847 Background: The biological behavior of appendiceal epithelial neoplasms (AENs) depends on histological subtype and grade. Due to their rarity, previous molecular analyses have grouped diverse biological types together. We aimed to examine genomic and outcomes differences among distinct biological subgroups of appendiceal cancer. Methods: Tempus Lens was used to analyze de-identified clinical genomic, and transcriptomic information for patients (pts) diagnosed with AENs (N=807): mucinous adenocarcinomas (MA) (N=282), non-mucinous adenocarcinomas (NMA) (N = 311), signet-ring cell carcinoma (SRC) (N=46), and goblet cell adenocarcinoma (GCA) (N = 168). Pts were stratified by GNAS/KRAS co-mutations (mut) (N=151) or wild-type (wt) (N=231). RNA-seq data were normalized and quantified as transcripts per million (TPM) and reported as log2(TPM+1). Immune infiltration was estimated via quanTIseq and enrichment via single sample gene set enrichment analysis (ssGSEA). Real-world overall survival (rwOS) was defined as the time from sample collection to death or loss to follow up. Median OS (mOS) was estimated using Kaplan-Meier curves and compared using log-rank tests. Results: Across the cohort, median age was 63 years; 87% were Stage IV with grade distribution of 18% G1, 34% G2, 48% G3; 54% were female; 79% were White, 10% Black, 2% Asian, 8% other and 9% Hispanic ethnicity. Most common mutations across histologies are shown in the table. In MA and NMA, the most common KRAS alterations were 37% and 25% G12D, 20% and 14% G12V, 7% and 6% G13D, and 5% and 4% G12C. GNAS / KRAS -mut was present in 38% MA, 14% NMA and 7% SRC. Grade 2 MA was genomically more like G1 than G3 with KRAS and GNAS rates for G1/2/3 of 90%/83%/46% and 64%/41%/17%, respectively. In MA pts, mOS was shorter for G3 compared to G2 and G1, respectively (13.2m vs 28.8m vs 25.9m, p=0.002). Although, immune cell infiltration was similar between MA and NMA pts; pts with GNAS/KRAS-mut showed higher levels of M1 macrophages (p<0.05), higher enrichment in the tertiary lymphoid structure signature (p<0.001) and lower levels of M2 macrophages (p<0.0001) and NK cells (p<0.0001) compared to wt pts. mOS was improved in GNAS/KRAS-mut (N=307) pts compared to wt pts (20.5m vs 16m, p=0.008). Conclusions: AENs show unique DNA alterations by histological subtype. Grade 2 MA closely resembles G1, not G3, in survival and genomics, supporting a three-tier grading system over a high-grade (G2/G3) grouping. KRAS G12D represented 37% of KRAS mutations, and pts with KRAS/GNAS co-mutations had better survival and a favorable immune profile, supporting further immunotherapy research in low-grade MA. Most common mutations across histological subtypes. MA NMA GCA SRC KRAS *** 75% 55% 14% 20% TP53 *** 44% 59% 34% 17% SMAD4 24% 26% 15% 30% GNAS *** 41% 15% 8% 7% APC *** 8% 23% 2% 4% RHOA *** 0.5% 3% 8% 4% KDM6A * 2% 3% 4% 15% PIK3CA 7% 14% 4% 11% ***p<0.001; *p<0.05.

e13562 Background: Asymptomatic incidental pulmonary embolism (iPE) is increasingly detected in cancer patients on routine imaging; however, the optimal management setting and real-world data on healthcare utilization remain poorly defined. Methods: We conducted a retrospective cohort pilot study of cancer patients with newly diagnosed iPE detected on routine imaging in the outpatient setting at MD Anderson Cancer Center. AI-assisted imaging review (Aidoc) identified CT scans with iPE from 9/29/2025 to 11/09/2025 and were manually confirmed. Asymptomatic iPE was defined as the absence of symptoms associated with PE such as chest pain, dyspnea, and cough. The primary endpoint was acute care utilization following diagnosis, defined as outpatient vs acute care setting (emergency department/urgent care/observation/inpatient). Secondary endpoints were time to anticoagulation (AC), time of radiologist notification, and 30-day clinical outcomes. Fisher’s exact and chi-squared tests were used to compare categorical variables. Results: Cancer patients with iPE (n = 153) were identified and 92% (n = 141) were asymptomatic (median age 64; 51% female, 51% gastrointestinal malignancy). Presence of symptoms was associated with management of iPE in the acute care setting (p < 0.001). Asymptomatic iPE patients were managed as outpatient (77%) or in the acute care setting (23%; emergency department 11%, urgent care 5%, observation 4%, inpatient 3%). BNP/Troponins (17%) and echocardiograms (11%) were obtained in patients, primarily in the acute care setting. iPE extent was categorized as distal (subsegmental, segmental; 87%) or proximal (central, lobar; 13%) but was not associated with acute care setting (p = 0.24). Radiologist notification of iPE occurred in the morning (8AM-12PM; 35%), afternoon (12PM-5PM; 43%), or after hours (5PM-8AM; 22%). Acute care management of asymptomatic iPE occurred in the morning (12%), afternoon (28%), and after hours (29%) (p = .096). AC was used in 97% (n = 137) of asymptomatic iPE patients. 12% of asymptomatic iPE patients were already on AC. AC was initiated within the same day of diagnosis in 70% and within two days in 94% of asymptomatic iPE patients. AC occurred within the same day in 66% outpatient vs 83% in the acute care patients (p = 0.11). Within 30 days, all cause mortality was 1% among outpatients compared with 6% in the acute care group, while recurrent VTE occurred in 2% vs 6%, respectively. Conclusions: In this pilot study, nearly one quarter of patients with asymptomatic iPE underwent acute care management. These results highlight substantial practice variation in the management of iPE and suggest further exploration of standardized outpatient pathways.

