Storandt, Michael H.

605 Background: Multiple treatment modalities are available for localized hepatocellular carcinoma (HCC), and current Barcelona Clinic Liver Cancer (BCLC) guidelines recommend ablation for patients with a limited number of small tumors, not amenable to resection or transplantation. However, in recent years, stereotactic body radiation therapy (SBRT) has been increasingly used for localized disease. Patient outcomes based on treatment modality are not well understood. Methods: We conducted a retrospective analysis using the National Cancer Database (NCDB) to identify patients with a history of stage I/II HCC with tumors ≤ 5 cm who had received local therapy with either radiofrequency ablation (RFA) or SBRT between 2006 and 2021. A propensity score matched analysis was conducted accounting for patient demographics, facility region and tumor level characteristics, as well as an inverse probability of treatment weight-adjusted (IPTW) analysis. Overall survival was estimated using the Kaplan-Meier method. Results: We identified 14,516 patients meeting inclusion criteria, including 13,036 who received RFA and 1,480 who received SBRT. Demographic factors associated with receipt of SBRT included age >50 years, female sex, and treatment in the Middle Atlantic and East North Central regions, as well as clinical factors including larger tumor size (>3 to 5 cm), severe fibrosis/cirrhosis, and stage II disease ( p <0.05 for all). Factors associated with receipt of RFA include black race, higher Charlson-Deyo Comorbidity Scores, treatment at a comprehensive cancer program or integrated network cancer program, and treatment in the East South Central, West North Central, West South Central, Mountain, and Pacific Regions ( p <0.05 for all). Median time from diagnosis to treatment initiation was longer for those who received SBRT (66.3 vs 84.6 days, p <0.001). In a propensity matched analysis, mOS was 45.1 months for those receiving RFA vs 30.8 months for those receiving SBRT ( p <0.001). An IPTW analysis showed similar survival benefit with RFA over SBRT (mOS 51.0 vs 30.5 months, p <0.001). This OS benefit was observed in subset of patients with tumors <3cm in size. Conclusions: In this propensity matched analysis controlling for relevant patient and tumor factors, RFA was associated with improved survival. Prospective studies will be important to further analyze differences in patient outcomes.

