Citations

Abstract Background Optimal treatment following first-line immunotherapy for advanced hepatocellular carcinoma (HCC) remains uncertain. This study evaluated futibatinib, a pan-FGFR inhibitor, combined with pembrolizumab in previously treated patients with FGF19-expressing HCC. Methods Eligible patients were ≥18 years old with advanced HCC, prior systemic therapy, Child-Pugh A-B7 liver function, ECOG 0–2, and FGF19 overexpression. Patients received futibatinib 20 mg orally daily plus pembrolizumab 200 mg intravenously every 3 weeks. The primary endpoint was progression-free survival at 6 months (PFS6). Secondary endpoints included overall survival (OS), objective response rate (ORR), quality of life, and safety. Results Between August 2021 and March 2024, 14 patients enrolled and 13 were evaluable. Median age was 72 years (range, 60–87), 53.8% were male, 92.3% had Child-Pugh A liver function, and all had received prior immunotherapy. Median progression-free survival was 15 weeks (95% CI, 9.0–NE), with a PFS6 rate of 23.1% (95% CI, 8.6–62.3%). ORR was 0% (95% CI, 0–24.7%), while stable disease was observed in 53.9% of patients. Median OS was 55.7 weeks (95% CI, 47.3–NE). Grade ≥3 adverse events occurred in 69.2% of patients, and grade ≥4 adverse events in 15.4%. One grade 5 event (acute-on-chronic kidney injury) was deemed unrelated to treatment. Common adverse events included hyperphosphatemia, fatigue, diarrhea, elevated transaminases, dry eye, nail changes, rash, and oral mucositis. Conclusions Futibatinib plus pembrolizumab demonstrated an acceptable safety profile but did not meet efficacy thresholds supporting further study in FGF19-expressing HCC. Effective post-immunotherapy treatment strategies remain an unmet need.

PURPOSE Deficient mismatch repair/microsatellite instability (dMMR, MSI-H) in biliary tract cancers (BTCs) is observed in 1%-5% of tumors. MSI-H across solid tumors has demonstrated durable response to immune checkpoint inhibitors (ICIs) regardless of the anatomic location. Here, we describe clinical outcomes and surgical conversion of MSI-H BTC treated with ICIs. Patients and Methods We conducted a multicenter, retrospective analysis of BTC patients with dMMR/MSI-H between 2017 and 2024 at Mayo Clinic, University of Michigan, and University Hospitals Seidman Cancer Center. Outcomes of interest were surgical resection rate, rate of pathologic response, 2-year overall survival (OS; time from initiation of treatment to death/last follow-up), and time to treatment discontinuation (TTD; time from initiation of treatment to cessation because of any cause). Analyses were descriptive. RESULTS Thirty patients with MSI-H BTC were identified: 19 with cholangiocarcinoma, three with gallbladder cancer, and 8 with BTC undefined. The median age at diagnosis was 61.5 years (range, 26-86). Twenty-six (86.7%) patients had advanced stage at diagnosis. Twenty-seven patients (90%) received first-line systemic therapy, and 13 (48.1%) continued onto second line. Six patients (23.1%) were restaged to resectable from advanced disease after ICI therapy and underwent resection; all remained recurrence-free at last follow-up. Of these six patients, 3 (50%) achieved a pathologic complete response. Among those receiving first-line therapy, the median TTD was 9.9 months (95% CI, 5.7 to 14.5 months) and the 2-year OS was 73% (95% CI, 56% to 94%). CONCLUSION ICI therapy in patients with MSI-H BTC demonstrated durable response and downstaged some BTC to a resectable stage. dMMR/MSI-H should be performed up-front to guide treatment decisions.