BACKGROUND:Patients with peritoneal metastases from colorectal adenocarcinoma (CRC) benefit from cytoreductive surgery (CRS). However, the role of heated intraperitoneal chemotherapy (HIPEC) remains unclear. We studied associations between HIPEC, peritoneal disease-free survival (PDFS), and overall survival (OS) in patients with CRC undergoing CRS. STUDY DESIGN:All patients with CRC undergoing CRS between 2008 and 2023 were retrospectively identified at our center. Patient clinicodemographic factors were determined by chart review. OS and PDFS were evaluated using the Kaplan-Meier method. Associations between clinical factors and survival were determined using Cox proportional hazard models. RESULTS:A total of 147 patients were identified with 24.5-month median follow-up. Most patients (111; 75.5%) had a low peritoneal cancer index (PCI; less than 11), whereas 36 patients (24.5%) had high PCI (11 or more). Eighty-three patients (55.8%) had CRS alone. Sixty-four patients underwent CRS with HIPEC (42 [66%] mitomycin C [MMC], 19 [30%] oxaliplatin [OX], 3 [4.7%] cisplatin). The median OS was 59.8 (95% CI 41.7 to 83.0) months. The median PDFS was 13.3 (95% CI 10.4 to 18.5) months. OS was equivalent comparing HIPEC with MMC, HIPEC with OX (hazard ratio [HR] 0.49, 95% CI 0.22 to 1.09, p = 0.08), and CRS alone (HR 0.74, 95% CI 0.41 to 1.32, p = 0.31). Multivariable analysis showed only PCI was associated with OS (HR 1.08, 95% CI 1.03 to 1.14, p = 0.003). Low PCI patients had similar PDFS after CRS-HIPEC (HR 1.07, 95% CI 0.61 to 1.87, p = 0.814) compared with CRS alone. High PCI patients had improved OS comparing CRS-HIPEC with CRS (MMC: HR 0.17, 95% CI 0.04 to 0.76, p = 0.02; OX: HR 0.048, 95% CI 0.006 to 0.37, p = 0.004). CONCLUSIONS:HIPEC was not associated with OS or PDFS in patients with PCI 10 or less but was associated with improved OS and PDFS in patients with PCI 11 or more. The use of HIPEC for high PCI may be warranted, although randomized prospective data are needed to confirm this.

3573 Background: Activation of the complement cascade pathway is associated with pro-oncogenic inflammation and immune-suppressing, myeloid-derived M2 macrophages for many solid tumors. Most colorectal cancers (CRC) are microsatellite stable that do not respond to immunotherapy. The role of complement activation (CA) in the “immune cold” CRC phenotype remains poorly detailed. We sought to identify molecular annotations of CRC subpopulations enriched for CA to guide future therapeutic strategies. Methods: CRC tumors from 207 patients with stages II-IV CRC at MDACC underwent bulk RNA sequencing. Transcriptomes were analyzed per GSEA “Hallmark Complement” gene set to assign a normalized enrichment score (NES) for CA to each patient and considered “complement high” (“CH”; N = 103) or “complement low” (“CL”; N = 104) if the complement NES score was above or below the median. Associations between CA and clinical and pathologic characteristics - e.g., demographics, mutation status, and Consensus Molecular Subtype (CMS) - were evaluated by chi-squared analysis. Single cell RNA (scRNA) sequencing was performed on a separate cohort of CRC primary tumors (N = 85) and liver metastases (N = 60) to compare CA among different cell types using a Wilcoxon’s test. To assess for an association between CA and response to immunotherapy in a previously annotated clinical trial of patients with MSS, BRAF V600E metastatic CRC (NCT04017650), we evaluated pretreatment biopsies by bulk RNA sequencing and compared transcriptomic differences in CA between responders versus non-responders to encorafenib, cetuximab, and nivolumab (E+C+N). Results: CH CRC featured a higher prevalence for MSI-H CRC (21.3% vs 4.2%; p = .005), CMS1 (30.1% vs 6.7%; p < .001), and CMS4 (26.2% vs 7.7%; p < .001) relative to CL CRC. CMS2 was more common among CL CRC (54.8% vs 14.6%, p < .001). CH CRC was associated with BRAF V600E mutations (29.7% vs 9.2% for CL, p = .002) but not with KRAS/NRAS mutations or RAS/BRAF wild-type CRC (p = n.s. for both). On scRNA analysis, CA scores were highest in myeloid cells and lowest for B cells (p < .0001). Among patients with MSS, BRAF V600E CRC, CH signature was associated with non-response to E+C+N (fold-change 3.0 relative to responders, p = .046). Conclusions: Association of CH status with MSI-H CRC is a novel finding that warrants further study in understanding differential patterns of benefit to immune checkpoint blockade. CH CRC, associated uniquely with BRAF V600E CRC, was distributed bimodally across the immune-activated CMS1 and the immune-suppressing CMS4 CRC, similar to known transcriptomic heterogeneity of BRAF V600E CRC. Our data suggest high CA, linked to immune-suppressing myeloid cell subpopulations, as a negative predictive biomarker for response to immunotherapy in MSS BRAF V600E CRC and support broader study of complement-targeting agents to improve treatment for selected patients with CRC.