451 Background: In first-line E/GEJ/G adenocarcinoma, anti-PD-1 + chemotherapy improves outcomes, yet many patients do not respond. Beyond PD-L1 CPS, tumor-intrinsic biomarkers of primary resistance remain limited. We applied a validated IFN-γ–linked T cell-inflamed (Tinfl) framework to define exclusionary programs and nominate targets. Methods: Bulk RNAseq was analyzed from TCGA ESCA/STAD adenocarcinoma (n=79, discovery) and a de novo Mayo cohort of pretreatment samples (n=74, validation) with harmonized survival and response data. Tinfl scores (160-gene signature) defined quartiles (Q1 cold, Q4 hot). Cold versus hot tumors were compared by edgeR + limma-voom to identify differentially expressed genes (DEGs) (Bioconductor v3.20). Pathway and upstream-regulator/causal-network analyses used Ingenuity Pathway Analysis seeded by top DEGs (|log2FC|>1.5, p<0.05). Survival was assessed by Cox proportional hazards models (two-sided α=0.05) and KM log-rank testing (α=0.05). A 14-gene Tinfl-weighted cold signature produced a per-sample composite score. Results: In the Mayo cohort, median age was 62 years; 72% were stage IV at diagnosis; 24% were HER2-positive and 3% MSI-H; primary sites were GEJ/esophagus/gastric 50%/34%/16%; PD-L1 CPS <1/1–5/6–49/≥50 occurred in 18%/46%/27%/4%; patients received a mean of 2.4 lines of therapy. Across discovery and validation cohorts, Tinfl-cold tumors showed significantly higher expression of developmental and lineage transcription factors (HOXC12, HOXC13, ZIC1, DLX3, EVX1), an oncofetal post-transcriptional hub (IGF2BP1), cancer-testis and piRNA components (MAGEA4, TDRD12, THEG), and neuronal or transport genes (GABRQ, KCNF1, LDLRAD1, SLC6A10P) (logFC >2, p<0.05). Pathway analysis highlighted chromatin and lineage regulators (KAT6A, SIRT1, LEF1), TGF-β signaling (TGFBR2), and repressors of innate DNA/IFN sensing (TREX1, IRF2BP2) (Z-score >2, p<0.05). The 14-gene Tinfl-weighted cold signature was higher in cold versus hot tumors (p<0.05) and showed a directional association with inferior overall survival in the Mayo validation cohort. Among patients who received first-line anti-PD-1–containing regimens, several signature members and the composite score were higher in non-responders (p<0.05). Conclusions: Using a discovery–validation design, we define tumor-intrinsic expression pathways that characterize Tinfl-cold E/GEJ/G adenocarcinoma. We also derive a concise 14-gene Tinfl-weighted cold signature that is enriched in non-responders and associated with inferior overall survival. Targetable nodes such as IGF2BP1 and MAGEA4, together with chromatin and Wnt/TGF-β regulators, support rational combinations with PD-1 blockade. Planned validation in a third cohort, single-cell confirmation of tumor-cell expression, and in vivo cytokine profiling in knockdown models will refine mechanisms and nominate clinical candidates.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have advanced the treatment of type 2 diabetes mellitus (T2DM), yet their association with cancer risk remains subject of ongoing research. Chronic pancreatitis (CP) is a well-established risk factor for pancreatic cancer, yet the impact of GLP-1 RA therapy in this high-risk population is unknown. In this study, we aimed to evaluate the association between GLP-1 RA use and pancreatic cancer incidence among patients with CP, and among those with CP and T2DM. Methods: We performed a retrospective cohort study using data from TriNetX, a healthcare database of over 150 million patients in the United States. In the first analysis, adult patients with pre-existing CP were identified and stratified by use of a GLP-1 RA (semaglutide, dulaglutide, tirzepatide, exenatide, liraglutide, lixisenatide, and albiglutide). Propensity score matching (PSM) was conducted between GLP1-RA users and non-users, matching for age, sex, race, tobacco use, alcohol use, hypertension, hyperlipidemia, obesity, and pancreatic cysts. Five-year incidence of pancreatic cancer was compared between GLP-1 RA users and non-users in the matched cohort between 2015 and 2025. We then restricted the cohort to patients with CP and T2DM and repeated this analysis. Results: We identified 89,596 patients with CP, including 3183 GLP-1 RA users and 86,413 non-users. After PSM, GLP-1 RA use was associated with a lower 5-year incidence of pancreatic cancer (hazard ratio (HR) 0.49, 95% confidence interval (CI) 0.30–0.80, p < 0.005). Similarly, amongst patients with CP and T2DM, GLP-1 RA use was associated with a lower 5-year incidence of pancreatic cancer (HR 0.53, 95% CI 0.31–0.91, p < 0.05). Conclusions: GLP-1 RA use was associated with a significantly reduced incidence of pancreatic cancer in all patients with CP, as well as the subpopulation with both CP and T2DM. Given the elevated cancer risk in CP, these findings suggest a potential beneficial effect of GLP-1RA use in this high-risk population. Prospective studies will be important to further analyze and confirm this potential benefit.

This cross-sectional study analyzes patient-reported outcome findings from the Enhanced, Electronic Health Record–Facilitated Cancer Symptom Control (E2C2) trial to investigate level of symptom burden in adolescents and young adults with cancer.

1543 Background: Treatment toxicity may limit the ability of cancer patients to receive all recommended cycles of therapy. Four to six cycles of docetaxel plus cyclophosphamide (TC) is a common adjuvant chemotherapy regimen for early-stage breast cancer. We assessed the impact of routine collection of patient-reported outcomes (PROs), coupled with a collaborative care model-based symptom management intervention, on the number of cycles of TC received by patients with breast cancer. Methods: The Enhanced, EHR-facilitated Cancer Symptom Control (E2C2) trial was a cluster-randomized, pragmatic clinical trial, conducted between March 2019 and January 2023 at Mayo Clinic Rochester and within the Mayo Clinic Health System in Minnesota and Wisconsin. Patients regularly reported the severity of 6 SPPADE symptoms (Sleep deficit, Pain, Physical function impairment, Anxiety, Depression, and Energy deficit/fatigue) on 11-point numerical rating scales. Each symptom score was interpreted as none to mild (0-3), moderate (4-6), or severe (7-10). The E2C2 intervention included symptom management education modules, clinician decision support aids, and the option to discuss severe symptoms with a nurse, physical therapist, or social worker. Patients with breast cancer who received at least one cycle of TC were included in this analysis. We compared the number of cycles of docetaxel and cyclophosphamide completed by patients in the control condition versus those in the intervention condition. Results: We identified 198 patients with breast cancer who received TC during the control condition and 128 who received TC during the intervention condition. Median age was 61.3 years in the control group and 60.3 years in the intervention group, and 94% and 95% were white, respectively. Those receiving treatment during the control condition, on average, completed 3.53 cycles of docetaxel, while those receiving TC during the intervention condition completed 3.77 cycles ( p = 0.014). Seventy-eight percent in the control group completed at least 4 cycles of docetaxel, compared to 84% in the intervention group. Those receiving TC during the control condition completed an average of 3.71 cycles of cyclophosphamide, compared to 3.78 cycles in the intervention condition (p = 0.231). Eighty-four percent of patients in the control group and 86% in the intervention group completed at least 4 cycles of cyclophosphamide. Conclusions: Routine PRO surveillance, coupled with guideline-based collaborative care interventions, was associated with completion of a greater number of cycles of docetaxel. These findings suggest that routine symptom surveillance and management may enhance the docetaxel tolerance profile and improve treatment adherence in patients with early-stage breast cancer, allowing for delivery of an optimized treatment course.

