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BREAKWATER: Analysis of first-line encorafenib + cetuximab + chemotherapy in BRAF V600E-mutant metastatic colorectal cancer.

16 Background: Encorafenib + cetuximab (EC) is approved for previously treated BRAF V600E-mutant metastatic colorectal cancer (mCRC) based on the BEACON phase 3 study (NCT02928224). Historically, first-line (1L) treatment of BRAF V600E-mutant mCRC with chemotherapy (chemo) regimens has had limited efficacy.BREAKWATER (NCT04607421) is an open-label, global, randomized, phase 3 study evaluating 1L EC with or without chemo vs standard of care (SOC; chemo with or without bevacizumab). Reported here are the primary analysis of objective response rate by blinded independent central review (ORR by BICR; dual primary endpoint [EP]), the first interim analysis of overall survival (OS; key secondary EP), other secondary EPs, and safety for the EC+FOLFOX (oxaliplatin, leucovorin, and 5-FU) vs SOC arms. Methods: Eligible patients (pts) had untreated BRAF V600E-mutant mCRC, measurable disease (RECIST 1.1), and ECOG PS 0-1. Pts were randomized 1:1:1 to receive EC, EC+FOLFOX, or SOC; EC arm enrollment was closed after a protocol amendment. Dual primary EPs were ORR (assessed in the first 110 pts randomized to each of the EC+FOLFOX and SOC arms) and progression-free survival by BICR (EC+FOLFOX vs SOC); OS was a key secondary EP (EC+FOLFOX vs SOC), other secondary EPs included response duration and time to response (TTR). Results: Four hundred seventy-nine pts were randomized to the EC+FOLFOX and SOC arms (EC+FOLFOX: n=236; SOC: n=243). Baseline demographics and disease characteristics were similar across arms (median age: 61.0 years; male: 50.5%; ECOG PS 0: 54.3%). At data cutoff (Dec 22, 2023), the EC+FOLFOX arm demonstrated a clinically meaningful and statistically significant improvement in confirmed ORR vs the SOC arm, 60.9% vs 40.0%, odds ratio=2.443, one-sided P -value=0.0008, meeting this dual primary EP. The response observed with EC+FOLFOX was rapid and durable. OS data were immature but indicated a sustained survival benefit with EC+FOLFOX vs SOC arm. Serious treatment-emergent adverse events (EC+FOLFOX: n=231; SOC: n=228) occurred in 37.7% vs 34.6% of pts in the respective arms. The safety profile was consistent with that known for each agent. Conclusions: BREAKWATER demonstrated a substantially improved response rate that was rapid and durable with EC+FOLFOX in BRAF V600E-mutant mCRC with manageable toxicities and no new safety signals. Clinical trial information: NCT04607421 . EC+FOLFOXn=110 SOCn=110 ORR by BICR % (95% CI) 60.9 (51.6, 69.5) 40.0 (31.3, 49.3) Odds ratio (95% CI) P -value a 2.443 (1.348, 4.380) 0.0008 n=67 n=44 Estimated median response duration by BICR (95% CI), mo 13.9 (8.5, NE) 11.1 (6.7, 12.7) Pts with a response duration of ≥6 mo, n (%)Pts with a response duration of ≥12 mo, n (%) 46 (68.7)15 (22.4) 15 (34.1)5 (11.4) Median TTR by BICR (range), weeks 7.1 (5.7-53.7) 7.3 (5.4-48.0) n=236 n=243 OS (95% CI), mo NE (19.8, NE) 14.6 (13.4, NE) Hazard ratio (95% CI) 0.47 (0.318, 0.691) a One-sided α=0.001. NE, not estimable.

Hepatocellular carcinoma: A 30-year trend analysis of global burden stratified by risk factors, and socio-demographic indexes.

529 Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related morbidity and mortality worldwide, driven primarily by chronic infections with Hepatitis B, Hepatitis C, and alcohol consumption. This study systematically examines global trends of HCC from 1991 to 2021, focusing on age-standardized mortality rates (ASMR) and Disability-Adjusted Life Years (DALYs) according to risk factors across Socio-Demographic Index (SDI) regions. By highlighting these patterns, the study provides insights into the interplay of socio-economic disparities and healthcare advancements on HCC trends. Methods: We utilized data from the Global Burden of Disease database to extract ASMR, and age standardized DALYs for HCC between 1991 and 2021. The data was stratified by etiology (Hepatitis B, Hepatitis C, alcohol consumption) and stratified across five SDI regions: low, low-middle, middle, high-middle, and high SDI. Results: The global HCC ASMR decreased by 4% from 1991 to 2021, with the largest reduction (20.4%) in low SDI regions. Hepatitis B-related HCC ASMR dropped by 16.3%, with reductions across all SDI groups. ASMR of Hepatitis C-related HCC remained stable globally but fell by 15.1% in low SDI regions. Alcohol-related HCC ASMR increased by 10% globally, with the highest rise in high SDI regions (24.5%), and NASH-related HCC ASMR increased by 26.7% globally, with a 42% rise in high SDI regions. Hepatitis B-related HCC DALYs decreased by 22.2%, with the sharpest declines recorded in high (31.4%) and low SDI regions (29%). Hepatitis C-related HCC DALYs saw a 8.8% global reduction, which was consistent across all groups. Alcohol-related HCC DALYs rose by 4.6% globally, with increases of 14.4% in high SDI and 20.5% in low-middle SDI regions. NASH-related HCC DALYs increased by 18.7%, with a 34.7% rise in low-middle SDI regions. Conclusions: The study reveals substantial progress in reducing the global burden of Hepatitis B- and C-related HCC, particularly in low SDI regions. This progress likely reflects advances in vaccination, antiviral treatments, and screening programs. However, the rising mortality and disability associated with alcohol- and NASH-related HCC, especially in high SDI regions, emphasize the growing impact of lifestyle-related risk factors. These findings underscore the need for tailored public health strategies to mitigate the increasing effects of these preventable risk factors on global HCC outcomes.

