3609 Background: Detection of circulating tumor DNA (ctDNA) is prognostic for recurrence after completion of curative-intent therapy for patients (pts) with colorectal cancer (CRC). Our MD Anderson INTERCEPT platform enrolls ctDNA(+) CRC pts onto matched clinical trials, with the goal of eradicating minimal residual disease (MRD) and curing more pts with CRC. To gain insights on how to identify CRC pts most likely to have true MRD, we retrospectively reviewed the role of non-specific radiographic abnormalities in forecasting CRC recurrence. Methods: For this retrospective review of CRC pts included in ctDNA intervention trials (Table) from 1/2019-12/2025, MRD at baseline was defined as (1) having no radiographically evident disease at time of study enrollment and (2) detection of ctDNA on an MRD assay (Signatera). ctDNA levels were quantified as mean tumor molecules (MTM) per mililiter (mL) plasma. Radiographic sites of disease progression on clinical trials were compared with pre-treatment imaging. Median recurrence-free survival (RFS) was estimated using Kaplan Meier and compared with Cox regression. Results: 54 pts with definitively treated CRC prior to subsequent ctDNA(+) were enrolled across 4 trials (Table); 45 pts (83%) had stage IV disease. No pts had radiographically evident CRC at trial start. Median ctDNA levels were 0.45 MTM/mL (IQR 0.12 – 2.4). After a median follow up of 6.4 months (IQR, 3.5-9.5), 42 (78%) pts had recurred after treatment on a ctDNA intervention trial. Median RFS was 8.1 months (95% CI 4.4 - 9.4). Sites of recurrence were liver (N=20, 48%), lung (N=13, 31%), lymph nodes (N=10, 24%), and peritoneum (N=3, 7%). Upon retrospective review, minute but discernible lesions were identified at the sites of recurrence in 25 (60%) of the pts who had a recurrence on MRD trials. At eligibility evaluation these were characterized as “benign” in 14 (56%) or as “post-procedural” in 11 (44%) of the cases. The presence of indistinguishable CRC deposits at the start of the trial was associated with inferior RFS (4.2 vs 9.3 months; HR 1.96 (95% CI 1.04-3.70; p = 0.04). Conclusions: Subclinical radiographic findings may confound true identification of pts with CRC MRD for clinical trials. Optimizing definitions of radiographically detectable disease is warranted in order to ensure homogenous populations of CRC that are the most likely to benefit from novel MRD therapies. Demographic characteristics across four trials. Number of Patients Percentage (%) Age at Enrollment < 30 1 2.4 30-39 3 7.3 40-49 8 19.5 50-59 12 29.3 60-69 14 34.1 70+ 3 7.3 Gender Male 34 63.0 Female 20 37.0 Race/Ethnicity White or Caucasian 34 63.0 Black or African American 5 9.3 Hispanic or Latino 11 20.4 Asian 1 1.9 Other 3 5.6 Stage at Enrollment I 0 0.0 II 0 0.0 III 9 16.7 IV 45 83.3 Trial Bintrafusp alfa 4 7 NK cells with cetuximab 15 27.8 Lifestyle interventions 16 29.6 Trifluridine/tipiracil 19 35.2

BACKGROUND:Mucinous cyst-associated pancreatic cancer (CA-PC) outcomes are varied. This study compares the presentation, management, and outcomes of CA-PC with classic pancreatic ductal adenocarcinoma (PDAC) using a national data set. METHODS:We queried the National Cancer Database (NCDB) from 2006 to 2019 for patients with AJCC Stage I-IV CA-PC and PDAC using histologic codes. Clinicopathologic characteristics and outcomes were analyzed, and overall survival (OS) was compared using Kaplan-Meier and Cox proportional hazard models. RESULTS:Among 239,563 patients, 8260 (4%) had CA-PC, while 231,303 (97%) had PDAC. CA-PC was diagnosed at earlier stages (Stage II-IV: 66% vs. 76%, P <0.001), with more patients undergoing pancreatectomy (34% vs. 24%, P <0.001). CA-PC patients more frequently had upfront surgery (91.% vs. 76%, P <0.001) but less chemotherapy (55% vs. 75%, P <0.001) and radiation (23% vs. 33%, P <0.001). Median OS after resection was longer for CA-PC (43.2 vs. 22.9 mo, P <0.001). CA-PC was associated with improved survival in stages I (HR: 0.49) and II (HR: 0.73), but not in stage III (HR: 1.07). DISCUSSION:CA-PC has a better prognosis than PDAC in early stages but not in advanced disease, offering important insights for therapeutic strategies.