4123 Background: Atezolizumab plus bevacizumab is the most commonly utilized first-line therapy for advanced HCC. However, the optimal choice for second-line treatment remains uncertain, particularly between different tyrosine kinase inhibitors including lenvatinib and cabozantinib. This study aims to compare survival outcomes of patients with metastatic HCC who received either lenvatinib or cabozantinib as second-line therapy following frontline treatment with atezolizumab plus bevacizumab. Methods: This retrospective cohort study utilized the TriNetX database, a large-scale platform providing access to deidentified electronic medical records from over 130 million patients across 94 healthcare organizations in the United States. The study included patients diagnosed with metastatic HCC (ICD-10 codes: C22, C22.8) who were aged 18 years or older, diagnosed between January 2019 and October 2024, and had received first-line chemotherapy with atezolizumab and bevacizumab. The cohort was divided into two groups: one receiving lenvatinib and the other cabozantinib as second-line therapy. The primary outcome was overall survival (OS), compared between the two treatment groups using 1:1 propensity score matching (PSM) to balance baseline demographics and comorbidities. Kaplan-Meier survival analysis, log-rank tests, and hazard ratios (HR) were employed to assess differences in OS. Results: Between January 2019 and October 2024, a total of 552 patients met the study criteria, including 397 patients who received Lenvatinib and 155 patients who received cabozantinib as second-line therapy. Median age was similar in two groups (65.2 vs 65.9 yrs). There were no differences between the two groups with respect to gender, albumin or bilirubin levels. Lenvatinib group had lower proportions of white patients (44.1% vs 55.3%). After PSM (matched on age, race, gender, albumin and bilirubin), the final analysis included 151 patients in each treatment group. Kaplan-Meier survival curves demonstrated no statistically significant difference in OS between the two groups (median OS: 16.6 vs 10.9 months; HR: 0.809; 95%CI: 0.576-1.136; p=0.597). Conclusions: This retrospective cohort study found no significant difference in OS in pts with metastatic HCC treated with lenvatinib or cabozantinib as second-line therapy following atezolizumab plus bevacizumab. These findings suggest that both agents may offer comparable survival benefits, highlighting the need for further prospective studies to refine second-line treatment strategies for advanced HCC.

Abstract Background Impact of BRAF V600E mutations (BRAFV600E), a poor prognostic factor in metastatic colorectal cancer, is lacking in non-CRC gastrointestinal (GI) cancers including pancreatic (PDAC), gastric/gastroesophageal (GEA), hepatocellular carcinoma (HCC), and cholangiocarcinoma (CCA). Due to tumor-agnostic approvals for patients with BRAFV600E, understanding the frequency and impact of BRAF alterations across non-CRC GI cancers is essential for clinical decision-making. Methods Patients with PDAC, GEA, HCC, or CCA who had cell-free DNA detected on Guardant360 (Guardant Health) from 2020 to 2023 were queried. Prevalence of characterized BRAF genomic alterations (GA) was calculated; GAs were grouped by class (Class I/II/III). The Chi-squared test assessed differences between cancer types. A subset of patients had outcomes analysis using GuardantINFORM, a real-world clinicogenomic database, to derive real-world overall survival (rwOS). Results Of 32 480 included patients, BRAF GAs were identified in 4.4%; 19% were BRAFV600E (0.81% prevalence overall). CCA had the highest rate of BRAF GAs and BRAFV600E (P &lt; .01); HCC and GEA had the highest rates of BRAF class II/III alterations. There were no significant differences in rwOS by alteration class or cancer type; numeric differences were observed by alteration class. Few patients were treated with BRAF inhibitors (2.2%). Prevalence of co-occurring alterations was unique by cancer type. Conclusions Frequency of BRAF GAs, including BRAFV600E, in non-CRC GI cancers detected by liquid biopsy is similar to tissue-based rates and can be reliably used to assess BRAF status. BRAF GAs have mixed prognostic implications on survival for patients with non-CRC GI malignancies that warrant further exploration.

