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Purpose: Neuroendocrine neoplasms (NENs) are increasingly recognized to have a hereditary predilection, yet the prevalence and clinical relevance of pathogenic germline variants (PGVs) in unselected patients with NEN remain poorly defined. This prospective, multicenter study aimed to evaluate the prevalence and clinical utility of PGVs through universal multigene panel testing in a diverse cohort of patients with NENs. Patients and Methods: Between 2018 and 2024, we enrolled unselected patients with NENs from 3 Mayo Clinic Cancer Centers. Germline genetic testing was performed using a next-generation sequencing panel of up to 84 cancer predisposition genes. Patients were not selected based on age, disease stage, ethnicity, or family history. Variants were classified as PGVs, variants of uncertain significance (VUS), or negative. Clinical and demographic data were analyzed descriptively. Results: Among 88 patients, PGVs were identified in 15.9% (n=14), most frequently in high- or moderate-penetrance genes including MEN1 , CHEK2 , MITF , and MUTYH . PGVs were most commonly found in pancreatic NENs [n=12/55 (21.8%)], followed by small bowel NENs [n=2/20 (10%)], with no PGVs detected in lung NENs. Mismatch repair (MMR) gene alterations were identified in 5.7% of patients, including 1 MLH1 PGV and 4 MSH2/MSH6 VUS, 2 of which demonstrated MMR deficiency by protein testing. VUS were reported in 34.1% of patients. Notably, 35.7% of PGV-positive patients did not meet current NCCN or ACMG testing criteria, and 53.9% had PGVs in genes outside of cancer-specific guideline recommendations. Conclusions: Universal germline testing in unselected patients with NEN identified clinically relevant PGVs in over 15% of cases. These findings support broader genetic testing approaches to guide treatment, enhance familial risk assessment, and inform cascade testing—regardless of traditional clinical selection criteria.

e15509 Background: Large language models (LLMs) are increasingly explored for oncology decision support, yet comparative evidence evaluating medical-specific versus general-purpose LLMs using expert-reviewed clinical cases is limited. We compared a medical-specific LLM (Google MedGemma 27B) with a general-purpose LLM (ChatGPT-5) using gastrointestinal (GI) and genitourinary (GU) oncology vignettes. Methods: This cross-sectional study evaluated 32 de-identified oncology vignettes (26 GI, 6 GU) created by a U.S. board-certified medical oncologist and informed by real-world cases. Vignettes included text-only information on the clinical context, description of pathology, tumor staging, biomarkers, and relevant comorbidities. Both LLMs were prompted to provide National Comprehensive Cancer Network(NCCN) guideline-based treatment recommendations, monitoring strategies, maintenance therapy considerations, and references, along with a self-reported confidence score (0–100). Board-certified U.S. medical oncologists independently reviewed outputs using a structured instrument; two disease specific expert oncologists evaluated each case. Outcomes included correctness and comprehensiveness (1–10 scales), hallucinations (factually fabricated or unsupported statements), NCCN traceability, potential patient harm, and clinician trust. Associations between accuracy and comprehensiveness were assessed using correlation coefficients. Inter-rater reliability was assessed using a two-way random-effects intraclass correlation coefficient (ICC). Results: ChatGPT-5 demonstrated higher mean correctness (8.65 vs 4.68) and comprehensiveness (8.68 vs 5.22) scores compared with MedGemma 27B. Accuracy and comprehensiveness were strongly correlated overall (Pearson r = 0.93, p < 0.001), with significant model-specific correlations (ChatGPT-5 r = 0.86, p < 0.001; MedGemma r = 0.77, p < 0.001). Hallucinations occurred less frequently with ChatGPT-5 (12.3% vs 65%), and NCCN-traceable recommendations were more common (75.4% vs 36.7%). Responses judged as potentially harmful occurred in 18.5% of ChatGPT-5 outputs versus 70% of MedGemma outputs. Clinician trust favored ChatGPT-5 (84.6% vs 15%). Inter-rater reliability improved with rater averaging (ICC(A,k): correctness 0.72; comprehensiveness 0.64). Conclusions: In expert-reviewed GI and GU oncology cases, ChatGPT-5 demonstrated higher clinical accuracy, comprehensiveness, and guideline alignment than a medical-specific LLM; however, a substantial rate of hallucinations and potentially harmful recommendations persisted across models. These findings underscore that, despite performance differences, current LLMs require rigorous clinician oversight and should not be used as standalone decision-support tools in oncology.