Abstract Background and Aims Primary sclerosing cholangitis (PSC) increases the risk of developing cholangiocarcinoma (CCA), which is the leading cause of premature death in these patients. Current diagnostic methods for early detection of either condition remain largely suboptimal. This study investigates serum metabolites as potential non-invasive diagnostic biomarkers. Methods This multicenter international study analyzed 459 serum samples from 13 international centers, including patients with PSC (n = 216), PSC who developed CCA during follow-up (PSC to CCA; n = 24), PSC with concomitant CCA (PSC-CCA; n = 88), ulcerative colitis (UC; n = 14), and healthy individuals (n = 79). Serum metabolomics was evaluated by ultra-high-performance liquid chromatography-mass spectrometry (UHPLC-MS) and the accuracy of the single candidate metabolite biomarkers was further assessed. Machine learning was used to generate the best diagnostic and predictive algorithms. Results Fifty-two serum metabolites were identified as markers of PSC, independent of age, biological sex, cirrhosis, UC, or ursodeoxycholic acid (UDCA) treatment. A diagnostic model based on only six lipids distinguished PSC patients from healthy controls with high accuracy (AUC 0.952 discovery, 0.918 validation), independently of the levels of transaminases or cholestasis markers (i.e., GGT, AP, bilirubin) in blood. Subgroup analyses were performed in PSC patients with and without inflammatory bowel disease (IBD), confirming the model’s consistent performance across both subgroups when compared with their respective control groups – UC and healthy controls (AUC 0.959 and 0.939, respectively). The PSC model also confirmed its diagnostic performance in patients with established PSC-CCA or progression to CCA within 2 years, when compared to UC and healthy controls, showing AUC values ranging from 0.911 to 0.976. Additionally, 20 metabolites were significantly altered in PSC patients with CCA (PSC-CCA), regardless of demographics, cirrhosis, UDCA treatment, IBD status, or CCA subtype, and independently of serum transaminases and cholestatic markers levels. A model incorporating six lipids accurately identified PSC-CCA cases compared to PSC patients (AUC = 0.912 discovery; 0.896 validation), showing excellent performance in early-stage tumor detection (AUC 0.921) and outperforming CA19-9 (AUC 0.708). Importantly, the model retained high accuracy even in CCA patients with low CA19-9 levels (AUC 0.905) and in PSC patients who developed CCA within a year of clinical diagnosis (AUC 0.792). Conclusion The PSC and PSC-CCA blood tests provide a non-invasive approach for diagnosing PSC and PSC-CCA, addressing an important need in this population. Their integration into clinical practice could enhance risk stratification, early detection, personalized surveillance, and treatment decision-making in PSC patients.

Abstract Background and Aims Cholangiocarcinoma (CCA) is a rare and aggressive malignancy originating from the bile ducts, characterized by a poor prognosis and limited treatment options. Potentially curative interventions include surgical resection with negative margins (R0) and liver transplantation. However, despite these treatments, the likelihood of post-surgical recurrence remains high, with 50–70% of patients experiencing disease recurrence within five years. This highlights the urgent need for reliable prognostic biomarkers to guide clinical decision-making and personalize postoperative care. Numerous prognostic biomarkers identified in tumor tissue for CCA have been proposed, but many studies suffer from limitations such as single-center designs, small patient cohorts, and semi-quantitative techniques such as immunohistochemistry. These methods often rely on observer interpretation and antibody specificity, which can compromise objectivity and reproducibility. To overcome these limitations, we aimed to identify and validate robust quantitative prognostic biomarkers for CCA by analyzing tumor mRNA expression, integrating them using machine learning (ML), and developing a web-based tool to predict tumor recurrence and overall survival (OS). Method A systematic literature review was conducted to identify candidate prognostic tissue biomarkers for CCA, which were further validated using Cox proportional hazards (PH) OS analyses in five independent transcriptomic cohorts. An international multicenter cohort of 221 patients undergoing tumor