Background: Rates of early-onset colorectal cancer (eoCRC), defined as disease diagnosed at <50 years of age, are increasing. The incidence and spectrum of somatic and pathogenic germline variants (PGV) in this population are not well understood. Methods: This cross-sectional study leveraged Tempus’ clinicogenomic database, including de-identified records of patients diagnosed with CRC between 2000–2022, to analyze and compare eoCRC and average-onset colorectal cancer (aoCRC, disease diagnosed ≥50 years of age) patients. The frequency and spectrum of somatic mutations and PGVs in patients with eoCRC and aoCRC were evaluated and compared. Results: Among 11,006 participants in this study, 57% were male, 76% were white, and 80% had stage 4 disease. Within the total cohort, 2379 had eoCRC and 8627 had aoCRC. Among patients with eoCRC, 4.2% had a tumor with high microsatellite instability and/or deficient mismatch repair (MSI-H/dMMR) and 6.8% with aoCRC had an MSI-H/dMMR tumor (p < 0.001). The most frequent somatic mutations involved TP53, APC, and KRAS, with the most significant difference in BRAF, which was more frequently mutated in aoCRC (9.8% vs. 4.7%, p < 0.0001). In total, 1413 (59.4%) eoCRC and 4898 (56.8%) aoCRC patients had matched normal specimen (blood or saliva) sequencing and a PGV was identified in 6.9% of eoCRC and 5.0% of aoCRC patients. Conclusions: Somatic and germline mutation profiles were similar for eoCRC and aoCRC patients and may not adequately explain differences in tumor behavior and age of disease onset.

5 Background: Metastatic anal squamous cell carcinoma is rare and associated with a poor prognosis. There is limited evidence on the impact of local interventions on survival outcomes in patients with metastatic disease. We aimed to evaluate the survival of patients with liver-only metastatic anal cancer following definitive local management of liver lesions. Methods: This is a single-institution retrospective cohort study of patients with liver-limited metastatic anal cancer who underwent curative-intent local therapy. Clinical characteristics were collected and analyzed. The Kaplan-Meier method was used to calculate disease-free survival (DFS) and overall survival (OS). Prognostic factors associated with DFS and OS were assessed using Cox-proportional hazards models. Results: Twenty-five patients were included, median age was 59 years, and 92% were female. None of the patients had known HIV infection, 92% had HPV-positive disease and 76% had metachronous liver metastases following locoregional disease. All patients received chemoradiation for the primary lesion Unilobar hepatic involvement was present in 76% of the patients, with 56% having a single metastatic lesion. Pre-intervention systemic therapy was provided to 52% of the patients, including 8 who received carboplatin and paclitaxel, with a median duration of 3 months and ORR of 69%. Definitive treatment of metastatic disease included surgical resection (60%), non-surgical interventions (20%), and multimodal therapy (20%). All patients had viable tumor in the pathological specimen. With a median follow-up of 22 months, median DFS was 7.3 months, and median OS was 51.3 months. An ECOG performance status of 2, poorly differentiated histology, and extrahepatic recurrence were identified as significant prognostic factors in the univariate analysis, but not in the multivariate analysis. Conclusions: Our results demonstrate potential for long-term survival in liver-limited metastatic anal squamous cell carcinoma amenable to local therapeutic intervention combined with systemic therapy. These findings warrant further prospective study of local therapy in oligometastatic anal cancer. Characteristics N=25 (%) Median number of liver metastases (range), lesions- 1- 2-3- >3 1 (1-20)14 (56)8 (32)3 (12) Median maximal diameter of liver metastases (range), cm 3 (0.9-11.9) Best response of liver metastases to chemotherapy (N=13)- Complete response- Partial response- Stable disease- Progressive disease 2 (15)7 (54)3 (23)1 (8) Surgical procedure (N=20)- Right/left hemi-hepatectomy- Segmentectomy- Wedge resection 4 (20)14 (70)2 (10) Non-surgical procedure (N=10)- Local ablation- Radiotherapy- Other 5 (50)3 (30)2 (20) Hepatic surgical margins (N=20)- Positive margins- Close margins (<1mm)- Negative margins 02 (10)18 (90) Recurrent disease- Yeso Intrahepatico Extrahepatic- No 20 (80)14 (70)6 (30)5 (20)