PURPOSE Homologous recombination deficiency (HRD) is a key determinant of sensitivity to DNA-damaging agents; however, its genomic characterization in colorectal cancer (CRC) remains limited. This study investigated whether low RNA expression of homologous recombination (HR) genes identifies patients with metastatic CRC who derive survival benefit from oxaliplatin- or irinotecan-based therapy. METHODS A total of 22,957 metastatic CRC samples were subjected to DNA and RNA sequencing (Caris Life Sciences, Dallas, TX). Patients with microsatellite instability–high or pathogenic HR gene mutations were excluded to define a HR-proficient cohort. Overall survival (OS) was compared between patients with low (bottom 25%) versus high (top 25%) RNA expression of HR genes after oxaliplatin or irinotecan exposure. Validation was performed in the PARADIGM phase III trial cohort (n = 262) of first-line modified fluorouracil, leucovorin, and oxaliplatin-treated patients with available RNAseq data. RESULTS In the discovery cohort, low expression of core HR genes correlated with significantly longer OS after oxaliplatin or irinotecan exposure, specifically RAD51 (43.0 v 36.3 months; P < .005) and BLM (42.9 v 34.2 months; P < .005). Similar associations were observed for RAD51 (28.1 v 22.9 months; P = .02) and BLM (29.1 v 23.2 months; P < .005) in irinotecan-treated patients. In the PARADIGM validation cohort, low BLM expression was associated with improved OS (41.5 v 22.4 months; HR = 0.52; P = .002), whereas RAD51 showed a favorable but nonsignificant trend. These findings remained significant after adjustment for treatment arm, tumor sidedness, and metastatic burden. CONCLUSION Low BLM RNA expression is associated with improved survival after treatment with DNA-damaging agents, whereas low RAD51 expression shows a favorable but nonsignificant trend. These findings are exploratory and suggest that RNA-based HR gene expression may warrant further investigation as a potential prognostic biomarker in metastatic CRC.

PURPOSE For patients with advanced biliary tract cancer (BTC), cancer-related time spent in health care systems, time toxicity, represents a critical but understudied burden affecting quality of life. This study aimed to quantify time toxicity in patients receiving first-line systemic therapy and evaluate whether the addition of durvalumab to gemcitabine plus cisplatin (GC) increases health care contact time. METHODS This international, multicenter, retrospective cohort study included patients with advanced BTC seen between January 2019 and April 2024 at Mayo Clinic Enterprise (US), and between January 2021 and April 2024 at Kyorin University Hospital (Japan), and Hospital Israelita Albert Einstein (Brazil). Patients received GC plus durvalumab (GCD) or GC. Time toxicity was recorded from treatment initiation until discontinuation or last follow-up during first-line systemic therapy. Multiple regression analysis identified factors associated with high time toxicity. RESULTS Among 193 patients (102 GCD, 91 GC; median age 65 years; 50% male; 49% Eastern Cooperative Oncology Group performance status [PS] 0), median time on treatment (TOT) was 156 days (95% CI, 122 to 190). The median proportion of total time toxicity was 14.4% (IQR, 10.9-20.6). Planned visits accounted for 11.9%, while unplanned visits were infrequent (1.8%). Time toxicity strongly correlated with TOT ( r = 0.824) and progression-free survival ( r = 0.827). Despite longer treatment in the GCD group than the GC group (212 v 134 days; P = .027), total time toxicity was similar (27 v 18 days; P = .19). Younger age and poor PS were independent factors of higher time toxicity. CONCLUSION Time toxicity represents a meaningful metric that allows for more comprehensive integration of the net benefit in patients with advanced BTC with a limited lifespan.