resection was assembled, and tumor mRNA expression was analyzed using high-throughput TaqMan OpenArray RT-qPCR. Associations between clinical and molecular features and recurrence-free survival (RFS) and OS were assessed using Cox PH analyses. Six ML survival models were trained and evaluated using nested cross-validation, followed by feature reduction. Shapley Additive exPlanations (SHAP) values were applied to assess feature importance and enhance model interpretability. Results Among 496 candidate CCA prognostic biomarkers identified from the literature, 52 showed prognostic value in Cox PH analyses across transcriptomic cohorts. In the multicenter validation cohort, integrative Cox PH analyses incorporating clinical variables and gene expression identified 11 genes significantly associated with RFS and 25 with OS. The 11 RFS-associated genes, combined with five clinical variables, were used to train six ML survival models, among which the random survival forest (RSF) model demonstrated the highest predictive accuracy. Following training of RSF models across all combinations of four genes and five clinical variables, and subsequent feature importance–based selection, a final model incorporating three genes (FSCN1, LDHA, and SLC2A1) and four clinical variables (CCA subtype, resection margin status, biological sex, and age at surgery) achieved a testing time-dependent AUC of 0.82. This model significantly stratified patients into high- and low recurrence-risk groups, with a median RFS (mRFS) of 8 months and 70 months, respectively. In addition, an OS prediction model using the same feature set achieved a testing AUC of 0.775 and significantly stratified patients according to 5-year OS risk, with a median OS (mOS) of 23 months in the high-risk group and 77 months in the low-risk group. Conclusion We identified and validated a robust panel of prognostic tissue biomarkers in patients with resected CCA. Integration of these biomarkers with clinical variables into ML-based prognostic models enabled accurate prediction of RFS and OS. The resulting web-based tool allows clinicians to input RT-qPCR results for the validated biomarkers and obtain precise, individualized prognostic predictions for postoperative recurrence and survival.

Abstract Background: Hepatocellular carcinoma (HCC) is largely refractory to immune checkpoint blockade due to immune exclusion, stromal barriers, and aberrant vasculature. We evaluated whether multimodal therapy - external beam radiotherapy (EBRT) for antigen release, intratumoral dendritic cell (DC) vaccination for antigen presentation, PD-L1 blockade for immune activation, and VEGF inhibition for vascular normalization - could convert “cold” HCC tumors into sustained immune-inflamed states. Methods: Serial biopsies (baseline, post-EBRT, end-of-treatment [EOT], and progression [PD] when available) from three patients enrolled in an ongoing phase II trial (NCT03942328) underwent multiplex immunofluorescence, spatial neighborhood analysis, and transcriptomic profiling. Longitudinal changes in cellular composition, immune-stromal architecture, spatial contact networks, and pathway activity were compared. Results: Baseline tumor microenvironments (TMEs) were strongly immune-excluded, dominated by tumor (PanCK+60-70%) and stroma (SMA+/Vimentin+25-30%) with sparse immune infiltration (<10-15%). Post-therapy, immune complexity and spatial connectivity increased 2-3-fold in all patients. Patient 1 showed robust cold-to-hot conversion with CD8+(3x), CD4+(2.2x), and DC (2.3x) expansion, increased CD8-DC interactions (2.5x), and reduced tumor fraction (-40%). Transcriptomics showed marked upregulation of IFN-γ (↑3.4x), HLA-DRA (↑2.7x), and reductions in VEGFR2 (↓50%) and HIF1A (↓40%), consistent with vascular normalization. Patient 2 exhibited stromal/vascular remodeling and improved T-cell infiltration but restricted immune diversity, with CD4+/CD8+ dyads (↑2.2x) and B/NK cells(↓ 60%). Neighborhood diversity rose (3→7 communities) and immune-tumor proximity improved (distance ↓ 35%). Patient 3 showed transient inflaming with CD8+(↑3x), DC(↑2x), and new CD4-CD20/CD4-CD56 interactions, followed by relapse marked by stromal/myeloid re-expansion (SMA+↑1.8x, CD14+↑2.5x), angiogenic resurgence (VEGFR2/CD34+↑2.2x), contraction of immune networks, and genomic shift from activating CTNNB1 mutation loss to ATM gain. DCs accumulated but localized mainly to DC-DC or DC-myeloid niches, indicating