Neoadjuvant immunotherapy can induce pathologic complete response (pCR) in patients with localized deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) tumors. The long-term outcomes of these patients are unknown, as is the clinical utility of measuring circulating tumor DNA (ctDNA). Follow-up was evaluated in patients enrolled in a phase II trial (NCT04082572) that evaluated the efficacy and safety of pembrolizumab in patients with localized dMMR/MSI-H tumors. The primary outcomes of this trial have previously been reported. 3-year EFS and OS rates were 80% (95% CI: 66% - 93%) and 94% (95% CI: 86% - 100%). Patients without detectable ctDNA after pembrolizumab had higher 3-year EFS and OS rates than patients with detectable ctDNA after pembrolizumab (3-year EFS 92% vs 20%; p < 0.001, 3-year OS 100% vs 80%; p < 0.001). Patients with colorectal cancer (CRC) who had undetectable ctDNA after pembrolizumab were more likely to have pCR compared to those with detectable ctDNA after pembrolizumab (91% vs 0%; p = 0.03). Patients with CRC who were managed non-operatively and had undetectable ctDNA after pembrolizumab had a higher 2-year EFS rate than patients with detectable ctDNA after pembrolizumab (100% vs 33%; p = 0.03). Pembrolizumab demonstrates long-term efficacy in patients with localized dMMR/MSI-H tumors.

e16067 Background: The incidence of brain metastasis in gastrointestinal (GI) malignancies is rare, estimated at less than 1%. However, its occurrence is associated with devastating outcomes. With the advent and prolonged use of Anti-HER2 therapy in patients expressing HER2 in their primary malignancy, there appears to be an increasing trend in brain metastasis, though the reason is unknown. Methods: This study included patients with a confirmed diagnosis of primary GI cancer treated at MD Anderson Cancer Center between 2000 and 2024. Data was extracted from electronic health records (EHR) and the tumor registry using the Palantir Foundry platform (Palantir Technologies, Denver, CO). Patients were included if their primary malignancy exhibited positive HER2 expression (IHC 3+) or ERBB2 amplification. The cohort was divided into two groups based on treatment received: (1) those who received Anti-HER2 therapy and (2) those who did not receive Anti-HER2 therapy. The Institutional Review Board (IRB) of MD Anderson Cancer Center approved the study. Results: Out of 83,329 patients with gastrointestinal cancers, HER2 testing was performed on 13,153 individuals, identifying HER2 positivity or ERBB2 amplification in 571 patients: 49% with gastroesophageal cancer, 37% with colorectal cancer, 11.5% with Biliary tract cancers, 1% with appendiceal cancer, 0.8% with small intestinal cancer, and 0.7% with anal cancer The cohort of 571 patients comprised 68% males (387 patients) and 32% females (184 patients), with a median age at diagnosis of 58 years (range 21–89 years).Among the 177 patients receiving anti-HER2 therapy, (trastuzumab and pertuzumab or trastuzumab deruxtecan) 33 (18%) developed brain metastasis, while 20 (5%) of the 396 patients not receiving anti-HER2 therapy developed brain metastasis, p < 0.001 (RR = 3.7). Of the 33 patients with brain metastases in the anti-HER2 therapy group, 31 (94%) had metastases to other sites, while among the 20 patients with brain metastases in the non-anti-HER2 therapy group, 15 (75%) had metastases to other sites, p = 0.08. The median time between disease diagnosis and the development of brain metastases was 19 months for the group receiving anti-HER2 therapy and 13 months for the group not receiving anti-HER2 therapy, with a statistically non-significant p-value of 0.7. The median duration from the start of anti-HER2 therapy to the development of brain metastasis was 14 months (range 1 to 86). Conclusions: These findings suggest a significantly higher incidence of brain metastasis in patients treated with anti-HER2 therapy (18%) compared to those who did not receive this treatment (5%). These findings underscore the need for further research to understand the mechanisms driving this trend and to explore strategies for early detection and prevention of brain metastasis in this population.

