tbuckley/cabot-search huggingface dataset:
Association of GPR120 and NGF with perineural invasion in cholangiocarcinoma: Clinical and experimental insights.
Authors: Jun He, Lei Qin, Yang Shi, Danyang Shen, Wangjianfei Yu, Weigang Zhang, Jialu Yao, Xiaoyuan Hu
Journal: Journal of Clinical Oncology (2025)

622 Background: Cholangiocarcinoma (CCA) is a highly malignant biliary tumor characterized by frequent perineural invasion (PNI), which is associated with a poor prognosis; however, the underlying mechanisms remain unclear. G-protein-coupled receptor 120 (GPR120) has been implicated in the development of various tumors, while nerve growth factor (NGF) has a strong correlation with PNI. This study aims to elucidate the role of GPR120 in the production of NGF and to investigate the mechanisms by which PNI is induced in CCA. Methods: We conducted a retrospective review of medical records for 386 patients with cholangiocarcinoma (CCA), including both extrahepatic (ECC) and intrahepatic (ICC) types, who underwent curative resection at the Department of General Surgery, First Affiliated Hospital of Soochow University, between January 2015 and December 2021. NGF and GPR120 expression were assessed in 60 paraffin-embedded archived CCA tissue samples via immunohistochemical staining (IHC), with an additional 60 normal bile duct samples serving as controls. All tissues were sourced from the aforementioned 386 patients, none of whom received preoperative treatment. Tumors were staged according to AJCC classification. Western blot analysis was employed to evaluate NGF and GPR120 expression in CCA cell lines (QBC 939, RBE, HUCCT-1, and HCCC-9810). To assess the invasion and migration capabilities of CCA cell lines, QBC 939 and HCCC-9810 were treated with TUG-891 (a GPR120 agonist) and AH7614 (a GPR120 inhibitor). Results: Both GPR120 and NGF were found to be upregulated in CCA tissues, correlating with aggressive clinicopathological features. IHC staining revealed cytoplasmic localization of GPR120 and NGF, with significantly higher expression in cancerous tissues compared to adjacent noncancerous samples. Among the 386 patients, PNI was observed in 339 (87.8%). PNI correlated with tumor diameter, CA 19-9 levels, TNM stage, preoperative bilirubin levels, tumor differentiation, and preoperative drainage. Notably, GPR120 expression increased in poorly differentiated tumors and advanced clinical stages, indicating a clinical association with CCA progression. In vitro studies demonstrated that GPR120 promoted invasion and migration in the QBC 939 and HCCC-9810 cell lines. Western blot analysis confirmed elevated GPR120 levels in these lines, which also exhibited higher NGF expression. The GPR120 inhibitor AH7614 significantly reduced invasion in QBC 939 and HCCC-9810 cells, while the GPR120 agonist TUG-891 showed no effect on any of the CCA cell lines tested. Conclusions: GPR120 and NGF are implicated in perineural invasion (PNI) in CCA, with a notable correlation between GPR120 and NGF in the context of PNI occurrence.
p53 pathway genes' mutations as prognostic factors in patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC): A single center study.
Authors: Giovanni Trovato, Diletta Barone, Alexia Spring, Angelo Minucci, Laura Chiofalo, Serena Perazzo, Anna Ceccarelli, Linda Di Francesco, Antonia Cosmai, Gloria Messina, Alessia Preziosi, Luciano Giaco', Maria Bensi, Cinzia Bagalà, Giampaolo Tortora, Lisa Salvatore
Journal: Journal of Clinical Oncology (2025)

771 Background: Mutations (muts) in oncosuppressor genes have been associated with poor prognosis in different solid tumors. This study aims to evaluate the prognostic impact of p53 pathway muts in mPDAC pts. Methods: For each mPDAC pt enrolled in this study a FFPE tumor tissue specimen was collected and Next Generation Sequencing (NGS) was performed by TSO500HT assay (DNA [523 genes], RNA [55 genes]). Primary endpoint was overall survival (OS). The Kaplan–Meier method was used to estimate efficacy outcome; log-rank test, Peto-Peto test and Cox-regression model were used to compare the differences, considering a statistically significant p value &lt; 0.05. Results: A total of 149 mPDAC pts were enrolled; TP53 was mutated in 115/149 (77.2%) pts, CDKN2A in 28 (24.3%), CDKN2B in 8 (5.3%), ATM in 6 (4%), TP53BP1 and MDM2 in 2 pts each (1.3%) and ATR in 1 (0.7%). No mutations were found in MDM4, CHEK1 and