non-productive antigen presentation. Conclusions: Multimodal EBRT+DC+PD-L1/VEGF blockade induces four-sided synergistic TME reprogramming - antigen release, immune priming, checkpoint release, and vascular normalization - promoting cold-to-hot conversion in HCC. Durable inflaming correlates with sustained T-cell/DC expansion and vascular remodeling, whereas relapse reflects stromal/myeloid reinforcement and genomic adaptation. These findings define mechanistic trajectories of TME remodeling and highlight actionable barriers to sustained immunotherapy response in HCC. Citation Format: Lionel Aurelien Kankeu Fonkoua, Christopher L. Hallemeier, Basim Salem, Arina Tkachuk, Kaitlynn McCay, Panwen Wang, Ying Li, Thomas D. Atwell, Krishan R. Jethwa, Caitlin Conboy, Nguyen H. Tran, Leslie A. Washburn, Melody Wu, Chen Wu, Andre De Menezes Silva Corraes, Rondell P. Graham, Jose Caetano Villasboas, Kevin Regan, Zuoyi Shao, Rayaan Kamal, Nathan R. Foster, Haidong Dong, Sean Park, Yi Lin, Lewis R. Roberts. Multimodal immunotherapy remodels the tumor microenvironment in hepatocellular carcinoma: Integrative spatial and transcriptomic profiling from a Phase II trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7935.

Abstract Introduction: Liver cancer remains a leading cause of cancer mortality globally with limited treatment options for patients (pts) with unresectable hepatocellular carcinoma [HCC] and intrahepatic cholangiocarcinoma [iCCA][1,2,3,4]. We hypothesize that combining the intratumoral dendritic cell (DC) vaccination after external beam radiotherapy (EBRT) without (phase I) and with (phase II) systemic atezolizumab and bevacizumab (atezo/bev for HCC) would enhance tumor-specific immunity and improve clinical outcomes, and present preliminary results from our phase I/II trial (NCT03942328). Methods: Peripheral blood mononuclear cells (PBMCs) were collected at baseline (PRE), after radiation (EBRT), and after completion of DC without or with atezo/bev (POST). Single-cell RNA sequencing with TCR sequencing were analyzed using CellRanger v7.0.1, Immunopipe, Seurat v5.3.0, & Gene-set enrichment analysis (GSEA). Long EFS (EFS-L) is defined as >=12 months (mo) for phase I and >=18mo for phase II, and short EFS (EFS-S) below that. Results: Seventeen patients have been analyzed to date (Phase I: n=8 [4 HCC, 4 iCCA]; Phase II: n=9 HCC). 674,106 cells were sequenced (146,843 PRE; 168,838 EBRT; 114,437 POST). GSEA for EFS-L vs EFS-S were comparable at PRE, EBRT and POST between phase I and phase II. EFS-S was associated with enrichment of interferon alpha (IFNα; B naïve, monocytes, pDC, cDC2, NK, Treg, CD8 Tcm and Tem at PRE and POST; B intermediate, CD4 Tem and NK at EBRT) and reactive oxygen species (ROS; PRE: pDC, CD8 Tcm, Tem. EBRT: CD4 Tem. POST: CD8 T naïve Tem, CD4 Tcm & Tem, cDC2) pathways. In contrast, EFS-L was associated with enrichment of WNT-β-catenin (WNT; CD14 mono at EBRT & POST, B intermediate at EBRT), TGFb (PRE: NK; EBRT: B intermed, CD4 Tem; POST: monocytes, CD4 naïve & Tem, pDC, cDC2), and angiogenesis (EBRT: NK; POST: monocytes, cDC2) pathways. Interestingly, enrichment of protein secretion pathway in NK cells was associated with EFS-L, but among other cells were associated with EFS-S (PRE: CD16 mono, Treg; POST: CD16 mono, CD4 & D8 Tem). Compared to phase I, addition of atezo/bev in phase II pts was associated with a significant increase in Gini coefficient (p<0.0001), suggesting expansion of certain TCR clones, along with a trend for increased Gini coefficient from Pre to Post in both phase I and II. Conclusions: Preliminary analysis of this study combining EBRT with intratumoral DC vaccination +/- PD-L1/VEGF blockade identified distinct treatment-related changes in systemic cellular immune profiles. Enhanced TCR clonal diversity in phase II suggests added immunologic benefit from PD-L1/VEGF blockade. As accrual continues, integrated analyses will identify systemic immune correlates of clinical benefit and resistance to this multimodal immunotherapy approach. Citation Format: Melody Wu, Panwen Wang, Chen Wu, Ying Li, Christopher L. Hallemeier, Thomas D. Atwell, Nguyen H. Tran, Andre de Menezes Silva Corraes, Kevin Regan, Zuoyi Shao, Rayaan Kamal, Haidong Dong, Lewis R. Roberts, Sean Park, Yi Lin, Lionel Aurelien Kankeu Fonkoua. Radiation-dendritic cell combination therapy drives systemic cellular immune shifts in liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3741.