The ubiquitin ligase Pellino1 targets STAT3 to regulate macrophage-mediated inflammation and tumor development

Abstract Receptor-mediated signaling could be modulated by ubiquitination of pathway intermediates, but the role of such modification in the pathogenesis of inflammation and inflammation-related cancer is lesser known. The ubiquitin ligase Pellino1 has been shown to modulate immune signals by enabling various immune cells to respond to their receptor signals effectively. Here, we show that Pellino1 levels are elevated in patients with colitis, patients with colitis-associated colon cancer (CAC), and murine models of these conditions. In a monocyte-specific Pellino1 knock-out mouse model, we find reduced macrophage migration and activation, leading to attenuated development of colitis and CAC in male mice. Mechanistically, Pellino1 targets STAT3 for lysine 63-mediated ubiquitination, resulting in pathogenic activation of STAT3 signaling. Taken together, our findings reveal a macrophage-specific ubiquitination signaling axis in colitis and CAC development and suggest that Pellino1 is a potential candidate for treating chronic inflammation and inflammation-related cancer.

Analysis of eIF4E-family members in fungi contributes to their classification in eukaryotes

Focusing on clinical trial ineligibility: Nivolumab plus chemotherapy for patients with advanced gastric cancer.

355 Background: Nivolumab demonstrates promising efficacy when combined with chemotherapy as first-line treatment in patients with advanced gastric cancer (AGC). However, a large proportion of patients are perceived as ineligible for clinical trials in clinical practice. The aim of this study is to analyze the treatment outcomes and safety among patients deemed ineligible in clinical trials for AGC. Methods: A retrospective examination was conducted involving 187 patients who received treatment for HER2-negative unresectable or recurrent AGC between December 2014 and October 2023 at six institutions. Eleven patients were excluded due to massive ascites or poor performance status (PS). Ineligible patients were defined as meeting any of the seven criteria: age 75 years or over, PS 2, bone marrow dysfunction, hepatic dysfunction, renal dysfunction, serious complications, and extended bone metastasis. Of the 104 patients meeting these criteria, individuals were divided into the ICI group (nivolumab plus chemotherapy) and the non-ICI group (chemotherapy only). A comparative assessment of survival outcomes and tumor responses between the two groups was performed. Additionally, the incidence of immune-related adverse events (irAE) in the ICI group was assessed. Results: The ICI group comprised 57 patients, while the non-ICI group comprised 47 patients. The median follow-up for survival analysis was 11.6 months. In the ICI group, response rate (RR), median progression-free survival (mPFS), and median overall survival (mOS) were 48.7% among patients with measurable lesions, 7.4 months (95%CI, 5.3-10.0), and 15.1 months (95%CI, 13.1-21.0). In the non-ICI group, RR, mPFS, and mOS were 33.3%, 6.4 months (95%CI, 4.1-7.8), and 11.8 months (95%CI, 10.1-14.6). The OS in the ICI group was significantly better than those in the non-ICI group (log-rank p = 0.0436). Furthermore, irAEs were observed in eight patients (14.0%), including hypothyroidism (n=3), arthritis (n=2), hypopituitarism (n=2), and dermatitis (n=1). No patients discontinued treatment due to intolerable irAEs. Conclusions: The combination of nivolumab and chemotherapy showed a favorable outcome even in AGC patients with ineligible group.

A phase III study of combination therapy with everolimus plus lanreotide versus everolimus monotherapy for unresectable or recurrent gastroenteropancreatic neuroendocrine tumor (JCOG1901, STARTER-NET).