CHEK2 genes. Overall, 121 (81.2%) pts had at least one mutation in a gene of p53 signaling pathway (p53sigmut) and 28 pts (19.8%) had none (p53sigwt). The most frequent TP53 alterations were single nucleotide variations (SNVs): R175 (10 pts-8.7%), R248 (9 pts-7.8%) and R273 (8 pts-7%); 27 TP53 muts (18.1%) occurred in exon 7, 26 (17.4%) in exon 5, 19 (12.8%) in exon 8 and 13 (8.7%) in exon 4. Median OS (mOS) was 15 months (mos) (CI 95%: 12.8-18.2) in TP53 mutated pts vs 24.3 mos (CI 95%: 17.3-Not reached) in TP53 wt pts, p=0.03. The site of TP53 alteration was correlated with pts’ survival: mOS was 34.9 mos (CI 95%: 31-Nr) in exon 4-mutated pts, 16.9 mos (CI 95%: 11.2-21.2) in exon 7-mut, 13.8 mos (CI 95%: 11.2-17.8) in exon 5-mut and 10.7 mos (CI 95%: 8.2-Nr) in exon 8-mut, p= 0.018. CDKN2A mutations were also associated with survival: mOS was 17.9 mos (CI 95%: 15.9-24.1) in wt pts vs 13.4 (CI 95%: 10.7-22.2) in mutated pts, p= 0.04. CDKN2B, ATM, TP53BP1, MDM2 and ATR mutations were not associated with OS. Overall, patients with at least one mutation in one of the genes of p53 pathway had a mOS of 15 mos (CI 95%: 12.8-18.2) vs 19.6 months (mos) (CI 95%: 17.3-Not reached) in p53sigwt patients. In terms of comutations, TP53 wt pts had a higher frequency of KRAS mutations: 94% vs 64.5%, p&lt;0.001. Conclusions: Our study suggests an important prognostic role of p53 signaling muts in mPDAC pts; wt pts resulted in a longer OS than mutated pts, although some mutations seem to be associated with a longer survival. Further studies are needed to investigate these findings, including an in-depth analysis of structural proteogenomic.
Impact of education on clinical confidence utilizing HER2-targeted therapies in colorectal cancer.
Authors: Karine Cohen-Solal, Tariqa Ackbarali, John H Strickler, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2025)

225 Background: Novel targeted therapies entered the treatment landscape in patients with HER2-positive metastatic colorectal cancer (mCRC). To ensure that these therapies are used effectively, clinicians must assess tumor HER2 status and recognize how HER2-directed treatment modalities fit into the current paradigm. To further enable clinicians to integrate HER2-targeted therapies, an educational program was designed in 2023. Methods: A one-hour online, video-based program was designed for clinicians and their teams and hosted on MedLive from February 2023 for one year. Knowledge and competence questions were administered pre-, and immediate post-activity. Additional questions assessed attitudes, barriers, and intended practice changes related to HER-positive mCRC. Results: Over 4,000 participants engaged in the educational activity, 67% of whom were physicians, and 63% noting their specialty as oncology. Approximately 68% identified as treaters seeing 14 patients with CRC per week with 78% of those patients have HER2-positive CRC. All pre-post questions showed significant improvements in knowledge and competence related to HER2 amplification testing methodologies, trial eligibility criteria, identification of patients who would benefit from anti-HER2 targeted regimens, and adverse events associated with anti-HER2 agents. Following the activity, 51% were more likely to incorporate testing for HER2 expression level or amplification prior to the selection of targeted therapy for their patients. The greatest challenges faced when managing patients with HER2-positive mCRC were affordability of therapy for patients (50%), adherence to treatment schedules (25%) and patient anxiety about treatment efficacy (24%). The most common barriers to patient enrollment in clinical trials identified by clinicians were lack of trials at their institutions (35%), lack of trials in their geographic region (21%), and patient lack of interest (20%). Qualitative insights on intended practice changes were shared by learners post-activity. Conclusions: The outcomes of this educational activity demonstrate the effectiveness of education in improving knowledge and confidence from testing to adverse event management to better integrate new regimens into practice. Encouraging practice changes were also seen from the write-in responses from learners. Additional needs were also identified to further solidify HER2 testing as a prerequisite for anti-HER2 targeted therapies, selecting eligible patients, and timely management of adverse events.