KRAS inhibitors showed promising results in clinical trials. Understanding KRAS mutations and immune regulation is critical for more effective and durable KRAS targeted therapy. KRAS Q61 is rare and less studied in cancer patients. Here we investigate the clinical, molecular, tumor microenvironment (TME) features of KRAS Q61 mutated gastrointestinal (GI) malignancies. We used the Palantir Foundry system to query electronic health records of patients diagnosed with colorectal (CRC), pancreatic (PDAC), appendiceal (AA), cholangiocarcinoma (CC), hepatocellular carcinoma (HCC) and gastroesophageal carcer who were tested for KRAS mutations in our institution between 2002-2025. Clinical, molecular, and overall survival (OS) data were collected and studied. Subsets of PDCA and CRC patients who had tumoral bulk RNA sequencing and their TME characteristics were also analyzed. KRAS mutation was tested in 13,535 patients with CRC, PDAC, CC, AA, and gastroesophageal cancer. KRAS was mutated in 46.4% (n= 4,516) of CRC, 87.1% of PDAC (n=1,357), 18.4% of CC (n=100), 50.3% of AA (n=393), 7.3% of gastroesophageal carcinoma (n=51) and 7.4% of HCC (n=16). KRAS Q61 consisted of 5.3% (n=340) of all KRAS mutations (n= 6,433). Frequencies of KRAS Q61 was 2.2% (n=210) for CRC, 6.2% (n=97) for PDAC, 2.4% (n= 13) for CC, 2% (n= 16) for AA and 0.6% (n= 4) for gastroesophageal carcinoma. KRAS Q61H was the most common KRAS Q61 allele. The other top mutated genes were TP53 (71%) and APC (63%) for CRC, TP53 (76%) and CDKN2A (28%) for PDAC, GNAS (34%) and TP53 (34%) for AA and TP53 (30%) and ARID1A (19%) for CC. Compared to KRAS wildtype, patients with KRAS mutations had worse OS in CRC (p<0.05) and longer OS in AA patients (p<0.05). Compared to other KRAS mutations, KRAS Q61 had worse OS in PDAC than other KRAS mutated PDAC and wildtype patients (19.9 months for KRAS Q61 , 24.6 months for other KRAS mutations and 38.7 months for wildtype, p<0.05). KRAS mutated tumors, especially KRAS Q61 mutated tumors, had more immunosuppressive, fibrotic TME than KRAS wildtype tumors and showed enrichment of hypoxia and TGF-β pathway gene expression in PDAC. KRAS Q61 mutations frequencies varied across different GI malignancies, with the highest frequency in PDAC (6.2%). KRAS co-mutation landscape showed cancer specificities such as APC mutation in CRC, CDKN2A in PDAC, ARID1A for CC and GNAS mutations in AA. KRAS Q61 mutations had worse OS in patients with PDAC and more immune suppressive and fibrotic TME and enrichment of hypoxia and TGF-β pathway gene expression. Dan Zhao, Sali Albarouki, Ahemd Elhariri, Abdelrahman Yousef, Saikat Chowdhury, Mark Knafl, Paul Roy, Brandon Smaglo, Robert A. Wolff, Shubham Pant, Jason willis, Ryan Huey, Michael J. Overman, Camila L. Lopez, Anthony B. Chen, Ethan B. Ludmir, Mark Hurd, Yang Chen, Haoqiang Ying, Rebecca A Snyder, Matthew H.G. Katz, Anirban Maitra, John Paul. Shen. Clinical and Molecular Characteristics of KRAS Q61 Mutated Pancreatic Cancer and Other Gastrointestinal Malignancies [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B076.

3534 Background: Acquired resistance limits the efficacy of anti-EGFR (EGFRi) therapy in RAS wild-type (WT) mCRC, often through MAPK reactivation driven by secondary RAS mutations or other genomic alterations. Preclinical studies on EGFRi-refractory models led by our group showed that LY3214996, a potent ERK1/2 inhibitor, combined with CET suppresses MAPK signaling and reduces tumor growth, while the addition of Abemaciclib further enhances anti-tumor activity by synergistically inhibiting cell cycle and survival pathways. Methods: In this open-label, phase Ib/II study, RAS/BRAF/EGFR/MEK1 WT mCRC pts who progressed on prior EGFRi-based therapy and ≥1 chemotherapy were treated with CET + LY3214996 (Arm A) or CET + LY3214996 + Abemaciclib (Arm B). Phase Ib employed a 3 + 3 design to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). Phase II followed a two-stage design with cohort expansion to assess ORR by RECIST v1.1 as the primary endpoint. Secondary endpoints included PFS and OS. Results: Of 44 pts treated on trial, 2 did not meet inclusion criteria; 39 were evaluable for activity, and 34 for efficacy. The RP2D was 200 mg LY3214996 p.o. daily + 500 mg/m² CET i.v. biweekly in Arm A with the addition of 150 mg Abemaciclib p.o. twice daily in Arm B. Median age was 53.0 years (IQR 47.0 – 63.8), and 59.1% (26/44) were male. Most pts (95.5%, 42/44) had a left-sided or rectal primary, and all were pMMR/MSS. Prior EGFRi-based rechallenge, retreatment/reintroduction, or both were noted in 9.1% (4/44), 25.0% (11/44), and 4.5% (2/44), respectively. ORR, DCR, median PFS and OS were 5.3% (1/19), 36.8% (7/19), 1.8 months (95% CI 1.5 – 4.8) and 7.0 months (95% CI 5.0 – 22.0) for the doublet and 15.0% (3/20), 65.0% (13/20), 3.6 months (95% CI 2.5 – 4.5), and 14.0 months (95% CI 5.9 – 21.0) for the triplet, respectively. Longer time elapsed from last EGFRi was associated with higher predicted probability of response after adjustment for trial regimen (OR 1.35, 95% CI 1.06 – 1.94, p = 0.038). Baseline ctDNA profiling drawn prior to rechallenge revealed acquired RAS mutations in two responders, one per arm. Grade 3 TRAEs occurred in 31.8% (14/44), with acneiform rash (9.1%, 4/44), diarrhea (9.1%, 4/44), thrombocytopenia (6.8%, 3/44), fatigue (4.5%, 2/44), and anemia (4.5%, 2/44) being the most frequent while one Grade 4 TRAE (thrombocytopenia, 2.3%) was reported. Conclusions: CET + LY3214996 ± Abemaciclib had a manageable safety profile with no unexpected adverse events. Although activity was modest, this study is the first to report objective responses to an EGFRi-based regimen in pts harboring acquired RAS mutations in pre-rechallenge ctDNA. Translational efforts are ongoing. Clinical trial information: NCT04616183 .