652 Background: There is limited evidence regarding the benefit of adding somatostatin analogs to molecular targeted agents for well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs). This phase III trial was conducted to compare everolimus plus lanreotide (EVE/LAN) with everolimus monotherapy (EVE) in patients with unresectable or recurrent GEP-NETs in the first-line setting. Methods: Patients with grade 1 or grade 2, nonfunctioning GEP-NETs with poor prognostic factors (Ki-67 labeling index (LI) 5-20% or diffuse liver metastases) were randomly assigned (1:1) to EVE (10 mg/day) or EVE/LAN (EVE + LAN 120 mg every 28 days). The primary endpoint was progression-free survival (PFS). The key secondary endpoint was overall survival (OS), and other secondary endpoints were objective response rate (ORR), disease control rate (DCR), and safety. The study was based on the hypothesis of an assumed median PFS of 11.0 months for EVE, expecting a 4-month improvement by EVE/LAN (HR: 0.73). The planned sample size was 250, requiring 195 events overall with a one-sided alpha level of 5%, a power of 70%, an accrual period of 5 years, and a follow-up period of 1.5 years. Results: Between April 2020 and June 2024, a total of 178 patients were enrolled, and the planned interim analysis was conducted in 145 patients (72 in the EVE and 73 in the EVE/LAN) in June 2024 with a data cut-off date of Nov 2023. The median PFS was 11.5 months in the EVE arm and 29.7 months in the EVE/LAN arm (HR 0.38 [99.91% CI 0.15–0.96], P = 0.00017 < the prespecified significance level of 0.00046, by the stratified log-rank test). The HR for OS was 0.97 (95% CI: 0.24-3.90). The ORR and DCR were 8.7% (6/69) and 87.0% (60/69) in the EVE arm and 26.8% (19/71) and 91.5% (65/71) in the EVE/LAN arm, respectively. Both hematologic and non-hematologic toxicities tended to be more frequent in the EVE/LAN arm than in the EVE arm. No treatment-related deaths were observed in either arm. Based on the efficacy results, the Data and Safety Monitoring Committee recommended early termination of the study. Conclusions: The EVE/LAN provides statistically significant prolongation of PFS compared with EVE monotherapy, and the safety profile of EVE/LAN was manageable. The EVE/LAN might be a new standard treatment in the first-line setting for well-differentiated grade 1/2 GEP-NETs with poor prognostic factors. Clinical trial information: jRCT1031200023.

A phase 3 study of first-line sotorasib, panitumumab, and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb for patients with <i>KRAS</i> G12C–mutated metastatic colorectal cancer (CodeBreaK 301).

TPS326 Background: CodeBreaK 300 (NCT05198934) evaluated sotorasib, a selective inhibitor that irreversibly binds to the Kirsten rat sarcoma ( KRAS ) G12C mutant protein, in combination with panitumumab, an anti–epidermal growth factor receptor inhibitor, and showed that 960 mg sotorasib + panitumumab provided a statistically and clinically significant improvement in progression-free survival compared with trifluridine/tipiracil or regorafenib in patients with chemorefractory metastatic colorectal cancer (mCRC) (1). In CodeBreaK 101 (NCT04185883) subprotocol H expansion cohort 2F, the addition of folinic acid, fluorouracil, and irinotecan (FOLFIRI) to this combination in the first-line setting demonstrated a manageable safety profile and promising response rate of 78% in patients with KRAS G12C–mutated mCRC (2). The current study aims to evaluate whether the combination of sotorasib, panitumumab, and FOLFIRI is superior to FOLFIRI with or without bevacizumab-awwb, a VEGF inhibitor, in the first-line setting for mCRC. Methods: CodeBreaK 301 (NCT06252649) is a phase 3, multicenter, randomized, open-label, active-controlled study of sotorasib, panitumumab, and FOLFIRI versus FOLFIRI with or without bevacizumab-awwb as first-line therapy for patients with KRAS G12C–mutated mCRC. Key eligibility criteria include mCRC with KRAS G12C mutation confirmed by central molecular testing, and no prior therapy for metastatic disease. Approximately 450 patients will be randomized 1:1 to receive either sotorasib, panitumumab, and FOLFIRI, or FOLFIRI with or without bevacizumab-awwb. The primary endpoint is progression-free survival assessed by a blinded independent central review of disease response per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1). The key secondary endpoint is overall survival, and additional secondary endpoints include objective response rate and depth of response. Global enrollment is ongoing. 1. Fakih, NEJM 2023. 2. Siena, ESMO 2024. Clinical trial information: NCT06252649 .

miR-142 deficit in T cells during blast crisis promotes chronic myeloid leukemia immune escape

Abstract We reported that an acquired miR-142 deficit transforms chronic phase (CP) chronic myeloid leukemia (CML) leukemic stem cells (LSCs) into blast crisis (BC) LSCs. Given the role of miR-142 in the development and activity of the immune system, we postulated that this deficit also promotes LSC immune escape. Herein, we report on IL-6-driven miR-142 deficit occurring in T cells during BC transformation. In CML murine models, miR-142 deficit impairs thymic differentiation of lymphoid-primed multipotent progenitors (LMPP) into T cells and prevents T cells’ metabolic reprogramming, thereby leading to loss of T cells and leukemia immune escape. Correcting miR-142 deficit with a miR-142 mimic compound (M-miR-142), alone or in combination with immune checkpoint antibodies, restores T cell number and immune activity, leading to LSC elimination and prolonged survival of BC CML murine and patient-derived xenograft models. These observations may open new therapeutic opportunities for BC CML and other myeloid malignancies.

Correction: Characterization of a cytochrome P450 that catalyzes the O-demethylation of lignin-derived benzoates

Prognosis of signet ring cell (SRC) gastric carcinoma (GC) compared with other histological subtypes.