Abstract Background: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide. Prognostic models for HCC primarily rely on tumor burden and liver function, with limited consideration of inherited genetic contributions to survival variability. Identifying germline variants associated with survival could refine prognosis and reveal biological mechanisms underlying disease progression. Methods: We conducted a genome-wide association study (GWAS) of overall survival among 864 patients with HCC from the M.D. Anderson Cancer Center cohort. Genotyping, quality control, and imputation procedures followed previously described protocols (PMID: 38381705). Associations between genetic variants and overall survival were assessed using Cox proportional hazards models adjusted for age, sex, and the first five principal components. Genome-wide significance was defined as P < 5×10-8. Functional annotation and pathway enrichment analyses (MAGMA) were employed to investigate the biological relevance of the identified loci. Results: After quality control, 8,525,017 single-nucleotide polymorphisms (SNPs) were analyzed. We identified seven new loci associated with HCC survival at the genome-wide significance level. Five out of seven loci are associated with anthropometric traits and hematological measurement traits, reflecting metabolism, hematopoiesis, immune function, and inflammation. A variant in the 3′ untranslated region (UTR3) of STX7 showed a genome-wide significant association with overall survival (HR = 3.23; P = 2.56 ×10-8). Carriers of the risk allele had significantly shorter survival times compared with noncarriers. Pathway analysis revealed enrichment in biologically relevant processes, including liver growth and regeneration (growth hormone and Interleukin-6 (IL-6) signaling pathway), implicating hepatocyte proliferation and IL-6/STAT3-mediated inflammatory signaling. Immune-related pathways, such as regulation of T cell activation and myeloid leukocyte migration, highlight the role of germline variation in immune surveillance. Moreover, pathways governing vascular remodeling and metabolic stress response (e.g., JAK activation, mitochondrial dynamics) suggest that inherited determinants of microenvironmental structure and hepatocyte resilience influence patient outcomes. Conclusion: This germline GWAS of HCC survival identifies seven new genome-wide significant loci and implicates pathways involved in liver regeneration, inflammation, and tissue remodeling. These findings support a role for inherited genetic variation in shaping HCC prognosis and underscore the potential of integrating germline genetics into prognostic modelling and therapeutic target discovery. Citation Format: Younghun Han, Jinyoung Byun, Lewis R. Roberts, Katherine A. McGlynn, Manal M. Hassan, Christopher I. Amos. Identification of survival-associated germline variants in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3606.