4179 Background: It is well documented that Pancreatic ductal adenocarcinoma (PDAC) metastasize to the liver had worse outcome than to the lung, but the molecular basis was less clear. We employ a large Real-World Evidence dataset to evaluate clinical and molecular features of PDAC according to involved metastatic sites. Methods: The Foundry software platform was used to query electronic medical records of patients with metastatic PDAC who underwent Next-Generation Sequencing (NGS) at MD Anderson. Involved metastatic sites were extracted using natural language process from imaging reports then manually verified. Overall survival (OS) was calculated from date of diagnosis. Results: We identified 1,095 patients with metastatic PDAC diagnosed between May 2003 and Oct 2024. Median follow up was 41.8 months and median OS was 22.8 (95%CI: 20.2-25.2) months. Most patients (52.9%) had multiple metastatic sites including liver, 28.5% had liver only metastases, while 8.7% had lung only metastases. 10% had metastases not including liver. Patients with lung only metastasis had the best outcomes (median = 57.6 months, HR = 0.37 relative to liver only, 95%CI = 0.27-0.52, p = 9.3e-9), followed by patients with metastases not involving liver (median = 41.3 months, HR = 0.65, 95%CI = 0.49-0.87, p = 0.003). Patients with liver only metastasis (median OS = 19.5 months) had similar survival to those with multiple sites including liver (median = 19.3 months, HR = 1.1, 95%CI = 0.96-1.4, p = 0.13). TP53 was more frequently mutated in patients with liver only metastasis (84%) and multiple metastases including liver (85%) compared to patients with lung only (73%) and multiple sites not including liver (67%, p = 9.3e-5). GNAS showed lower frequency (5%) in patients with liver only and patients with multiple metastasis including liver (2%) compared to patients with lung only (8%) or non-liver metastases (10%, p = 0.003). In patients with liquid biopsy (n = 240), lung only metastasis showed significantly lower positivity rate for mutation detection (50% vs 65% for liver only, 62% for other or multiple not including liver and 79% for multiple including liver, p = 0.009), and lower TP53 detection rate (23% for lung only vs 46% for liver only, p = 0.02). The frequency of KRAS mutation and mutant allele distribution were not significantly different in tissue NGS. However, patients with lung only metastasis showed significantly less frequent KRAS mutation detection by liquid biopsy (10% vs 52% in liver only metastasis, p = 9.6e-4). Conclusions: PDAC patients without liver metastasis have markedly improved OS relative to patients with liver metastasis, and lower rates of TP53 mutation. Similar frequencies of KRAS mutation were found in different patients by tissue testing. However, patients with lung only metastasis had lower positivity rate of ctDNA, and lower detection rate of KRAS mutation by liquid biopsy.

Early-onset colorectal cancer (EOCRC) is a distinct clinical entity and a rising global challenge. As presentation and symptom patterns at diagnosis have implications for early detection and prognosis, we aimed to characterize differences between EOCRC and late-onset colorectal cancer (LOCRC) at scale. A retrospective cohort of colorectal cancer (CRC) cases diagnosed 1990-2025 was collected. EOCRC and LOCRC were defined as age <50 and ≥50 years at diagnosis. Presentation mode (symptomatic, emergency, screening, incidental, or unclear) and symptoms at diagnosis were classified using the GPT-4o large language model (LLM) through prompt engineering based on manually curated clinical notes relevant to diagnosis and validated on 500 random samples. Patient-level clinical and demographic data were obtained from institutional datasets. Chi-square and odds ratios were used for comparisons. LLM-based classification showed strong agreement with manual review (Cohen’s κ=0.90). Of 41,152 CRC cases, 29% were EOCRC and 71% LOCRC. Stage IV at diagnosis (38% vs 31%, p<0.001) and left-sided primaries (76% vs 66%, p<0.001) were more prevalent in EOCRC compared with LOCRC. EOCRC patients more often presented as symptomatic (72% vs 65%, OR 1.36, 95% CI 1.29-1.44, p<0.001) or emergent (23% vs 20%, OR 1.22, 95% CI 1.15-1.29, p<0.001) and were less often detected by screening (3% vs 12%, OR 0.24, 95% CI 0.21-0.27, p<0.001), whereas no meaningful difference was observed for incidental cases. The symptomatic or emergent presentation of EOCRC was more frequently characterized by abdominal/rectal pain (45% vs 35%, OR 1.49, 95% CI 1.41-1.57), bleeding-related symptoms (49% vs 44%, OR 1.25, 95% CI 1.19-1.32), and changes in bowel habits (30% vs 27%, OR 1.16, 95% CI 1.09-1.23), and less often by anemia (11% vs 16%, OR 0.63, 95% CI 0.58-0.68) or constitutional symptoms (13% vs 16%, OR 0.79, 95% CI 0.73-0.85, p<0.001 for all) compared with LOCRC. The proportion of screening-detected cases rose from 3% to 4% in EOCRC (p=0.007) and 9% to 15% in LOCRC (p<0.001) between 1990-2009 and 2010-2025. After the 2021 national screening guideline update, lowering the starting age from 50 to 45 years, screening-detected cases among 45–49-year-old patients increased from 4% to 13% (p<0.001). EOCRC predominantly presents as symptomatic or emergent and at a more advanced stage, underscoring the need for enhanced screening strategies and increased public awareness. Emerik Osterlund, Berta Martin-Cullell, Sebastian Correa Cautino, Mahmoud M. G. Yousef, Songwit Payapwattanawong, Neha Y. Agrawal, Paul M. Roy, Kaysia Ludford, John Paul Y. C. Shen, Xiling Shen, Michael J. Overman, Kanwal P. S. Raghav, Arvind Dasari, Van K. Morris, Christine M. Parseghian, Luisa M. Solis Soto, Michael G. White, Yi-Qian Nancy. You, Victoria Serpas Higbie, Scott Kopetz, Guglielmo Vetere. Mode of presentation and symptoms at diagnosis of early- and late-onset colorectal cancer: a large retrospective AI-powered analysis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(23_Suppl):Abstract nr A027.