PURPOSE:To determine whether wash-in (WI) and wash-out (WO) rates of contrast involving the future liver remnant (FLR) based on 2-dimensional venograms following portal vein embolization (PVE) can predict liver hypertrophy. METHODS:This is a single-center, retrospective, observational, cohort study of consecutive patients who underwent PVE from August 2019 to March 2024 during which the post-PVE venogram was obtained for more than 15 s. Enhancement of the FLR on post-PVE venograms was plotted as a function of time. Piecewise linear fits were applied to the datasets to derive WI and WO rates. Rates were compared to degree of hypertrophy (DH) and kinetic growth rate (KGR). RESULTS:16 patients who underwent PVE were included in the analysis (RPVE, n = 10; RPVE+4, n = 6). Median standardized FLR (sFLR) prior to PVE increased from 23% (median, range 15-49%) to 34% (median, range 24-54%), P = 0.0008. DH was 11.9% (median, range 2.0-19.9%) and KGR was 2.5% (median, range 0.5-4.7%). WI rates measured 0.0878 (median, range 0.0669-0.1760). WO rates measured 0.0315 (median, range 0.0039-0.0473). WO:WI ratios measured 0.2886 (median, range 0.0538-0.5760). Spearman's rank order correlations were calculated between WO:WI and DH (ρ = 0.6265) as well as WO:WI and KGR (ρ = 0.6529). Multivariate linear regression analysis of WO:WI with DH and KGR yielded P-values of 0.0470 and 0.0980, respectively. CONCLUSIONS:WO:WI ratios of the FLR calculated from 2-dimensional venograms following PVE may correlate with DH, providing immediate post-PVE assessment of the regenerative capacity of the FLR.

3615 Background: During nonoperative management (NOM) for rectal cancer after a clinical complete response (cCR) or near-CR (nCR), 25–30% develop local regrowth and 5–10% develop distant metastasis, highlighting the need for improved risk stratification and surveillance. Circulating tumor DNA (ctDNA) has emerged as a prognostic biomarker, but its utility in NOM decision making remains undefined. Methods: We retrospectively studied 110 patients with stages I-III, microsatellite stable rectal adenocarcinoma achieving cCR/nCR after neoadjuvant therapy (2020-2024) managed with NOM and tumor-informed ctDNA testing in the INTERCEPT program (Signatera Exome). We assessed longitudinal ctDNA status during NOM and the first post-treatment ctDNA in relation to local regrowth and/or distant metastasis (Kaplan–Meier/log-rank; Fisher’s exact). We also evaluated per-sample accuracy for events occurring within ±90 days of each blood draw. Results: Over a median follow-up of 25 months, 23 (20.9%) patients developed local regrowth and 12 (10.9%) developed distant metastases (Table 1). Patients with ever positive longitudinal ctDNA had an associated worse 2-year regrowth-free survival (41.7% vs 83.9%, P=0.0002) and metastasis-free survival (41.7% vs 94.9%, P<0.0001) than those with persistently negative ctDNA. Among patients with an evaluable first post-treatment ctDNA result (within 180 days post treatment; n=72), those with a positive result had an associated lower regrowth-free survival (P = 0.0006) and metastasis-free survival (P < 0.0001). In per-sample analysis (n=669), ctDNA showed low sensitivity and high specificity for local regrowth (41.4% and 94.3%) and higher sensitivity and specificity for distant metastasis (73.8% and 97.4%). Twenty-two of 23 patients with local regrowth underwent salvage surgery; ctDNA positivity at local regrowth was associated with more advanced pathological T stage (66.7% of ypT3–4 vs 15.4% of ypT0–2, P=0.01). Conclusions: During NOM for rectal cancer, ctDNA may be used to identify a small subgroup at high risk of local regrowth and/or distant metastasis. However, many local regrowth occurs despite persistently negative ctDNA, consistent with limited sensitivity. Negative ctDNA results should therefore not prompt de-escalation of endoscopic and radiologic surveillance when a NOM strategy is used. Overall rates of local regrowth and distant metastasis. Local regrowth (n=23) a P Distant metastasis (n=12) P Longitudinal ctDNA <.0001 <.0001 Persistently negative (n=95) 14/95 (14.7%) 3/95 (3.2%) Ever positive (n=15) 9/15 (60.0%) 9/15 (60.0%) First post-treatment ctDNA b 0.005 <.0001 Negative (n=67) 15/67 (22.4%) 5/67 (7.5%) Positive (n=5) 4/5 (80.0%) 4/5 (80.0%) a Two had synchronous and 5 had metachronous distant metastasis. b Within 6 months post treatment, n = 72.