Abstract Background: Hepatocellular carcinoma (HCC), the most prevalent primary liver cancer, develops through multiple pathways; however, the extent to which HBV, HCV, and non-viral etiologies shape tumor biology and influence treatment responses remain incompletely understood. The availability of viral detection methods from sequencing data and multiomics workflows give us a new opportunities to study how etiology influences the molecular landscape of HCC. Here, we analyze TCGA's LIHC samples categorized into HBV-, HCV-, and non-viral tumors to compare genomic, transcriptomic and methylation profile of these HCC tumors to identify biological pathways specific to each group. Methods: Whole-exome, RNA-seq, and clinical data from TCGA-LIHC (n=325) were analyzed. Viral status was assigned using Exogene (≥5 HBV/HCV reads; mixed infections excluded; non-viral = 0 reads). Mutation and clinical comparisons were performed using cBioPortal. RNA-seq data were processed with edgeR for 3-way differential expression (median count ≥25; |log2FC|>2; FDR<0.05). Pathway enrichment used ShinyGO. Findings were validated using the GSE62232 microarray cohort analyzed with limma. Results: Demographic patterns reflected known risk profiles: HBV patients presented younger (mean 53.9 years) and were predominantly male (78.8%) and Asian (92.9%), while HCV and non-viral groups were older and primarily White. Non-viral HCC showed the highest proportion of females (42.7%) and nearly half lacked significant fibrosis, consistent with metabolic disease. In contrast, HCV had the highest cirrhosis burden (47.2%), and HBV tumors showed the greatest proportion of poorly differentiated histology (52.2%).The comparison of the expressed genes between the 3 tumor subtypes revealed distinct etiology-associated pathways. Metabolic and mitochondrial including fatty acid β-oxidation differential expressed in Non-viral HCC. Activation of antiviral and interferon signaling, including type I IFN response and OAS-mediated defense pathways are observed in HCV-HCC. Finally, Cell-cycle and proliferation pathways are differentially expressed in HBV-positive, a finding consistent with effects of viral integration. Clustering analysis separated HBV and non-viral tumors into distinct groups. These signatures were reproduced in a validation cohort. Conclusion: Our analyses highlight that HBV-, HCV-, and non-viral HCC harbor distinct transcriptional and signaling pathways. These etiology-specific signatures provide a framework for developing more precise biomarkers and for tailoring therapeutic strategies to the molecular biology of each etiology. Acknowledgement: We acknowledge the late Dr. Sean Cleary, MD, for his invaluable contributions to this project. Disclosure: AI has been used to trim sentences in order to fit in the word limit. Citation Format: Amerti Guta, Daniel O'Brien, Aditya V. Bhagwate, Jean-Pierre A. Kocher, Lewis R. Roberts. Multiomic dissection of HBV-, HCV-, and non-viral HCC reveals distinct proliferation, interferon, and metabolic signatures [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2682.

Abstract Prostate-specific membrane antigen (PSMA) is highly expressed in tumor-associated neovasculature in hepatocellular carcinoma (HCC), highlighting its promise as a theranostic target. This prospective study aimed to evaluate the utility of novel biomarkers derived from PSMA positron emission tomography computed tomography (PET/CT) to assess treatment response in advanced HCC patients (pts) receiving first line immune checkpoint inhibitors (ICI). Methods: This study (NCT05176223) enrolled unresectable, advanced HCC pts eligible for first-line ICI (atezolizumab/bevacizumab [A/B] or durvalumab/tremelimumab [D/T]) with measurable disease according to RECIST criteria. Primary endpoints: progression-free survival (PFS) per RECIST 1.1 and mRECIST; overall survival (OS); and best overall response. The survival distribution was estimated using the Kaplan-Meier method. Observed agreement is defined as the proportion of pts whose responses, as classified by PET/CT or CT, were concordant. Weighted kappa and