830 Background: Immune checkpoint inhibitors (ICIs) are standard therapy for MSI-H GI cancers. Lynch syndrome, caused by germline mutations in mismatch repair (MMR) genes, leads to MSI-H tumors and robust ICI responses, but its effect on irAEs remains poorly defined. Clarifying this risk may inform treatment selection and toxicity monitoring. Methods: We retrospectively reviewed MSI-H or MMR-deficient (dMMR) GI cancer patients (pts) treated with ICIs across Mayo Clinic (AZ, MN, FL) from January 2017 to June 2025. Eligible pts were identified using Mayo Data Explorer. Demographics, treatment, and irAEs (graded per CTCAE v5.0) were collected. Lynch status was determined by germline testing when available. Logistic regression estimated odds ratios (ORs) for any grade and grade ≥3 irAEs, adjusting for age, cancer type, prior chemotherapy, and treatment regimen. Results: A total of 209 pts with dMMR/MSI-H GI cancer were included: 61 with Lynch syndrome and 148 without. Lynch pts were younger (median 58 vs 76 years, p < 0.001) and more likely to have received prior chemotherapy (62% vs 43%, p = 0.009). Colorectal cancer was the predominant cancer type (74%), but Lynch pts had proportionally more non-colorectal GI cancers (15% vs 2.7%, p = 0.007). Overall, 29% of pts experienced an irAE, with rates significantly higher in Lynch vs non-Lynch pts (43% vs 24%, p = 0.005). The most frequent irAEs were gastrointestinal, endocrine, and dermatologic, followed by hepatic and pulmonary events. Grade ≥3 irAEs occurred in 16% overall, with no significant difference between groups (p = 0.124). In adjusted models, Lynch syndrome was independently associated with a higher risk of any grade irAE (OR 2.14, 95% CI 1.09 - 4.19, p = 0.026), while risk of severe irAEs was not increased (OR 1.55, 95% CI 0.64 - 3.59, p = 0.316). Lynch syndrome pts were more likely to have combination therapy (17% vs 6.8%, p = 0.029). However, there were no differences observed in any grade irAE between monotherapy and combination immunotherapy (OR 1.36, 95% CI 0.49 - 3.54, p = 0.535). Conclusions: Lynch syndrome is associated with a higher prevalence of any-grade irAEs among dMMR/MSI-H GI cancer pts treated with ICIs, though severe events were not increased. Incorporating Lynch status into immunotherapy planning may improve risk stratification and guide regimen selection.

776 Background: Surgery is the only potentially curative option for PC. However, only a minority of patients (pts) undergo resection with current perioperative (periop)-chemotherapy (CT). In the absence of phase III trials, selection between mFOLFIRINOX and gemcitabine/nab-paclitaxel (gem-nab) is based on limited evidence. We assessed whether NGS–based tumor profiling can guide tailoring of CT. Methods: pts with resected PC (resectable, borderline resectable, and downstaged locally advanced) that underwent Tempus xT, xF (DNA), and/or xR (RNA) testing were selected (89% tissue, 11% blood). Most samples (73%) were collected post-CT. Samples were stratified by KRAS status into KRAS -mutated ( KRAS mut) and KRAS wild-type ( KRAS wt). PD-L1 IHC was reported as tumor proportion score (TPS). Primary endpoint was median overall survival (mOS) defined from CT initiation to death with censoring of pts alive at the last follow-up or at a study cutoff of 5 years. Secondary endpoint was molecular profiling by KRAS status. Pearson chi-square and Wilcoxon rank-sum tests were used for descriptive comparisons; univariate Cox regression and log-rank tests (p<0.05) for survival. Results: We included 1,325 pts (median age 66 years [IQR 59–72]) with resected PC [stage II (15%), stage III (12%) and stage I (10%), unknown (62%)]. 