Surgical and systemic management of neuroendocrine liver metastases (NELM) has evolved over the past decades. This study aimed to evaluate temporal changes in prognosis and identify factors associated with improved survival after hepatic cytoreduction for NELM. Patients who underwent hepatic cytoreduction for NELM during 1998–2023 were retrospectively analyzed and divided into earlier period (EP, 1998–2008) and later period (LP, 2009–2023) cohorts. Clinicopathological features, perioperative outcomes, and survival were compared. Covariate-adjusted survival curves and propensity score matching were used to compare overall survival (OS) between major hepatectomy and liver-parenchyma-sparing cytoreduction (LPSC). The study included 293 patients, 132 in the EP cohort and 161 in the LP cohort. The LP cohort had a lower rate of major hepatectomy (32.9

BackgroundHepatocellular carcinoma (HCC) incidence and mortality are rising. Liver transplantation (LT) offers the best outcomes, but current tumor size- and number-based selection criteria restrict access. Molecular profiling may better reflect tumor biology and guide precision-based selection strategies.MethodsThis prospective single-center study included patients with HCC who had undergone LT between 11 November 2016 and 4 April 2023 with sufficient tumor cellularity in explanted livers. Tumor DNA was subjected to targeted sequencing for 38 genes, with the results returned to clinicians. Altered genes were grouped into HCC-relevant signaling pathways. Outcomes included post-LT overall survival (OS), recurrence-free survival (RFS), and recurrence sites. The Cancer Genome Atlas (TCGA) HCC cohort was used for validation.ResultsAmong 1,103 LT recipients, 261 were for HCC and 91 underwent sequencing. Most patients were male (n = 68), white (n = 56), and hepatitis C positive (n = 34). The median tumor size was 3 cm (IQR 1.8–4.5), the number was 1 (IQR 1–3), and the follow-up time was 1,982 days. Of the 36 unique mutations found across 11 genes, six were potentially actionable. Cell cycle pathway alterations (n = 14) were prognostic for worse OS (3-year 90.9% without vs. 62.5% with alterations) and RFS in uni- and multivariable models. Recurrences were more common in the liver and lungs with cell cycle alterations (p < 0.05).ConclusionPost-LT molecular profiling of HCC reveals tumor-specific alterations associated with outcomes, supporting the incorporation of tumor biology into future LT selection criteria.