357 Background: Signet ring cell (SRC) gastric cancer (GC) has its unique clinicopathological features with poor tissue differentiation, high invasiveness, diffuse growth pattern and poor prognosis. Survival rates and clinicopathological characteristics of patients with SRC GC regardless of the stage of the disease has not been well studied. Methods: The retrospective analysis was undertaken of 993 patients with diagnosed gastric cancer. These patients received surgical resection in period from January 2013 to December 2018 in N.N. Blokhin National Medical Research Center of Oncology. We compared clinical and pathological features as well as prognostic factors between these groups. Results: For early SRC carcinoma, the median survival rates weren’t reached; 3- and 5-year survival rates were 100% and 89.0 %; for non-SRC carcinoma 91.4 and 85.3 % (HR=0.73; 95 % CI 0.22–2.42, р = 0.6) respectively. For locally advanced/metastatic SRC carcinoma, the median survival rates, 3- and 5-year survival rates were 38 months, 53.0 and 38.4 %; for non-SRC carcinoma 51.1 months, 59.2 and 48.0 % (HR=1.2; 95 % CI 0.91–1.54, р = 0.2). At univariate analysis SRC morphology was found as independent risk factor for overall survival (HR=1.19; CI 95% 0.94 – 1.50; p&lt;0.0001). Multivariate analysis did not reveal SRC morphology to be significant and independent risk factor for overall survival (HR=1.00; CI 95% 0.72 – 1.38; p=0.98). Conclusions: Overall survival rates in patients with early (mucosal and submucosal tumor regardless of lymph nodes status) SRC gastric cancer did not show any significant differences in comparison with other histological types of GC. Thus, the prognosis of early SRC GC is equivalent or better than that of other histological subtypes of GC. Overall survival rates of locally advanced/metastatic SRC gastric cancer are worse than non-SRC cancer, but the differences are not statistically significant.

Preliminary safety, antitumor activity, and circulating tumor DNA (ctDNA) changes with RMC-9805, an oral, RAS(ON) G12D-selective tri-complex inhibitor in patients with KRAS G12D pancreatic ductal adenocarcinoma (PDAC) from a phase 1 study in advanced solid tumors.

724 Background: RMC-9805 is a potent, oral, RAS(ON) G12D-selective, covalent, tri-complex inhibitor targeting the active, GTP-bound state of oncogenic RAS G12D isoforms. Despite low response rates to current standard of care (SOC), no RAS-targeted therapy is approved for G12D PDAC. Methods: In this Phase 1 study (NCT06040541), patients with previously treated, advanced KRAS G12D solid tumors received escalating RMC-9805 doses (150-1200 mg once daily [QD] or 300-600 mg twice daily [BID]). Treatment cycles were every 3 wks. Antitumor activity was assessed every 6 wks the first 24 wks then every 9 wks. Additional patients were enrolled at RMC-9805 doses that cleared the dose-limiting toxicity (DLT) evaluation to further characterize pharmacokinetics, safety, antitumor activity, and biomarkers. Plasma for ctDNA analysis was collected at baseline (BL; cycle 1, day 1 [C1D1] or screening), and on treatment (OT; C2D1 or C3D1). Results: As of Sept 2, 2024, 179 patients with KRAS G12D solid tumors (most having PDAC; n=104 [58%]) received 5 escalating dose levels of RMC-9805 (150-1200 mg daily). No DLTs or Grade 4 or 5 treatment-related adverse events (TRAEs) were reported, and the maximum tolerated dose (MTD) was not reached. Among patients who received a candidate recommended phase 2 dose (RP2D) of 1200 mg daily (1200 mg QD [n=60] or 600 mg BID [n=39]), the most common (≥10% of patients) TRAEs were nausea (27%), diarrhea (20%), vomiting (15%), and rash (10%), all of which were Grade 1 or 2 severity. One Grade 3 TRAE (ALT elevation) was observed in a patient with PDAC and a history of ALT elevation, biliary stenting, and liver metastasis. No patients treated with 1200 mg daily discontinued treatment due to TRAEs and 4% of patients had dose reductions due to TRAEs. In patients with PDAC receiving RMC-9805 daily at 1200 mg QD (n=20) or 600 mg BID (n=20) who enrolled at least 14 wks prior to data cutoff, the objective response rate (confirmed response or pending confirmation) was 30%, and the disease control rate was 80%. Of 28 patients who had KRAS G12D mutations detected in ctDNA at BL and were evaluable for OT assessment, 86% had an OT decrease &gt;50% from BL of detectable KRAS G12D mutations, and 39% had a 100% OT clearance. Updated data will be presented. Conclusions: Oral RMC-9805 showed encouraging initial antitumor activity with early and deep reductions in KRAS G12D ctDNA in patients with KRAS G12D PDAC. Tolerability was favorable relative to SOC chemotherapy for PDAC and manageable. This overall safety profile and antitumor activity support continued evaluation as monotherapy in patients with KRAS G12D PDAC, and in combination with chemotherapy and targeted therapies, including the RAS(ON) multi-selective inhibitor RMC-6236. Clinical trial information: NCT06040541 .

Prognosis of patients with liver single-organ metastases: Updated survival results of BBCAPX-II.