Evaluating immune cell abundance across hepatocellular carcinoma disease stages I-III: Findings from TCGA analysis.
Authors: Jaber H. Jaradat, Nosakhare Paul Ilerhunmwuwa, Meghana Singh, Ibrahim Halil Sahin, Anwaar Saeed
Journal: Journal of Clinical Oncology (2025)

621 Background: Hepatocellular carcinoma (HCC), the predominant form of primary liver cancer, is the sixth most prevalent cancer globally and a leading cause of cancer-related mortality. The tumor microenvironment (TME) in HCC, characterized by complex interactions between immune and tumor cells, significantly influences tumor progression and immune suppression. Understanding the immune landscape across the different stages of HCC can inform prognosis and therapeutic strategies. Methods: We analyzed RNA seq data from 333 HCC patients (disease stages I-III), from The Cancer Genome Atlas (TCGA), using the immune deconvolution algorithms CIBERSORT and xCell. Differential gene expression analysis was performed using the DESeq2 package in R. Immune cell abundance across various HCC stages was imputed, and survival analyses was conducted using Kaplan-Meier curves and log-rank tests. Results: Of the 19,514 genes analyzed, 2,774 were up-regulated and 947 were down-regulated in stage II and III in comparison to stage I. CIBERSORT and xCell analyses revealed significant variability in the immune cell composition between HCC stages. Notable differences were observed in the T cells (CD4 and CD8 subsets), B cells, plasma cells, and stromal components. ANOVA and post hoc tests identified significant stage-specific differences in several immune cell types. For the survival analysis, we categorized patients into low and high groups based on median cell abundances. Overall survival showed no statistically significant differences among the various groups for common myeloid and lymphoid progenitor cells. In contrast, disease-free survival demonstrated statistically significant differences across the groups for both cell types. Conclusions: This study emphasizes the tumor microenvironment's pivotal role in HCC, revealing that immune cell composition significantly influences disease-free survival, despite limited effects on overall survival. These findings advocate for further exploration into targeted immunotherapies and the development of predictive models that integrate immune landscape characteristics, ultimately aiming to enhance patient outcomes in HCC. Cell type xCell Cibersort Mean SD Mean SD T cell CD4 naive 0.00466 0.01994 1.31e-5 1.69e-4 T cell CD8 0.01368 0.03253 0.03161 0.04947 Eosinophil 3.96e-5 3.41e-4 1.67e-4 8.69e-4 Macrophage 0.02323 0.02441 0.02924 0.04345 Macrophage.M1 0.00914 0.01526 0.01806 0.02054 Macrophage.M2 0.02303 0.01697 0.05439 0.04815 B cell memory 0.00196 0.01418 0.00107 0.00733 B cell naive 0.00163 0.01034 0.01319 0.02148 Neutrophil 2.14e-4 0.00137 0.00112 0.00539 Immune score 0.04621 0.06817 - - Table presents various cell type abundances for each algorithm used.
Development of new therapeutic strategies to enhance the effectiveness of irinotecan in colorectal cancer treatment.
Authors: Koji Ando, Yuho Ebata, Eiji Oki, Tomoharu Yoshizumi, Ajit Bharti
Journal: Journal of Clinical Oncology (2025)

217 Background: Chemotherapy plays an important role in the treatment of colorectal cancer. Irinotecan, a topoisomerase I inhibitor, is used in therapies such as FOLFIRI and FOLFOXIRI. However, many patients become resistant to irinotecan, and the detailed mechanisms of resistance are not fully understood. The aim is to develop new therapeutic strategies by elucidating the mechanisms of irinotecan resistance. Methods: We used in vitro approach to demonstrate the mechanism of topoI degradation. Immunohistochemistry staining was used to explore the biomarker for irinotecan, Finally, in vivo approach was used to develop a new strategy for irinotecan treatment. Results: Mechanism of topoisomerase I (topoI) degradation: We investigated the molecular mechanism of topoI degradation in detail. After irinotecan administration, double-strand breaks occur in the DNA, activating DNA-PK. This activated DNA-PK phosphorylates the S10 residue of topoI, and BRCA1-BARD1 ubiquitinates the phosphorylated topoI. Eventually, topoI is degraded by the proteasome. Colorectal cancer cell lines where topoI degradation occurred after irinotecan administration showed irinotecan resistance. Development of a biomarker for irinotecan sensitivity: We created a monoclonal antibody that labels the phosphorylated S10 residue of topoI (topoI-pS10). We examined topoI-pS10 expression in colorectal cancer cases with a history of irinotecan treatment. The results showed a sensitivity of 87.5%, accuracy of 70%, positive predictive value of 70.7%, and negative predictive value of 87%, indicating that topoI-pS10 expression could serve as a biomarker for irinotecan sensitivity.Development of new therapeutic strategies: The degradation of topoI, which causes irinotecan resistance, is carried out via the ubiquitin-proteasome pathway. It is expected that combining irinotecan with a proteasome inhibitor, which blocks this pathway, will enhance irinotecan’s effectiveness. When irinotecan was combined with a proteasome inhibitor in irinotecan-resistant colorectal cancer cell lines, cell death occurred at a higher rate compared to when they were not combined. Similar results were observed in experiments using mice. Conclusions: Based on the mechanism of topoI degradation, we developed a biomarker for irinotecan sensitivity and a new therapeutic strategy. This study suggests the potential for further improvements in irinotecan therapy.