BACKGROUND:Total neoadjuvant therapy for localized rectal cancer entails delivery of all systemic chemotherapy and pelvic radiation before proctectomy to improve pathologic response, disease-free survival, and potentially organ preservation. In patients who develop liver metastases during or after total neoadjuvant therapy, the effects of total neoadjuvant therapy on patient outcomes and chemotherapy-associated liver injury are unknown. METHODS:A single-institution prospectively maintained database was queried for patients who underwent hepatectomy for metastatic rectal cancer, with or without total neoadjuvant therapy between 2014 and 2024. Surgical pathology reports were reviewed for histologic changes in the background liver. RESULTS:Among 286 patients undergoing hepatectomy for metastatic rectal cancer, 30 patients received total neoadjuvant therapy, and 256 patients did not receive total neoadjuvant therapy. Overall survival was significantly lower among patients in the total neoadjuvant therapy group (median overall survival 48.7 months, total neoadjuvant therapy vs 99.5 months, non-total neoadjuvant therapy, P = .01). On multivariable analysis, total neoadjuvant therapy remained an independent predictor of worse overall survival (hazard ratio 0.41, 95% confidence interval 0.22-0.79, P = .008). Sinusoidal injury rates were not significantly different with or without total neoadjuvant therapy (26.9% total neoadjuvant therapy vs 32.9% non-total neoadjuvant therapy, P = .69). Patients who received total neoadjuvant therapy had significantly higher rates of steatosis or steatohepatitis (30.8% total neoadjuvant therapy vs 8.7% non-total neoadjuvant therapy, P = .002). CONCLUSION:In this preliminary analysis, patients who developed liver metastases during or after total neoadjuvant therapy for rectal cancer had significantly worse overall survival after hepatectomy than patients who did not receive total neoadjuvant therapy. Steatosis and steatohepatitis rates were higher with total neoadjuvant therapy. Further study is needed to identify factors associated with worse outcomes in patients who undergo hepatectomy after total neoadjuvant therapy.

BACKGROUND:The AJCC staging system has assigned variable prognostic weight to multifocal disease across versions for intrahepatic cholangiocarcinoma (iCCA). We aimed to better delineate how multifocality influences survival in patients with resectable iCCA to refine clinical staging and better inform treatment sequencing. PATIENTS AND METHODS:We retrospectively identified patients undergoing curative-intent hepatectomy for iCCA between 2000 and 2024 from 6 international, high-volume hepatobiliary centers. Patients were stratified by multifocality, T classification, and N classification. Overall survival (OS) was evaluated using Kaplan-Meier and Cox regression analyses, and a novel modified system was proposed based on current AJCC groupings. RESULTS:A total of 731 patients met the study inclusion criteria. Multifocal disease was present in 36% of patients with T2-T4 tumors and was independently associated with worse OS (hazard ratio, 1.64; 95% CI, 1.21-2.22; P=.002) compared with solitary tumors on multivariable analysis. This survival disadvantage persisted across T2 classification (28.8 vs 44.8 months; P=.001) and T3 classification (21.2 vs 36.5 months; P=.003), and remained significant after adjustment for nodal status (P=.003 and P=.017, respectively). Compared with solitary disease, multifocality also conferred worse OS in patients with node-negative (36.0 vs 58.9 months; P=.003) and regionally node-positive disease (19.2 vs 23.8 months; P=.016). Current AJCC staging failed to distinguish prognostic differences between stage II and stage IIIA disease (48.3 vs 46.9 months; P=.190). However, our proposed modifications, which classify multifocal tumors as T3 and upstage multifocality from stage II to stage IIIA in node-negative disease and from stage IIIB to a newly defined stage IIIC in node-positive disease, better stratified overall risk (P<.001). CONCLUSIONS:Multifocality independently predicts poor prognosis in resectable iCCA. Refining the current staging system by reclassifying multifocal tumors as T3 may improve prognostic stratification and better inform treatment sequencing.