157 Background: Although immunotherapy has changed the treatment strategy for many cancers with great success, patients with microsatellite stable (MSS) and RAS-mutant metastatic colorectal cancer (mCRC) especially with liver metastases have a low response rate to immunotherapy. Sintilimab plus bevacizumab and CapeOX (BBCAPX) has proved its efficacy and safety in above unresectable mCRC patients (1). Here, we report subgroup analysis of updated survival results of this single arm, open-label, phase 2 trial. Methods: Eligible patients were histologically confirmed unresectable metastatic colorectal adenocarcinoma by multidisciplinary team, and had RAS gene mutation and confirmed MSS status. All patients received treatment with sintilimab plus bevacizumab, oxaliplatin and capecitabine of each 21-day cycle. ORR, DCR, PFS, OS, and subgroup analyses based on metastasis site were performed. Results: From April 2021 to December 2021, 25 patients were enrolled. The ORR was 84% and the DCR was 100%. Six (24%) patients including 5 patients with liver single organ metastases underwent surgical treatment and unexpectedly achieved no evidence of disease status. At the data cut-off day (September 13, 2024), patients with liver single organ metastases presented better prognosis. Median PFS was 25.3 months (95% CI, 4.8-NA) in the patients with liver single organ metastases and 11.5 months (95% CI, 4.83-24.3) in the patients with other metastasis. Median OS was not reached in the patients with liver single organ metastases and 35.5 months (95% CI, 9.36-NA) in the patients with other metastasis. The OS rate at 24 months was 72% (95% CI, 56.4-91.9) in FAS. Median OS was not reached in FAS and 35.5 months (95% CI, 11.4-NA) in PPS. 32% patients had at least one grade 3 or 4 TRAEs. No grade 5 adverse events occurred during the study. Conclusions: This study provides a highly promising regimen for patients with RAS-mutant, MSS, unresectable mCRC, especially those with liver single organ metastases. Furthermore, we are launching a phase III, randomized, open-label, multicentric clinical trial (NCT05171660) to further analyze the effects, safety, and prognostic biomarkers of this regimen. 1. Xuefeng Fang et al. ASCO 2022. Clinical trial information: NCT04194359 . PFS and OS results of BBCAPX-II study. Median PFS 6m PFS rate (%) 12m PFS rate (%) Median OS 12m OS rate (%) 24m OS rate (%) Full analysis set (FAS), n = 25 17.9 (95% CI, 8.84-27) 84 (70.8-99.7) 56 (39.6-79.3) NA 76 (61-94.7) 72 (56.4-91.9) Per-protocol set (PPS), n = 19 9.79 (95% CI, 6.44-27.9) 78.9 (62.6-99.6) 42.1 (24.9-71.3) 35.5 (95% CI, 11.4-NA) 68.4 (50.4-92.9) 63.2 (44.8-89) Classified by metastatic organs (FAS, n = 25) Liver single organ metastases, n = 10 25.3 (95% CI, 4.8-NA) 90 (73.2-100) 70 (46.7-100) NA (11.4-NA) 90 (73.2-100) 80 (58.7-100) Other metastases, n = 15 11.5 (95% CI, 4.83-24.3) 80 (62.1-100) 46.7 (27.2-80.2) 35.5 (9.36-NA) 66.7 (46.6-95.3) 66.7 (46.6-95.3)

Maternal obesity alters histone modifications mediated by the interaction between EZH2 and AMPK, impairing neural differentiation in the developing embryonic brain cortex

Comparative analysis of demographics and outcomes in hospitalized patients with young- versus average-onset colorectal cancer in New York state (2017-2022).

27 Background: Recent studies have shown an increasing incidence of colorectal cancer (CRC) among young patients. This study investigates clinical outcomes and healthcare utilization among young (&lt;50) versus average onset (≥50) CRC patients admitted to hospitals in New York State (NYS). Methods: We performed a retrospective analysis using the Statewide Planning and Research Cooperative System (SPARCS) database from 2017 to 2022. Patients were divided into two groups: young-onset colorectal cancer patients (YOCRC, &lt;50 years) and average onset colorectal cancer patients (AOCRC, ≥50 years). The study population was further stratified by demographic and clinical characteristics. All associations were compared using the Kruskal-Wallis test, along with multivariate linear and logistic regression in RStudio version 4.4.1, at a significance level of ≤0.05. Clinical characteristics, including severity of illness and risk of mortality, were defined using the All Patient Refined (APR) grading system. Results: A total of 9,904 patients were identified (948 YOCRC and 8,956 AOCRC) with a primary admitting diagnosis of CRC from 2017 to 2022. In comparing the two age groups, AOCRC patients had a higher proportion of White, and female patients, whereas the YOCRC group included a higher proportion of Black and male patients (p&lt;0.001). The median length of stay was greater for AOCRC patients (5 days) compared to YOCRC patients (4 days), p&lt;0.001. Both age groups showed an upward trend in total cost of stay in the recent years. AOCRC patients were more likely to have increased severity of illness graded as major-extreme (60% vs 48%), while a higher proportion of YOCRC patients were classified as minor-moderate disease (51% vs 40%), p&lt;0.001. Similarly, AOCRC patients experienced a higher risk of mortality compared to YOCRC patients (p&lt;0.001). Regarding procedures, AOCRC patients needed more transfusions (13%) than YOCRC patients (9.3%), p&lt;0.001. YOCRC patients were also more likely to be discharged home (71% vs 46%), while AOCRC patients often required home health services or skilled nursing (p&lt;0.001). Notably, while the risk of mortality was higher for AOCRC patients, it has been decreasing overall from 2017 to 2022 [OR 0.92 (95% CI: 0.84-0.99), p=0.039]. Conclusions: AOCRC patients experienced greater severity of disease, higher mortality risk, and required more assistive care at discharge compared to YOCRC patients. The total cost of hospital stays has been rising for both groups. Policies focused on earlier outpatient interventions may help reduce the burden of inpatient care and rising costs.