Personalized oncogenomic analysis of metastatic squamous cell carcinoma of the anus: Utilizing whole-genome sequencing to guide clinical decision-making.
Authors: Renata D'Alpino Peixoto, Melissa McConechy, Howard J. Lim, Marco A Marra, Jing Xu, Kathleen Wee, Erin D. Pleasance, Janessa J. Laskin
Journal: Journal of Clinical Oncology (2025)

11 Background: Metastatic squamous cell carcinoma of the anus (SCCA) is associated with significant morbidity and mortality. Due to its relative rarity, there is limited evidence to support systemic therapy regimens informed by genomic data. This study aims to utilize whole-genome and transcriptome sequencing to enhance the understanding of the genetic alterations driving metastatic SCCA and to identify potentially actionable therapeutic targets. Methods: This report examines nine cases of metastatic SCCA in patients enrolled in the Personalized Oncogenomics (POG) Program at the BC Cancer Agency. Comprehensive genomic profiling, including whole-genome and transcriptome analysis (WGTA) was conducted on fresh tumor biopsy or formalin fixed paraffin embedded (FFPE) tissue. Tumor genomic alterations were analyzed in detail including: SNVs, indels, copy number alterations, structural variants, mutation signatures, viral presence, tumor mutation burden (TMB), expression outliers, and immune cell scores. The somatic alterations were integrated with existing knowledge of drug-target interactions to identify actionable therapeutic targets. Results: Of the nine patients, eight were found to be HPV-positive, with one exhibiting high tumor mutational burden (TMB&gt;10mut/Mb). Mutation signatures included seven cases with AID/APOBEC signatures (commonly seen with HPV), and one case with an ID2 DNA replication slippage signature. The PI3K/AKT/mTOR pathway was the most commonly affected signaling pathway (n=4), followed by FGFR amplification and overexpression (n=3), and RAS/RAF alterations ( BRAF mutation and KRAS overexpression, n=2). EGFR amplification was identified in two cases, one of which also exhibited EGFR overexpression. Additionally, FBXW7 mutations were present in two cases. Immunotherapy was recommended for all nine patients: eight based on HPV positivity, either alone or in combination with other alterations, such as high TMB, SWI/SNF complex alterations, and presence of immune infiltrating cells, and the remaining case based on a SWI/SNF complex mutation. Only two patients ultimately received immunotherapy, both of whom derived clinical benefit. One patient, treated with atezolizumab as part of the phase II CAPTIV-8 trial (NCT04273061), demonstrated progression-free survival (PFS) of 10 months (ongoing), while the other, treated with nivolumab, achieved a PFS of 6 months. Conclusions: Genomic analysis using WGTA supported the recommendation of immunotherapy for all patients in this cohort. Although only two patients received immunotherapy, both experienced clinical benefit, underscoring the potential of personalized genomic-guided treatment in metastatic SCCA.
Phase I/Ib study of afatinib with capecitabine in patients with refractory solid tumors and pancreaticobiliary cancers.