Importance Disparity in overall survival (OS) and differences in the frequency of driver gene variants by race and ethnicity have been separately observed in patients with colorectal cancer; however, how these differences contribute to survival disparity is unknown. Objective To quantify the association of molecular, socioeconomic, and clinical covariates with racial and ethnic disparities in overall survival among patients with colorectal cancer. Design, Setting, and Participants This single-center cohort study was conducted at a tertiary-level cancer center using relevant data on all patients diagnosed with colorectal cancer from January 1, 1973, to March 1, 2023. The relative contribution of variables to the disparity was determined using mediation analysis with sequential multivariate Cox regression models. Main Outcome OS, from diagnosis date and from start of first-line chemotherapy. Results The study population of 47 178 patients (median [IQR] age, 57.0 [49-66] years; 20 465 [43.4%] females and 26 713 [56.6%] males; 3.0% Asian, 8.7% Black, 8.8% Hispanic, and 79.4% White individuals) had a median (IQR) follow-up from initial diagnosis of 124 (174) months and OS of 55 (145) months. Compared with White patients, Black patients had worse OS (hazard ratio [HR], 1.16; 95% CI, 1.09-1.24; P <.001), whereas Asian and Hispanic patients had better OS (HR, 0.66; 95% CI, 0.59-0.74; P <.001; and 0.86; 95% CI, 0.81-0.92; P <.001, respectively). When restricted to patients with metastatic disease, the greatest disparity was between Black patients compared with White patients (HR, 1.2; 95% CI, 1.06-1.37; P <.001). Evaluating changes in OS disparity over 20 years showed disparity decreasing among Asian, Hispanic, and White patients, but increasing between Black patients and White patients (HRs, 1.18; 95% CI, 1.07-1.31 for 2008-2012; 1.24, 95% CI, 1.08-1.42 for 2013-2017; and 1.50; 95% CI, 1.20-1.87 for 2018-2023). Survival outcomes for first-line chemotherapy were worse for Black patients compared with White patients (median OS, 18 vs 26 months; HR, 1.30; 95% CI, 1.01-1.70). Among 7628 patients who had clinical molecular testing, APC, KRAS, and PIK3CA showed higher variant frequency in Black patients (false discovery rate [FDR], 0.01; < 0.001; and 0.01, respectively), whereas BRAF and KIT were higher among White patients (FDR, 0.001 and 0.01). Mediation analysis identified neighborhood socioeconomic status as the greatest contributor to OS disparity (29%), followed by molecular characteristics (microsatellite instability status, KRAS variation and BRAF variation, 10%), and tumor sidedness (9%). Conclusions This single-center cohort study identified substantial OS disparity and differing frequencies of driver gene variations by race and ethnicity. Socioeconomic status had the largest contribution but accounted for less than one-third of the disparity, with substantial contribution from tumor molecular features. Further study of the associations of genetic ancestry and the molecular pathogenesis of colorectal cancer with chemotherapy response is needed.JAMA Oncol. 2024;10(11):1519-1529. doi:10.1001/jamaoncol.2024.3666Published online September 12, 2024.Invited Commentarypage 1530Supplemental contentAuthor Affiliations:Authoraffiliations are listed at the end of thisarticle.Corresponding Author:John PaulShen, MD, MD Anderson CancerCenter, 1515 Holcombe Blvd,Houston, TX 77030 (jshen8@mdanderson.org).ResearchJAMA Oncology |Original Investigation(Reprinted)1519 (c) 2024 American Medical Association.