The importance of treatment handling and compliance on overall response rate in a phase III study of metastatic colorectal cancer: Post-hoc per protocol analyses of the AGENT trial.

205 Background: To study the compliance in handling the investigational medicinal product (IMP) and its impact on outcomes in patients with metastatic colorectal cancer participating in the AGENT trial (NCT03750786). Methods: In a randomized, multicenter, multinational, phase III study, patients were randomized to receive either arfolitixorin (n=245) or leucovorin (n=245) with 5-fluorouracil (5-FU), oxaliplatin and bevacizumab as a first-line treatment. Logistic regression was applied for overall response rate (ORR) and Cox regression for all-cause death, and all-cause death or progression, adjusted for randomization strata. Results: Missing or incorrect IMP handling was reported for 28 (11%) patients in the arfolitixorin and 23 (9%) in the leucovorin arm, &lt;80% compliance for duration of bolus 5-FU 2-4min for 101 (42%) and 97 (41%), respectively. Considering the time between the bolus 5-FU and arfolitixorin, non-compliance, defined by &lt;80% doses given within 25-35min PP window, was reported for 92 (38%) in arfolitixorin patients. Adherence to the timing between the first and second arfolitixorin dose (30-60min) was high. In total, 91 (37%) patients in the arfolitixorin and 134 (55%) in the leucovorin arm fulfilled PP definitions (cPP population). The bolus 5-FU dose was equally likely to be reduced in both the arfolitixorin and leucovorin arms across regions (ranging from 22% to 39%), except for Japan where 55% of patients in the arfolitixorin arm had their bolus 5-FU dose reduced, compared to 28% in the leucovorin arm. In the cPP population, the ORR was achieved by 54 (59%) in the arfolitixorin and 69 (51%) in the leucovorin arm, adjusted odds ratio (aOR) 1.40 (95% CI 0.81-2.45), p=0.23. Excluding Japan, the ORR was 41 (62%) in the arfolitixorin and 49 (46%) in the leucovorin arm, aOR 2.11 (95% CI 1.09-4.06), p=0.026. Corresponding aOR for Europe was 1.50 (95% CI 0.71-3.15), p=0.29, and for North America aOR 7.95 (95% CI 1.45-43.62), p=0.017. In Japan, the ORR had better outcome in the leucovorin arm (71.4%) compared to the arfolitixorin arm (52.0%), aOR 0.42 (95% CI 0.13-1.31), p=0.14. However, the relationship was numerically opposite for patients without bolus 5-FU dose reduced. All-cause death during the complete follow-up was reported for 37 (41%) in the arfolitixorin and 61 (46%) in the leucovorin arm. Conclusions: In the AGENT trial, 46% of the included patients met per protocol compliance for treatment handling. In this cPP population, there was a non-significant, but clinically relevant, increase in the overall response rate in the arfolitixorin compared to the leucovorin arm. Notably, in all regions excluding Japan, the overall response rate was higher for arfolitixorin, with statistical significance. Adherence to the treatment protocol is crucial for the outcomes of patients with metastatic colorectal cancer. Clinical trial information: NCT03750786 .

Refining colorectal cancer screening strategies using polygenic risk scores and classical risk factors: A proof-of-concept study in the UK Biobank cohort.