155 Background: Modern therapy can achieve a clinical complete response (cCR) of the primary tumor in the patients with rectal cancer (RC). However, use of a rectal organ preservation (OP) strategy for patients achieving cCR among patients who present with synchronous liver metastases (SLM) remains an area of active investigation. This study aimed to evaluate the outcomes of OP in patients with a cCR after liver first treatment sequencing for metastatic RC. Methods: Patients with RC and SLM who underwent liver-first approach at an NCI-designated Comprehensive Cancer Center from 1998-2024 were identified. Patients who achieved a cCR of the primary tumor were stratified with respect to whether the primary tumor was resected or managed nonoperatively via an OP strategy. A time benchmark of 12 weeks from the date of cCR was used to control for immortal time bias. Rates of local regrowth (LReg) in the rectum, local recurrence in the pelvis after rectal resection (LRec), and extrapelvic recurrence (DR) were modeled with cumulative incidence functions, and 3-year overall survival (OS) was compared between groups. Results: Among 217 patients identified, 48 (22.1%) patients achieved a cCR of the primary tumor. Among these patients, 8 patients (16.7%) demonstrated progression prior to the benchmark and were excluded from analyses. Of these, 5 patients demonstrated extrahepatic DR, 1 intrahepatic DR, and 2 LReg. An additional 3 patients (6.2%) underwent rectal resection following the benchmark date without documented evidence of LReg and were also excluded. Of the remaining 37 patients, 12 underwent rectal resection prior to the 12-week benchmark (32.4%) while 25 did not (67.6%). At a median follow-up of 36.9 months, 14 patients managed with an OP strategy experienced LReg (56.0%). Of these patients, 9 patients (64.3%) underwent salvage resection, with an R0 resection rate of 88.9%. None of these patients experienced post-salvage LRec, and LRec rate was also 0% among patients who underwent initial resection. The remainder of those who did not undergo salvage resection had developed prior DR at the time of LReg (4/5, 80%), with one patient electing to continue OP. Rates of DR as the initial site of disease progression were similar between groups (52.0% resection vs. 58.3% OP, p=0.892). 3-year OS rates were not significantly different between groups (100.0% resection vs. 82.5% OP, p=0.18). Conclusions: In patients with RC who have SLM, undergo liver-first approach, and achieve cCR, an OP strategy is associated with high rates of LReg but has high rate of successful salvage and is not associated with significant differences in DR or 3-year OS rate compared to primary tumor resection. An OP strategy for metastatic RC may be a feasible management strategy for select patients, with future work aimed at identifying patients with favorable tumor biology in whom this strategy would be most oncologically appropriate.

