrolled and randomized to FTD/TPI (n=122) or placebo (n=121). Baseline characteristics were balanced, and 96.3% of pts received SoC treatment postoperatively. FTD/TPI group had a median DFS of 9.30 months vs. 5.55 months in the placebo group, but this difference did not reach statistical significance in the primary population (HR, 0.79; 95% CI, 0.60-1.05; P = 0.107). The FTD/TPI benefit was highly significant in resected oligometastatic stage IV pts as shown in Table. The baseline MTM/ml levels were significantly higher in resected oligometastatic Stage IV pts vs non-Stage IV (0.68 vs 0.32, P = 0.024). Overall, FTD/TPI benefit was significantly pronounced with higher MTM/mL, with linear benefit observed with increasing MTM/mL values at the enrollment time point. OS data remain immature, with 24 events reported across both arms. Grade ≥3 adverse events occurred in 73.0% of the FTD/TPI arm versus 3.3% in the placebo arm, with no new safety signals. Conclusions: Although statistical significance was not reached in the primary population, FTD/TPI showed clinically meaningful DFS benefit in pts with resected oligometastatic disease and a trend towards increasing DFS benefits with increasing MTM/mL values. Clinical trial information: NCT04457297 . Number Baseline MTM/ml Median DFS FTD/TPI(months) Placebo (months) Primary population 243 0.40 9.30 5.55 HR, 0.79 P = 0.107 Stage IV 66 0.68 9.76 3.96 HR, 0.53 P = 0.012 Non-Stage IV 177 0.32 9.26 6.05 HR, 0.86 P = 0.378

LBA14 Background: CALGB/SWOG 80702 previously showed that the addition of celecoxib to standard adjuvant chemotherapy with FOLFOX did not significantly improve disease-free survival (DFS) in patients with stage III colon cancer. Here, we evaluated the prognostic and predictive value of ctDNA in identifying a subpopulation of patients who may benefit from celecoxib. Methods: In the subset of patients with adequate biospecimens who participated in CALGB/SWOG 80702, a randomized phase III trial of 3 versus 6 months of adjuvant 5-FU, leucovorin, oxaliplatin (FOLFOX) +/- celecoxib, ctDNA assessment was performed using a clinically validated, tumor-informed 16-plex mPCR-NGS assay (Signatera(TM), Natera, Inc.) after surgery and before the start of adjuvant therapy (baseline). The Kaplan-Meier method was used to describe the distribution of survival time based on ctDNA positivity and log-rank testing was performed. Cox proportional hazards models were used to examine unadjusted associations between ctDNA positivity and disease-free (DFS) and overall survival (OS). Two-sided P values equal to or less than 0.05 were considered statistically significant, except for interaction P values (tested with a likelihood ratio). Results: In total, 1,011 of the 2,526 patients who participated in 80702 had ctDNA testing results from baseline; 189 were ctDNA positive (18.7%). ctDNA positivity associated with male sex, higher T stage, and N2 (versus N1) stage. ctDNA positivity was significantly associated with worse DFS (hazard ratio [HR] 6.52 [95% confident interval (CI) 5.09-8.34; p<0.0001] and OS (HR 6.28 [95% CI 4.63-8.51; p<0.0001]). Three-year DFS was 86.6% in ctDNA-negative cases and 36.8% in ctDNA-positive cases. Among patients who were ctDNA negative, celecoxib use was not significantly associated with worse DFS as compared to placebo (HR 0.75 [95% CI 0.54-1.05; p=0.095]) with a three-year DFS of 87.7% versus 85.5%, respectively. Among ctDNA-positive patients, celecoxib significantly improved DFS compared to placebo (HR 0.59 [95% CI 0.42-0.85; p=0.004]) with a three-year DFS of 44.1% versus 26.6% (P interaction = 0.25). Similar results were seen for overall survival with a hazard ratio of 0.86 (95% CI 0.56-1.33; p=0.49) for ctDNA negative cases and 0.63 (95% CI 0.41-0.96; p=0.028) for ctDNA-positive cases for celecoxib versus placebo (P interaction = 0.28). Conclusion: In a randomized phase III adjuvant therapy trial for stage III colon cancer, ctDNA was highly prognostic of DFS and OS. ctDNA positivity also appeared predictive of the benefit of adjuvant celecoxib for DFS and OS. These results suggest a potential role for ctDNA in determining which patients should consider celecoxib in addition to standard FOLFOX adjuvant therapy. Clinical trial information: NCT01150045 .