104 Background: While the rising incidence of CRC in younger populations has led to a push for lowering the screening age to 40, current clinical guidelines lack sufficient consideration of individual risk variations, raising concerns about the potential harms of over-diagnosis and false positives. Our proof-of-concept study evaluates the utility of risk stratification for multi-target stool DNA (mt-sDNA) testing by integrating polygenic risk scores and traditional clinical risk factors, addressing gaps in current clinical CRC screening guidelines. Methods: Our study utilized the UK Biobank prospective cohort, consisting of 311,544 unrelated individuals of White British ancestry, aged 40-69, excluding those with any prior malignant cancer diagnosis. We developed a sex-specific Cox proportional hazards model to estimate the risk of developing CRC, with the primary outcome being the first incidence of CRC. Three models were assessed: a polygenic risk score (PRS)-only model, a classical risk factors (RF)-only model, and a combined (PRS + RF) model. The traditional risk factors considered were BMI, smoking status, pack years of smoking, and family history of bowel cancer in first-degree non-adoptive relatives. Model performance was evaluated using the area under the curve (AUC), hazard ratios (HR), and the positive and negative predictive values of mt-sDNA across various risk profiles. Results: The combined model for early CRC screening using mt-sDNA demonstrated superior risk stratification (Table) and improved PPV compared to the risk factors-only model, with enhanced performance even among younger individuals at lower baseline risk. If risk stratification was not used, the average PPV for the test in the general population (ages 40-80) would be 2.13% for males and 1.44% for females. In contrast, individuals in the top 1% of risk would have significantly higher PPVs: 5.62% for males and 3.51% for females. If we limit testing to only the high-risk group, per 100,000 individuals, approximately 3,490 additional cases for males and 2,070 additional cases for females would be detected compared to the average-risk population without stratification. Conclusions: The findings suggest that risk stratification may enhance the effectiveness of screening by identifying high-risk individuals who would derive the greatest benefit. In contrast, broad application of the test across the general population may not achieve an optimal risk-benefit ratio, given the relatively low PPV in average-risk individuals. Model performance of the PRS-only, RF-only, and PRS + RF (Combined) models for females and males, respectively. Hazard Ratio (95% CI) C-index (SE) 5-Year AUC Female PRS-Only 1.50 (1.37 - 1.64) 0.62 (0.01) 0.61 RF + PRS 1.49 (1.36 - 1.63) 0.62 (0.01) 0.61 RF Only 1.09 (0.99 - 1.20) 0.53 (0.02) 0.51 Male PRS-Only 1.49 (1.38 - 1.61) 0.63 (0.01) 0.69 RF + PRS 1.49 (1.38 - 1.61) 0.64 (0.01) 0.71 RF Only 1.23 (1.15 - 1.31) 0.57 (0.01) 0.57

EORTC1527/JCOG1609INT/ESSO02: Diffusion-weighted magnetic resonance imaging (DW-MRI) assessment of initially unresectable liver metastasis to improve surgical planning (DREAM)—Primary analysis.

257 Background: Disappearing liver metastases (DLMs) diagnosed on post-chemotherapy (Cx) computed tomography (CT) is a favorable prognostic factor in patients (pts) with colorectal liver metastases (CRLM). However, the optimal treatment of DLMs - whether they should be resected or left behind - is controversial. This is a prospective, multi-centred, international study examining the added value of MRI (DWI, T1/T2 and contrast-enhanced) to that of CT alone in accurate assessment of the viability of DLMs. Methods: Pts with initially unresectable CRLM downstaged to a planned liver resection after Cx were enrolled, based on the obligatory decision of a multidisciplinary team. Pts were imaged by both CT and MRI at baseline and presurgical timepoints. DLMs were defined as disappeared lesions diagnosed by CT alone, while confirmed DLMs (cDLMs) were defined as lesions that disappeared on both CT and MRI. cDLMs were either resected or followed-up for 2 years if not resected. All imaging scans were collected centrally for quality assurance. The primary endpoint was the negative predictive value (NPV) of MRI and CT in confirming the status of cDLMs using either pathological complete response or the absence of a local recurrence at the site of cDLMs during the 2 year follow up. The study was aimed at excluding a NPV ≤0.85 with a 1-sided alfa of 5% and power of 90% under the alternative that the NPV ≥0.95. The planned sample size was 92 evaluable (resected or left behind) cDLMs, assuming a within-patient correlation between cDLMs of 0.2 and an average number of 2 cDLMs per pt. Results: 233 pts were registered at 22 participating centres, and 112 were enrolled for analysis. A median of 8 cycles of Cx was delivered, and pts had a median of 7 CRLMs at baseline. A total of 203 cDLMs were identified while the number of DLMs diagnosed by CT was 296. Of these, 152 cDLMs and 227 DLMs, respectively, were evaluable according to the imaging protocol. Intraoperative ultrasound was performed for 195 cDLMs and, of these, 59 (30.2%) were still detected. The rate of R0/R1 resection was 95.5%. The NPV of evaluable cDLMs either resected or left behind was 62.5 % (95/152, 95% CI:50.8-74.2), which was lower than the prespecified threshold. The NPV of DLMs was 52.9% (119/227, 95% CI:42.7, 63.0). The NPV of resected cDLMs, and those left behind were 56.8% (50/88, 95% CI: 44.2, 69.5) and 70.3% (45/64, 95% CI: 48.6 -92.0), respectively. For DLMs, the NPV of resected DLMs and those left behind were 45.6% (72/158, 95% CI: 35.4-55.7) and 69.6% (48/69, 95% CI: 47.7-91.5), respectively. Conclusions: For pts with initially unresectable CRLM, cDLMs diagnosed by both CT and MRI do not correspond to tumor viability, even after highly effective chemotherapy. Ongoing survival analysis (to be presented at the annual meeting) may impact the treatment strategy of pts with DLMs. Clinical trial information: NCT02781935 .

Pancreatic expression of CPT1A is essential for whole body glucose homeostasis by supporting glucose-stimulated insulin secretion

Analysis of tumor microenvironmental features of primary and synchronous liver metastases from patients with colorectal cancer using a deep learning algorithm.