3623 Background: ctDNA positivity is a strong prognostic biomarker for recurrence after curative-intent procedures for CRC and defines MRD in the absence of radiographic disease. Our aim was to assess stage-specific positivity rates across follow-up intervals and the clinical actions associated with ctDNA+. Methods: The INTERCEPT program enrolled patients undergoing curatively intended procedures for stage I-IV CRC at MD Anderson Cancer Center. Tumor informed MRD assays (Signatera) were drawn postoperatively and every 3 months according to reimbursement guidelines. ctDNA draws were grouped into 6-month intervals from completion of definitive therapy. Clinical decisions after the first ctDNA+ result in the MRD window were classified as: MRD-trial, systemic therapy, diagnostic escalation, early follow-up, ctDNA confirmation, or no change. Results: The final cohort included 1,603 patients (40% stage IV, 32% stage III, 20% stage II, 8% stage I). Median follow-up was 18.4 months. Patients that were ctDNA- on first post-definitive draw had longer recurrence-free survival (RFS) than ctDNA+ patients (median RFS 62.6 vs 4.8 months, HR 11.6 [95% CI 9.6-14.1]), remaining significant in stage subgroups. Among all patients 28% were ctDNA+ at any post-definitive timepoint, the rates were highest for stage IV, followed by stage III, II, and I (Table). ctDNA+ rates were highest in early follow-up and got lower at later intervals (21% to 5%), with similar patterns for all stages. Among 271 patients that were ctDNA+ in the MRD window the initial therapeutic approach was MRD trial screening for 59 (22%), diagnostic escalation in 73 (18%), early follow-up in 57 (21%), confirmation of ctDNA+ by repeat testing in 23 (8%), no change in management for 38 (14%), and 21 (8%) patients started other systemic therapy. MRD trials were discussed prior to recurrence with 144 (53%) of the patients. Conclusions: ctDNA positivity is more common in higher stage tumors and becomes less frequent during follow-up. ctDNA positivity confirms its established prognostic value and meaningfully impacts clinical management, including diagnostic workup and MRD trial enrollment. Even within a single center, heterogeneity in initial management of ctDNA+ patients and timing for MRD trial enrollment is evident. Stage-specific ctDNA+ rates during follow-up after definitive therapy. All Stage IV Stage III Stage II Stage I p Any time 444 / 1,603 (28%) 313 / 646 (48%) 87 / 513 (17%) 40 / 322 (12%) 4 / 122 (3%) <0.001 <6 months 329 / 1603 (21%) 249 / 646 (39%) 57 / 513 (11%) 21 / 322 (7%) 2 / 122 (2%) <0.001 6 to <12 months 151 / 1,018 (15%) 97 / 349 (28%) 36 / 351 (10%) 17 / 230 (7%) 1 / 88 (1%) <0.001 12 to <18 months 75 / 672 (11%) 50 / 197 (25%) 15 / 250 (6%) 10 / 161 (6%) 0 / 64 (0%) <0.001 18 to <24 months 16 / 264 (6%) 10 / 71 (14%) 3 / 94 (3%) 3 / 71 (4%) 0 / 28 (0%) 0.019 ≥24 months 9 / 147 (6%) 5 / 41 (12%) 2 / 58 (3%) 1 / 33 (3%) 1 / 15 (7%) 0.259

Advances in technology have allowed for the characterization of tumors at the genomic, transcriptomic, and proteomic levels. There are well-established targets for biliary tract cancers, with exciting new targets emerging in pancreatic ductal adenocarcinoma and potential targets in hepatocellular carcinoma. Taken together, these data suggest an important role for molecular profiling for personalizing cancer therapy in advanced disease and need for design of novel neoadjuvant studies to leverage these novel therapeutics perioperatively in the surgical patient.

BACKGROUND:Acute kidney injury after abdominal surgery is associated with increased morbidity, but little is known about acute kidney injury after hepatectomy, which was the focus of our study. METHODS:Patients undergoing curative-intent hepatectomy during 2017-2023 were included. Creatinine levels were collected within 2 weeks after hepatectomy. Acute kidney injury was defined as a creatinine level increase by ≥0.3 mg/dL within 48 hours or ≥1.5 times the baseline within 7 days; early acute kidney injury was defined as acute kidney injury by postoperative day 2. RESULTS:The study included 1,658 patients, of whom 180 (11%) had early acute kidney injury. Age >65 years, cardiovascular disease, diabetes mellitus, liver disease, kidney disease, longer operative time, and higher estimated blood loss were independently associated with an increased risk of early acute kidney injury. Median length of hospital stay was longer among patients with early acute kidney injury than among those without, for both low-risk (5 vs 3 days; P < .001) and high-risk hepatectomy (5 vs 4 days; P = .002). Patients with early acute kidney injury had a higher rate of major (Accordion ≥3) complications (22% vs 10%, P < .001). Multivariable analysis revealed 3 predictors of major complications: early acute kidney injury (odds ratio, 1.81; 95% confidence interval, 1.18-2.76), high-risk hepatectomy (odds ratio, 1.57; 95% confidence interval, 1.12-2.19), and operative time >7 hours (odds ratio, 2.66; 95% confidence interval, 1.90-3.73). The major complication rate was 6% for patients without the aforementioned factors, 13% for patients with 1 factor, and 33% for patients with all 3 factors. CONCLUSION:Early postoperative acute kidney injury is associated with extended hospital stay and predicts major complications, especially for patients with high-risk hepatectomy and extended operative time.