95% had adenocarcinoma. Pts received neoadjuvant (50%), neoadjuvant plus adjuvant (26%), neoadjuvant with indeterminate adjuvant allocation (13%) or adjuvant CT (11%). First-line periop-CT was mFOLFIRINOX in 73% and gem-nab in 27% (median duration 4.3 months (mo) [range, 2.6–6.7]). KRAS mutations were present in 75% (G12X 91%: G12D 44%, G12V 34%, G12R 21%, G12C <1%). mOS was 26.7 mo (95%CI, 22.4-35.7) in the total cohort; KRAS mut pts showed a clinically meaningful worse mOS compared to KRAS wt [24.1 vs 35.7 mo; HR 1.61 (95%CI, 0.98 - 2.63); p=0.06]. In the KRAS G12D pts, mFOLFIRINOX showed a trend towards longer mOS compared to gem-nab [17.79 vs 14.53 mo; HR 0.75, (95% CI, 0.56 - 1); p=0.050]; no significant differences were observed in other KRAS subgroups. Compared to KRAS wt, KRAS mut pts were enriched for TP53 (76% vs 22%; p<0.001), SMAD4 (28% vs 5.8%; p<0.001), CDKN2A (33% vs 8.5%; p<0.001), MTAP deletions (7.7% vs 1.2%; p<0.001), and chromatin-regulator alterations ( ARID1A 7.8% vs 1.2%; p<0.001; KMT2C 2.5% vs 0.6%; p=0.034). KRAS wt pts were enriched for BRAF V600E (1.5% vs 0%; p<0.001). PD-L1 TPS ≥1% was more frequent in KRAS mut compared to KRAS wt (11.0% vs 8.1%; p=0.033). Conclusions: KRAS status does not predict benefit from mFOLFIRINOX vs gem-nab in resected PC. Interestingly, resected PC showed a higher prevalence of KRAS wt compared to the metastatic setting. KRAS status is associated with distinct profiles of potentially targetable co-alterations. These findings may suggest the integration of genomic profiling in clinical trials to develop biomarker-driven tailored strategies in the early stage.

679 Background: DNA-damaging agents improve outcomes in metastatic pancreatic cancer (mPC) with homologous recombination repair (HRR) deficiency, albeit use is limited to 6-9% of patients (pts) with BRCA1/2 or PALB2 mutations. We hypothesized that BRCA/PALB2 wildtype mPC may exhibit platinum sensitivity driven by altered HRR gene expression. We correlated HRR gene RNA profiles with real-world overall survival (rwOS) following first-line (1L) platinum therapy (PT). Methods: Tempus Lens, a platform used to query multimodal data from millions of de-identified patient records in the Tempus Database was used to identify mPC pts with wildtype somatic BRCA1/2 and PALB2 who had Tempus xT DNA and xR RNA testing. RNA-seq data were normalized to correct for assay/batch effects, quantified as transcripts per million (TPM) and reported as log2(TPM+1) for 17 HRR genes and GATA6 . Pts were classified as high and low expressors based on the top and bottom quartile gene expression. Pts were grouped as PT-treated (received 1L PT) or PT-naïve (never received PT). Real world overall survival (rwOS) was calculated from 1L start to death or loss to follow up. Risk set adjustment was applied to mitigate immortal time bias. Median rwOS was estimated using Kaplan-Meier and univariate Cox models. A multivariate Cox Proportional (CoxPh) model included PT use, RAS status, and expression of genes (as continuous variables). Results: Among 1,068 pts, the median age was 66 years and 609 (57%) received 1L PT. In low RAD51 expressors, PT-treated pts (n=136) had significantly longer rwOS than PT-naïve (n=112): 11.4 months (95% CI, 7.8–13.8) vs 8 months (95% CI, 5.5–9.0); p=0.028. In contrast, in high RAD51 expressors, rwOS was similar between PT-treated (n=150) and PT-naïve (n=97): 7.9 vs 6.9 months (p=0.236). High GATA6 expression was also associated with improved rwOS in PT-treated pts vs PT-naïve: 13.5 vs. 9.3 months; p=0.011. In multivariate analysis, increased GATA6 expression remained a positive predictor of rwOS (HR 0.82; 95% CI, 0.76–0.88; p<0.001), and high RAD51 expression was associated with shorter rwOS with PT (HR 1.18; 95% CI, 1.01–1.39; p=0.043). Conclusions: In BRCA/PALB2 wt mPC, transcriptomic profiling identified low RAD51 and high GATA6 expression as predictors for improved rwOS when treated with PT. Integrating these biomarkers may improve development of DNA-damaging therapies beyond canonically defined HRD. Hazard ratios of mPC mortality by selected HRR genes estimated by multivariate CoxPh models. HR 95% CI p value 1L PT (vs PT-naïve) 0.87 0.75, 1.00 0.054 BRCA1 1.15 0.98, 1.35 0.079 BRCA2 0.89 0.77, 1.04 0.14 GATA6 0.82 0.76, 0.88 <0.001 NBN 0.97 0.81, 1.15 0.7 RAD51 1.18 1.01, 1.39 0.043 RECQL4 0.94 0.84, 1.04 0.2 Any RAS mutation 1.43 1.14, 1.81 0.002