251 Background: The development of colorectal liver metastases (CRLM) is associated with poor prognosis, and recent data suggest that metastasis to the liver is associated with resistance to immunotherapy. We characterized the microenvironment of primary colorectal carcinomas (CRCs) relative to their synchronous CRLM using a validated segmentation algorithm that quantifies 15 distinct morphologic tumor features. Methods: Adult CRC patients with synchronous CRLM (N=57) at Mayo Clinic were identified from the electronic health record using Epic Slicer Dicer and from an internal database. Tumor H&amp;E sections were digitized and reviewed for quality control (RKP). QuantCRC (Aiforia, Inc) was applied to digitized images to extract 15 GI pathologist pre-defined morphological features. Tumor features were compared between primaries and CRLM using the Kruskal–Wallis test. The project was approved by the Mayo Clinic Institutional Review Board. Results: The study included 57 patients (median age 59 years [IQR 50, 73], 51% female) with CRC primaries and synchronous CRLM. Among primaries, 20 (35%) were right-sided and 37 (65%) were left-sided. QuantCRC identified 6 of 15 morphological features that differed significantly between primaries and their CRLM, including reduced stroma, more high-grade and necrosis, and a higher tumor: stromal ratio (TSR) in CRLM (Table). The increase in TIL density in CRLM vs the primary tumor was of borderline significance (p =0.053). Among patients with left-sided primary tumors, their CRLM had significantly higher TSR, percent high-grade, percent necrosis, and TIL density compared to the primary (all p values ≤ 0.02). Among right sided primaries, CRLM had a significantly reduced percent mature stroma (p=0.034) whereas percent necrosis was increased (p =0.01). Conclusions: Using deep learning, we identified tumor morphological features that differed significantly between primary CRC and their synchronous CRLM. This included higher TSR in CRLMs compared to primaries that is associated with epithelial-mesenchymal transition and has been shown to contribute to treatment resistance. Analysis of tumor morphological features with patient prognosis is ongoing. Deep learning-derived morphological features of primary CRC and CRLM. Morphological feature (Median) Primary tumor Liver metastasis P-value Tumor-Stroma Ratio 0.78 1.50 0.008 % High-grade 23.08 31.72 0.005 TIL Count 44.36 60.20 0.053 % Necrosis 6.35 19.32 &lt;0.001 %Signet Ring Cells 0.25 0.13 0.088 TB/PDC 0.89 1.13 0.484 % Stroma 54.89 40.98 &lt;0.001 % Immature Stroma 46.76 34.13 &lt;0.001 % Mature Stroma 6.27 5.08 0.030

Telotristat ethyl to promote weight stability in patients with advanced pancreatic cancer.

747 Background: Cachexia a key feature of pancreatic ductal adenocarcinoma (PDAC), affects up to 80% of patients (pts), and is associated with worse outcomes. Serotonin, due to its tumorigenic potential and effect on gut function may contribute to weight loss in PDAC. Telotristat ethyl (TE) inhibits serotonin production and improves gut motility dysfunction. We developed a phase II trial to evaluate the impact of TE on the weight of patients with metastatic PDAC (mPDAC) receiving first-line chemotherapy. Methods: Treatment-naïve pts with mPDAC who had lost at least 10% of baseline weight (Group 1) received gemcitabine and nab-paclitaxel (GnP) in combination with TE (250mg administered orally three times a day). Pts with &lt; 10% weight-loss were recruited in Group 2 and received chemotherapy without TE. Serum serotonin was collected monthly during the study. The primary endpoint was weight stability, evaluated as % weight change at 3 months compared to baseline, with a goal of &lt; 5% decrease. A key secondary endpoint was change in serotonin levels at 3 months compared to baseline. The groups were analyzed independently. Results: We enrolled 22 pts, 14 in group 1 (planned 40) and 8 in group 2 (planned 40). The median age was 70 years (IQR 62-75), majority were male (n = 15; 68%) and 11 (50%) were Black. Mean weight at treatment start was 77.9 kg (SD 19.16) group 1, and 90.6kg (SD 24.71) group 2. Mean serotonin level at baseline was 165.07 ng/ml (SD 60.49) group 1, and 296.9 ng/ml (SD 166.65) group 2. Mean % weight change over 3 months in group 1 was -2% (90% CI -5.2 to 1.3, P &lt; -5% = 0.0595). Mean change in group 2 was -5.6% (90% CI -9.4 to -1.7%, P &lt; 5% = 0.53). At 3 months, the median change in serotonin level in group 1 was -37.8% (IQR -59.1 to -13, P = 0.064) and -42.6% (IQR-57.8 to -29.9, P = 0.016) for group 2. Adverse events (AE) were consistent with known AE for GnP and TE. The median overall survival was 10.7 months (95% CI 5.4-16.9) group 1 and 12.2 (95% 6.1 to 21.4) group 2, HR 1.41 (95% CI 0.57 to 3.52 P = 0.46). Conclusions: Among pts with mPDAC and cachexia, the addition of TE to chemotherapy led to weight stabilization. These pts experienced 2% weight loss on average during the study (the upper limit of the CI just crossed -5% at -5.2%). The average weight loss was 5.6% in those who did not receive TE suggesting a signal of activity. A larger study is warranted to evaluate the role of TE in the management of cachexia in mPDAC. Funded by Lexicon Pharmaceuticals (NCT03910387). Clinical trial information: NCT03910387 .