Background PD-1 inhibitors have been shown to be effective in advanced cancer patients with mismatch repair deficient tumors (dMMR) in a tumor agnostic fashion. dMMR testing by immunohistochemistry (IHC) is infrequently performed outside of colorectal and endometrial cancer. In contrast, comprehensive genomic sequencing (CGS) for somatic genomic alterations, is frequently perfomed across tumor types. We hypothesized that CGS may identify alterations in dMMR genes (MLH1, MSH2, MSH6, PMS2), and that patients with genomic MMR alterations will have higher rates of dMMR loss by IHC. Methods From Jan 2016 to Dec 2021, 15,701 patients were identified as receiving CGS. Sequencing results were analyzed for mutations in dMMR genes, tumor type distribution and concordance with IHC results. Results 627 (4%) of 15,701 patients had mutations in one of the dMMR genes; mutations were found across tumor types. Majority of patients with mutations in MMR genes had single nucleotide variants (SNV, 430, 68.6%) followed by frameshift/truncating (155, 24.7%), splice site (31, 4.9%) and in frame deletions/indel (11, 1.6%) mutations. A subset of the MMR gene mutant patients (n=279) had IHC testing for dMMR proteins: 99 (35.5%) demonstrated dMMR loss, including 55 (53.4%) of 103 patients with colorectal cancer, 3 (25%) of 12 patients with endometrial cancer and 41 (25%) of 164 with other tumor types. dMMR loss on IHC was found in 70 (71%) of 99 patients with frameshift/truncation/splice site/indel mutations compared with 29 (29%) of patients with SNVs (x2=8.49; p=0.00038). Conclusion Mutations in MMR genes are found in multiple tumor types. Reflex IHC testing of patients carrying dMMR mutations inferred to be inactivating may identify patients with dMMR, expanding the pool of patients eligible for immunotherapy. Citation Format: Vijaykumar Holla, Arash Ronaghy, Richard K. Yang, Keyur P. Patel, Mark J. Routbort, Michael J. Overman, Ecaterina E. Dumbrava, Kenna R. Shaw, Daniel D. Karp, Funda Meric-Bernstam. Genomic alterations in DNA mismatch repair (dMMR) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2128.

Patient characteristics with statistical comparison between sequenced and unsequenced cohorts among 233 patients.

Abstract Purpose Many clinical trials supporting new drug applications underrepresent minority patients. Trials conducted by the NCI's clinical trial network (NCTN) have greater outreach to community sites, potentially allowing better representation. We compared the representation of black patients in pharmaceutical company-sponsored cancer clinical trials to NCTN trials and the U.S. cancer population. Procedures We established a large cohort of study publications representing the results of pharmaceutical-company sponsored trials that supported new U.S. Food and Drug Administration (FDA) drug approvals from 2008-2018. NCTN trial data were from the SWOG Cancer Research Network. U.S. cancer population rates were estimated using Surveillance, Epidemiology, and End Results (SEER) survey data. We compared the proportion of black patients by enrollment year for each cancer type and overall. Comparisons between groups were conducted using tests of proportions. Results 227 trials (pharmaceutical company-sponsored trials, 74; SWOG trials, 153) comprised of 79,592 patients (pharmaceutical company-sponsored trials, 43,567; SWOG trials, 36,025) for nine specific cancer types were analyzed. Overall, the proportion of black patients was 2.9% for pharmaceutical company-sponsored trials, 8.3% for SWOG trials, and 12.1% for the U.S. cancer population (p<.001 for each pairwise comparison). For each cancer type, the proportion of black patients was statistically significantly lower for pharmaceutical company-sponsored trials compared to SWOG trials (except for melanoma) and compared to the U.S. cancer population. Conclusions The poor representation of minority groups in pharmaceutical company-sponsored trials is of vital scientific concern. These trials could support the use of new drugs with little data about efficacy or side effects in key populations. Because pharmaceutical company-sponsored trials test the newest available therapies, limited access to these trials represents a disparity in access to potential breakthrough therapies. Pharmaceutical companies could improve racial/ethnic diversity in their trials - and expand access to all patients - through increased outreach to community sites, as suggested by the findings for the NCTN trials. These results have the potential to directly influence policy, as the FDA, in partnership with the American Association for Cancer Research, is currently examining ways to improve representation of black patients in FDA registration trials. Citation Format: Joseph M. Unger, Dawn L. Hershman, Raymond U. Osarogiagbon, Anirudh Gothwal, Seerat Anand, Arvind Dasari, Michael Overnman, Jonathan M. Loree, Kanwal Raghav. Racial representativeness of cancer clinical trials sponsored by the National Cancer Institute compared to pharmaceutical companies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4344.

828 Background: Predictive factors for immunotherapy benefit across gastrointestinal (GI) cancers are limited to those with deficient mismatch repair (dMMR). Mutations in DNA polymerase E (POLE) can cause a hypermutated phenotype irrespective of MMR status and may serve as a predictor factor for immunotherapy. Methods: All POLE-mutant GI cancers with tumor mutation burden (TMB) measured at MD Anderson Cancer Center were identified (N = 58) from 2014 to 2019 and those that had received immunotherapy (N = 18) were studied. TMB was measured by genomic profiling assays FoundationOne or STGA 2018. Samples were analyzed using Kaplan-Meier method and compared using log rank test, with a predefined high TMB threshold of 20 muts/mb. Results: Of the 58 POLE-mutant GI tumors a high TMB was present in 50% of the cases. 18 patients (median age 64, female gender 16.7%, median prior lines of therapy 2) with locally advanced (N = 4) or metastatic (N = 14) POLE-mutant GI cancers (13 colorectal, 1 small intestine, 1 esophageal, 1 pancreatic, and 2 gallbladder) were identified. Immunotherapy agents were PD-1/PD-L1 based in 17 and CTLA-4 based in 1. High TMB was present in 11 patients. dMMR was present in 7 patients, all with high TMB. Treatment response was seen in 3 patients (2 CR and 1 PR), all TMB high and dMMR. Progression-free survival (PFS) was significantly longer in those with high TMB (median: 10.1 months vs. 3 months, p = 0.048). Of the 11 pMMR patients median PFS was 9.3 months in high TMB and 3 months in low TMB (p = 0.246). Conclusions: POLE mutations in GI cancers were associated with a high TMB ( > 20muts/mb) in 50% of patients. Within POLE mutant GI cancers a high TMB may identify patients who benefit from immunotherapy irrespective of mismatch repair status.