Authors: Gentry Teng King, Kelsey K. Baker, Andrew L. Coveler, Rachael A. Safyan, Kit Wong, Veena Shankaran, David Bing Zhen, Hannah H Lee, Jeniece Hensel, Reina Hibbert, Greg Andrew Durm, Mary Weber Redman, Colin C. Pritchard, Safi Shahda, E. Gabriela Chiorean
Journal: Journal of Clinical Oncology (2025)

594 Background: The epidermal growth factor receptor (EGFR) and ErbB2/HER2 signaling is overactive in many solid tumors. Afatinib, an irreversible inhibitor of ErbB signaling, downregulates thymidine synthase and synergizes with capecitabine in preclinical models. This phase I trial evaluated the safety, maximum tolerated dose (MTD) and preliminary efficacy of afatinib plus capecitabine in patients (pts) with refractory solid tumors and pancreatic ductal adenocarcinoma (PDA) and biliary tract cancers (BTC). Methods: The phase I study had a 3+3 design with capecitabine 1000 mg/m 2 twice daily (BID) on days 1-14 and afatinib 20 mg, 30 mg or 40 mg daily (QD) in 21-day cycles. In phase Ib, 15 pts each with PDA and BTC were treated at MTD. Results: 41 pts enrolled from November 2016 to October 2021, who received a median of 2 (range 1-5) prior therapies. No dose-limiting toxicities were observed. The MTD was 40 mg afatinib QD plus 1000 mg/m 2 capecitabine BID. Grade 3 treatment related adverse events were diarrhea (12.2%) and nausea (4.9%). Among 36 response evaluable pts, best response was 1 partial response (PR, 3%) in a pt with KRAS wild type (WT)/EGFR amplified BTC, and 8 stable diseases (SD, 22%), with disease control rate (DCR) of 25%. PDA pts (n=20) had DCR of 24%, median progression-free (PFS) and overall survival (OS) of 1.9 months (95% CI 1.05, 2.03) and 3.2 months (95% CI 2.01, 5.82) respectively. BTC pts (n=18) had DCR of 31%, median PFS and OS of 1.9 months (95% CI 1.55, 3.39) and 4.6 months (95% CI 1.88, 6.09), respectively. Eight pts with cancers with EGFR/HER2/HER3 pathway alterations, most KRAS WT (n=6), had DCR of 29%, and median PFS and OS of 2.1 months (95% CI 1.05, 4.14) and 3.5 months (95% CI 1.64, 6.09), respectively. Conclusions: Afatinib plus capecitabine is tolerable but does not have significant efficacy in pts with refractory PDA/BTC, including in KRAS WT cancers with EGFR/HER2/HER3 alterations. Clinical trial information: NCT02451553 .
Radiomics-based prediction of HCC response to atezolizumab/bevacizumab.
Authors: Isaac Rodriguez, Abhinay Vellala, Timo Itzel, Michael Vácha, De-Hua Chang, Michael Dill, Max Seidensticker, Julia Mayerle, Stefan Munker, Stefan O. Schönberg, Lukas Mueller, Peter Robert Galle, Arndt Weinmann, Dietmar Tamandl, Matthias Pinter, Bernhard Scheiner, Andreas Teufel, Matthias Froelich, Matthias Philip Ebert, Marino Venerito
Journal: Journal of Clinical Oncology (2025)

636 Background: Advanced hepatocellular carcinoma (HCC) treatment has evolved with the introduction of atezolizumab/bevacizumab, showing improved outcomes over sorafenib. However, the response varies among patients, particularly between viral and non-viral etiologies. This study aimed to develop and evaluate multimodal prediction models combining quantitative imaging and clinical markers to predict treatment response in HCC patients. Methods: From March 2020 to May 2023, patients with advanced HCC treated with atezolizumab/bevacizumab were retrospectively identified from six centers in Germany and Austria. Patients underwent baseline contrast-enhanced liver MRI and follow-up imaging to assess therapy response. Machine learning models, including RandomForestClassifier, were developed for radiomics, clinical, and combined datasets. Hyperparameter tuning was performed using RandomizedSearchCV, followed by cross-validation to evaluate model performance. Results: The study included 103 patients, with 70 achieving disease control (DC) and 33 experiencing disease progression (PD). Key findings included significant differences in treatment response and progression-free survival between DC and PD groups. The radiomics model, using 14 selected features, achieved 73.1% accuracy and a ROC AUC of 0.635 on the test set. The clinical model, with 4 selected features, achieved 73% accuracy and a ROC AUC of 0.649 on the test set. The combined model showed improved performance with 69% accuracy and a ROC AUC of 0.753 on the test set. Hyperparameter tuning further enhanced the combined model's accuracy to 80.1% and ROC AUC to 0.771 on the test set. Conclusions: The hybrid model combining clinical and radiological data outperformed individual models, providing better predictions of response to atezolizumab/bevacizumab in HCC patients.