484 Background: The histopathological growth patterns (HGPs) of liver metastasis reflect the complicated and varied interactions between tumor cells and the host microenvironment. We studied HGPs of gastric cancer liver metastasis (GCLM) and sought to predict them using radiomic and clinical variables. Methods: Hepatectomy was performed in 62 patients with GCLM at our university hospital between 2011 and 2021. HGPs were evaluated according to international consensus guidelines, and were classified as either desmoplastic HGP (dHGP) or non-dHGP. CD4, CD8, VEGF and CD31 were analyzed by immunohistochemistry. Eight hundred and fifty-one radiomics features were extracted from CT portal venous phase images and the optimal radiomics signature was determined by univariate analysis and LASSO regression. Multivariable regression analyses and ROC curves were used to assess the predictive performance of HGPs with a radiomic and clinical combined model. Results: Among 62 patients, 14 were categorized as dHGP, and 48 as non-dHGP. Non-dHGP vs. d-HGP was associated with higher tumor N stage and CEA level, and with decreased CD8 + T cells, and lower VEGF and CD31 expression. HGP status was independently associated with patient cancer-specific survival (CSS) (P＜0.05) multivariately.Analysis of percent relative contribution revealed that HGP ranked first for CSS (35.9%), ahead of T (28.9%) and N (28.9%) stage. A model with combined radiomic and clinical features demonstrated robust performance with area under the curve (AUC) values of 0.993 and 0.933 in the training and validation sets, respectively. Conclusions: Non-invasive determination of radiomic and clinical features was shown to predict HGPs types. Compared to dHGP, GCLM with non-dHGP exhibited significantly lower immune cell infiltration and decreased angiogenesis. Among features examined in GCLM, HGP was the most robust for prognostication. Univariate and multivariate analysis of prognostic factors for cancer-specific survival. Characteristics Univariate analysis Multivariate rergression analysis HR (95%CI) P HR (95%CI) P Gender ( Women vs Men ) 1.13(0.61-2.09) 0.71 Age ( >60years vs ≤60years) 1.08(0.60-1.70) 0.98 HGP ( non-desmoplastic HGP vs desmoplastic HGP ) 3.63(1.78-7.41) 0.00 3.48(1.37-8.88) 0.01 T stage ( T3-T4 vs T1-T2 ) 2.03(1.08-3.80) 0.03 2.29(1.15-4.58) 0.02 N stage ( N1-N3 vs N0 ) 3.46(1.66-7.23) 0.00 2.54(1.17-5.56) 0.02 CEA ( >5ng/ml vs ≤5ng/ml ) 2.37(1.25-4.48) 0.01 1.56(0.70-3.48) 0.27

483 Background: Heterogeneity exists in recurrence and survival among patients with intestinal-type gastric cancer (IGC). Nucleotyping is the alterations in chromatin organization. We sought to identify the prognostic utility of nucleotyping, tumor stroma ratio (TSR) and DNA ploidy in these patients. Methods: Radical resection of gastric carcinoma (> 15 LNs removed) was performed in 283 patients (stage I, n=73; stage II, n=102; stage III, n=108) at our university hospital between 2010 and 2018. Automated image cytometry tools were used to quantitatively measure nucleotyping, TSR and DNA ploidy. Cutpoints of nucleotyping and TSR were 0.044 and 50%, respectively. Associations of these features with clinicopathological characteristics, time-to-recurrence (TTR) and cancer specific survival (CSS) were analyzed by univariate and multivariate analysis. Results: Among 283 patients, chromatin heterogeneity, high TSR and non-diploid were significantly associated with larger tumor size, higher T and N stage, and poorer TTR and CSS at 5 years. In a Cox multivariable analysis, nucleotyping and TSR were independently associated with TTR and CSS (P＜0.05) (Table). The top three contributors to TTR were N stage (33.9%), nucleotying (29.7%) and TSR (25.5%). The top three contributors to CSS were N stage (35.6%), nucleotying (29.7%) and TSR (18.0%). As a combined variable, the percent relative contribution of nucleotyping and TSR ranked first for TTR and CSS (56.0%, 50.0%), ahead of N stage (33.4%, 34.6%) and TILs (8.4%, 10.6%). Conclusions: Nucleotyping and TSR were each significantly and independently associated with TTR and CSS, and their combined variable was more strongly prognostic than either alone. Cox multivariable analysis of TTR and CSS. Features TTR HR (95%CI) TTR P value CSS HR (95%CI) CSS P value Tumor size (>3cm vs ≤3cm) 1.10 (0.48-2.54) 0.83 0.77 (0.35-1.70) 0.56 T stage (T3-T4 vs T1-T2) 1.07 (0.46-2.49) 0.87 1.41 (0.53-3.76) 0.49 N stage (N2N3 vs N0N1) 2.84 (1.39-5.78) <0.01 7.69 (3.37-17.55) <0.01 Adjuvant Therapy (with vs without) 1.32 (0.72-2.40) 0.37 0.85 (0.48-1.52) 0.59 TB (high vs low) 1.29 (0.62-2.69) 0.50 1.61 (0.85-3.07) 0.15 TILs（low vs high） 1.73 (0.96-3.13) 0.07 1.90 (1.06-3.40) 0.03 Nucleotyping (Chromatin heterogeneous vs Chromatin homogeneous) 2.19 (1.21-3.99) 0.01 3.44 (1.96-6.03) <0.01 TSR (high vs low) 2.12 (1.16-3.82) 0.01 2.51 (1.43-4.41) <0.01 DNA ploidy (Non-diploid vs Diploid) 1.20 (0.55-2.63) 0.65 0.98 (0.44-2.15) 0.95 1 TTR, time-to-recurrence; 2 CSS, cancer specific survival.