Abstract Background This phase 1 study aimed to determine the maximum tolerated dose (MTD) and evaluate the safety and preliminary efficacy of rucaparib (RUB), a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor, combined with liposomal irinotecan (nal‐IRI) and 5‐fluorouracil (5‐FU) in metastatic gastrointestinal (GI) cancers. RUB targets DNA repair pathways, showing efficacy in tumors with homologous recombination deficiency, such as BRCA mutations. Preclinical data suggest synergy with irinotecan, but overlapping toxicities pose challenges. Methods Eighteen patients with metastatic GI cancers, who previously progressed on at least one systemic therapy, were enrolled. A novel sequential dosing regimen, informed by nal‐IRI pharmacokinetic analysis, was used. Twelve patients were evaluable for dose‐limiting toxicity (DLT) and 12 for response per Response Evaluation Criteria in Solid Tumors v1.1 criteria. Results The MTD was established as RUB 600 mg twice daily, nal‐IRI 50 mg/m 2 , and 5‐FU 2400 mg/m 2 over 46 hours. The objective response rate (ORR) was 33% (4 of 12), and the disease control rate (DCR) was 75% (9 of 12). Common grade 3 adverse events included diarrhea (33%) and neutropenia (25%), with no grade 4/5 events. Responses were notable in patients with somatic ATM and BRCA mutations, especially those with prior platinum exposure. No DLTs occurred at the recommended phase 2 dose. Conclusions This optimized dosing schedule successfully established the MTD for RUB with nal‐IRI and 5‐FU, overcoming prior challenges with PARP inhibitor and irinotecan combinations. The promising ORR and DCR support further evaluation of this regimen in advanced GI malignancies.

PURPOSE Neoadjuvant immune checkpoint inhibitors (nICIs) have demonstrated high response rates in deficient mismatch repair/microsatellite instability–high (dMMR/MSI-H) gastroesophageal adenocarcinoma (GEA). The NEONIPIGA and INFINITY trials demonstrated high rates of pathologic complete response (pCR) in this patient population. Furthermore, the INFINITY trial explored the feasibility of managing these patients nonoperatively, demonstrating promising results. This study aimed to evaluate clinical outcomes of nICIs in resectable dMMR/MSI-H GEA, with a focus on the feasibility of nonoperative management (NOM). MATERIALS AND METHODS This retrospective cohort study included patients with resectable dMMR/MSI-H GEA and treated with nICIs ± surgery at the Mayo Clinic. Patients were identified from institutional records, and clinical data were retrospectively reviewed. Primary outcomes were clinical complete response (cCR) and pCR. Secondary outcomes included event-free survival (EFS), radiologic complete response (rCR), and immune-related adverse events (irAEs). RESULTS A total of 26 patients treated between April 1, 2017, and July 30, 2025, were identified. Nine patients (34.6%) underwent surgery, of whom six (66.7%) achieved pCR. Seventeen patients (65.4%) pursued NOM, with 10 (71.4%) of 14 evaluable patients achieving cCR and 14 (82.4%) of 17 evaluable achieving rCR. One patient who initially achieved cCR had a local recurrence on surveillance endoscopy and underwent salvage endoscopic resection. At a median follow-up of 19.3 months, 15 (88.2%) of 17 patients in the NOM cohort were alive and metastasis-free, with EFS rates of 87.3% at 12 and 24 months for all patients. irAEs occurred in nine patients (34.6%), with no grade ≥3 toxicities. CONCLUSION In this retrospective cohort study, nICIs led to high cCR and pCR rates in resectable dMMR/MSI-H GEA, supporting the use of immune checkpoint inhibitors in this setting and the feasibility of NOM in select patients.