Cohen’s kappa were used to quantify the strength of agreement between PET/CT and CT. Pts completed up to five 68Ga-PSMA PET/CT scans and blood collections. Results: Twenty-six pts were enrolled (25 evaluable) between Oct 2022 and Nov 2024. Median follow up was 22.1 months (m) (Q1, Q3: 14.5-23.7). Median age 68 yrs, 72% male, 88% White, 68% Child-Pugh [CP] A, 32% CP B, 32% Barcelona Clinic Liver Cancer [BCLC] stage B, 68% BCLC stage C, 36% with microvascular invasion; 56% received A/B and 40% received D/T treatment. PSMA was positive in 96% of pts at baseline with median SUVmax 14.3 (range 5.1-40.5) and median background liver SUVmax 3.9 (range 2.1-6.8). Median (95%CI) PFS was 5.6 m (4.6-12.5) by both RECIST and mRECIST. Median (95%CI) OS was 18.6 m (7.2-not estimable), with 56% deceased. The observed agreement between PET/CT adapted PERCIST criteria compared to RECIST and mRECIST in determining the best response was 46% and 50% and weighted kappa of 0.63 (95% CI: 0.37-0.90) and 0.66 (0.41-0.92), respectively. Observed agreement between PERCIST compared to RECIST and mRECIST for responders’ assessment was 67% and 71% with Cohen’s kappa of 0.36 (0.03-0.68) and 0.43 (0.11-0.76), respectively. Conclusion: In this cohort, PSMA PET/CT avidity was observed in all but one pt with advanced HCC, each demonstrating moderate to high SUVmax values. Median OS and PFS were consistent with outcomes reported in clinical trials. Response assessment using 68Ga-PSMA PET/CT according to PERCIST criteria showed good concordance with both RECIST and mRECIST standards. Analysis of immune biomarkers is ongoing. Citation Format: Nguyen H. Tran, Jacob Hirdler, Ajith Antony, Jacob Teske, Sudhakar K. Venkatesh, Amit Mahipal, Michael S. Torbenson, Scott M. Thompson, Thor R. Halfdanarson, Zhaohui Jin, Lionel Aurelien Kankeu Fonkoua, Leslie A. Washburn, Alexander Revzin, Haidong Dong, Robert R. Mcwilliams, Aminah Jatoi, Hani M. Babiker, Mitesh J. Borad, Tanios Bekaii-Saab, Gregory J. Gores, Lewis R. Roberts, Geoffrey B. Johnson, Ajit H. Goenka. Prospective evaluation of 68Ga-PSMA PET imaging in advanced hepatocellular carcinoma patients undergoing first line immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2611.

PURPOSE Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The higher incidence and earlier onset of HCC in sub-Saharan Africa suggest a potential role for a genetic predisposition. This study evaluated the association of TERT -rs2242652-(A), a variant linked to lower HCC risk, with HCC in populations from Ghana, Nigeria, and Cameroon, compared with a population from the United States. METHODS The study included 537 patients with HCC: United States (n = 348), Ghana (n = 79), Nigeria (n = 43), and Cameroon (n = 67). The control group had 2,872 cancer-free individuals: United States (n = 2,399), Ghana (n = 323), Nigeria (n = 85), and Cameroon (n = 65). Whole-exome sequencing was conducted using germline DNA, and data for TERT -rs2242652 were analyzed. Odds ratios (ORs) and 95% CIs were calculated using unconditional logistic regression. Chi-square tests assessed protective allele frequencies. RESULTS In the US cohort, TERT -rs2242652 was significantly associated with lower HCC risk (OR, 0.75 [95% CI, 0.58 to 0.96]; P = .02), with an allele frequency of 18.8% (15.4% in HCC cases v 19.3% in controls). In the combined sub-Saharan African population, no significant association was observed, but there was a trend toward decreased HCC risk (OR, 0.80 [95% CI, 0.53 to 1.22]; P = .29), with an allele frequency of 12.2% (10.6% in HCC cases v 12.9% in controls). Separate analyses of Ghanaian, Nigerian, and Cameroonian populations showed similar nonsignificant trends. The protective allele frequency in the combined African populations was significantly lower than in the US cohort ( P < .0001). CONCLUSION In sub-Saharan African populations, there was a lower frequency of the HCC protective allele TERT -rs2242652 compared with European Americans. These findings underscore the importance of multiethnic genetic studies in understanding population differences in HCC risk and developing prevention strategies.