TPS309 Background: Patients with oligometastatic colorectal cancer (CRC) often experience long-term progression-free survival and overall survival (OS) following aggressive local treatment of isolated metastases, especially in the liver. However, the effectiveness of local ablative therapies, such as microwave ablation (MWA) and stereotactic body radiation therapy (SBRT), in patients with inoperable limited metastatic CRC or those with additional metastases outside the liver or lungs, remains uncertain. Despite the historical use of local therapy for oligometastatic CRC, often influenced by provider bias rather than strong evidence, questions persist about the potential benefits of applying this approach to patients with more extensive disease. This trial aims to address this clinical challenge by evaluating the safety and efficacy of adding total ablative therapy (TAT) of all disease sites to standard systemic treatment in patients with limited metastatic CRC. Methods: A022101/NRG-GI009 is a randomized phase III study within the National Clinical Trials Network, set to enroll 364 patients with newly diagnosed metastatic CRC (BRAF wild-type, microsatellite stable). Patients with liver-only metastatic disease are excluded. Pre-registration during first-line systemic therapy induction is encouraged. Eligible lesions must be treatable with surgical resection, MWA, and/or SBRT. Patients without significant radiographic progression after 12-39 weeks of first-line systemic therapy, with 4 or fewer disease sites post-induction chemotherapy, will be randomized 1:1. Randomization will be stratified by the number of metastatic organ sites (1-2 vs. 3-4), timing of metastatic disease diagnosis (de novo vs. secondary), and the presence of metastatic disease outside the liver/lungs in at least one site. Patients in Arm 1 will receive TAT, targeting all metastatic sites with a combination of surgical resection, MWA, and/or SBRT, followed by standard systemic therapy. Patients in Arm 2 will continue with standard systemic therapy alone. The choice of systemic therapy is at the discretion of the medical oncologist and may include continued therapy, maintenance chemotherapy, or observation. The primary endpoint is OS, with secondary endpoints including event-free survival, treatment-related toxicities, and local recurrence. Exploratory biomarker analyses will also be conducted. The study requires 346 evaluable patients across the two arms to demonstrate an OS improvement with a hazard ratio of 0.7, providing 80% power with a one-sided alpha of 5%. The trial employs a group sequential design with two interim analyses (at 25% and 50% of events) to assess futility. The trial began in January 2023, and patient recruitment is ongoing. Clinical trial information: NCT05673148 .

Abstract Background We previously identified circulating and MRI biomarkers associated with the surgical management of Crohn’s disease (CD). Here we tested associations between these biomarkers and ileal resection inflammation and collagen content. Methods Fifty CD patients undergoing ileal resection were prospectively enrolled at 4 centers. Circulating CD64, extracellular matrix protein 1 (ECM1), GM-CSF autoantibodies (GM-CSF Ab), and fecal calprotectin were measured by ELISA. Ileal 3-dimensional magnetization transfer ratio (3D MTR), modified Look-Locker inversion recovery (MOLLI) T1 relaxation, diffusion-weighted intravoxel incoherent motion (IVIM), and the simplified magnetic resonance index of activity (sMaRIA) were measured by MRI. Ileal resection specimen acute inflammation was graded, and collagen content was measured quantitatively using second harmonic imaging microscopy. Associations between biomarkers and ileal collagen content were tested. Results Median (interquartile range [IQR]) age was 19.5 (16-33) years. We observed an inverse relationship between ileal acute inflammation and collagen content (r = −0.39 [95% confidence interval {CI}: −0.61, −0.10], P = .008). Most patients (33 [66%]) received biologics, with no variation in collagen content with treatment exposures. In the univariate analysis, CD64, GM-CSF Ab, fecal calprotectin, and sMaRIA were positively associated with acute inflammation and negatively associated with collagen content (P &lt; .1). The multivariable model for ileal collagen content (R2 = 0.31 [95% CI: 0.11, 0.52]) included log CD64 (β = −.27; P = .19), log ECM1 (β = .47; P = .06), log GM-CSF Ab (β = −.15; P = .01), IVIM f (β = .29, P = .10), and IVIM D* (β = 1.69, P = .13). Conclusions Clinically available and exploratory circulating and MRI biomarkers are associated with the degree of inflammation versus fibrosis in CD ileal resections. With further validation, these biomarkers may be used to guide medical and surgical decision-making for refractory CD.