PURPOSE:Calcium aluminosilicate clay (CASAD) is a naturally occurring clay that serves as a cation exchange absorbent. We hypothesized that oral administration of CASAD would reduce the rate of grade 3/4 diarrhea associated with irinotecan use for metastatic colorectal cancer (CRC) by adsorbing the SN-38 metabolite.METHODS:Patients receiving irinotecan-based chemotherapy were randomized equally between CASAD and placebo arms in this multicenter trial in order to assess differences in the proportions of patients with grade 3/4 diarrhea within 6 weeks. Additionally, we compared symptom severity between the two arms using the M.D. Anderson Symptom Inventory.RESULTS:Between May 2009 and May 2012, 100 patients were enrolled. In evaluable patients, 7 of 43 (16 %) on the CASAD arm compared to 3 of 32 (9 %) on the placebo arm experienced grade 3/4 diarrhea (P = 0.70). The rate of any diarrhea among all patients was similar (CASAD arm, 64 % vs. placebo arm, 70 %). The rate of study dropout was 14 % in the CASAD arm and 38 % in the placebo arm (P = 0.01). No differences were found in symptom severity, individual symptom items, and in serious adverse events between the two arms.CONCLUSION:Compared to placebo, CASAD use was safe but ineffective in preventing diarrhea in metastatic CRC patients treated with irinotecan-containing chemotherapy regimens. There were no distinct signals in terms of patient symptoms between arms, but there was significantly more patient dropout in the placebo arm. Future CASAD trials will focus on the active treatment of diarrhea.

Background. Appendiceal adenocarcinomas (AAs) are rare and this has limited their molecular understanding. The purpose of our study was to characterize the molecular profile of AA and explore the role of targeted therapy against cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR). Patients and Methods. We performed a retrospective review of 607 patients with AA at a single institution. A total of 149 patients underwent molecular testing for at least one of the following: activating mutations in KRAS, BRAF, cKIT, EGFR, or PI3K; protein expression of c-KIT or COX-2; or microsatellite instability (MSI) status by immunohistochemistry. Kaplan-Meier product limit method and log-rank test were used to estimate overall survival (OS) and to determine associations among OS, COX-2 expression, KRAS mutations, and other characteristics. Results. Age, grade, stage, signet ring cells, mucinous histology, and completeness of cytoreduction score correlated with survival outcomes. COX-2 expression, KRAS, PI3K, and BRAF mutations were seen in 61%, 55%, 17%, and 4% of patients, respectively. High MSI was seen in 6% of patients. KRAS mutation was strongly associated with well differentiated or moderately differentiated AA (p < .01). COX-2 expression (p = .33) and the presence of KRAS mutation (p = .91) had no impact on OS. The use of celecoxib in patients whose tumors expressed COX-2 (p = .84) and the use of cetuximab or panitumumab in patients with KRAS wild-type tumors (p = .83) also had no impact on OS. Conclusion. In this cohort, we demonstrated that COX-2 expression and KRAS mutations were frequently seen in AA, although neither exhibited any prognostic significance. MSI was infrequent in AA. Targeted therapy against COX-2 and EGFR appeared to provide no clinical benefit. Well and moderately differentiated AA were molecularly distinct from poorly differentiated AA.

568 Background: AEN is a malignancy including both indolent well-differentiated and highly aggressive signet ring carcinoma. Optimal therapy is believed to be cytoreductive surgery (CRS) followed by heated intraperitoneal chemotherapy (HIPEC). Yet, some patients (pts) will recur, are suboptimal for surgery, and are considered for systemic chemotherapy (SC). The purpose of this study is to compare SC regimens in treatment-naïve surgically unresectable AEN pts. Currently, no standard exists. Methods: A retrospective review of AEN pts who were registered in our tumor registries between Jan. 2005 to Dec. 2009 was completed. Electronic medical records were reviewed for CRS, HIPEC, histology, stage, SC received, CEA, CA-125, and/or CA 19-9, response (R), and progression-free survival (PFS). All patients were required to be restaged at their respective institution with R defined as clinical or radiographic benefit. K-M method, Log-Rank, and Cox proportional hazard regression models were used for statistical analysis. Results: Of 659 pts with AEN diagnosis, 134 pts were evaluable for PFS and R. Forty-eight (36%) pts were poorly-differentiated; 29 (22%) signet ring; and 22 (16%) had both features. Thirty-four (25%) were well-differentiated. After a median follow-up of 35M, adjusting PFS for prior CRS, HIPEC, histology, ascites, and biologic therapy, pts who received 5-FU alone fared worse vs. FOLFOX [HR: 2.39; 95% CI: 1.2-4.6; p-value = 0.01]. FOLFIRI trended in favor of improved PFS, but was underpowered. No statistical difference in R was noted (Table). Conclusions: In the treatment of surgically unresectable AEN, combination chemotherapy resulted in improved PFS vs. single agent 5-FU. Quality of life analysis will be reported at a later date. Randomized prospective analysis should be considered. [Table: see text]