tbuckley/cabot-search huggingface dataset:
Highly accurate detection of early-stage colorectal cancer using tumor and immune extracellular vesicles biomarkers.
Authors: Todd A. Hembrough, Poorva Mudgal, Zachary Opheim, Cheryl Bandoski, Issa Isaac, Martin Mehnert, Valesca Anschau, Alan Ezrin
Journal: Journal of Clinical Oncology (2025)

262 Background: Colorectal cancer (CRC) is one of the most common cancers worldwide, and early detection is critical for successful treatment and improved survival rates. However, precancerous and early-stage CRC present significant diagnostic challenges due to the small size of lesions and the very low expression of tumor-specific biomarkers in the bloodstream. Current genomics-based diagnostic methods struggle to detect these early-stage and precancerous lesions, making it imperative to develop more sensitive and specific approaches. Circulating extracellular vesicles (EVs) are emerging as a promising solution for early-stage CRC detection. Since EVs are produced by tumor cells as well as tumor microenvironment and host immune response cells, EVs offer the means to detect and monitor small early-stage tumors through both direct detection of tumor-associated biomarkers as well as tumor specific host response and tumor microenvironment biomarkers. Methods: To identify novel early-stage CRC specific biomarkers, we performed proteomics analysis on EVs purified from patient plasma using size exclusion chromatography and a proprietary buffer system that enhances EV and corona protein recovery. TrueDiscovery Data-independent acquisition (DIA) mass spectrometry (MS) analysis was conducted on 24 pre-cancer/stage 0 and 25 stage 1 CRC patients and 75 normal patient plasma samples. An in-house developed machine learning pipeline was used to identify differentially expressed proteins and model candidate multiplexes to identify those with extremely high diagnostic accuracy (&gt; 0.99). Results: An average of ~2,500 proteins were identified per sample and included in bioinformatics analysis. Comparative analysis between control patient EVs and either pre-cancerous/Stage 0, or Stage 1 colon cancer EVs using an in-house Machine Learning pipeline identified 336 and 493 differentially expressed proteins for each group (FDR adjusted p-value &lt; 0.001). Of these, the best 17 pre/stage 0 proteins and 53 stage 1 proteins were trained and tested using Support Vector Machine to assess all potential 3-plexes in order to identify those with mean diagnostic accuracy &gt; 99%. This yielded 5 3-plexes in precancer/stage 0 and 34 3-plexes in stage 1 with near perfect diagnostic accuracy. These plexes are currently being assessed in single analyte and multiplex immunoassays with the goal of translating candidate 3-plexes to the clinical. Conclusions: Key biomarkers from CRC patient EVs indicate the potential to detect and diagnose early-stage and low tumor burden cancers using our methods. Interestingly, the most accurate 3-plexes consist of proteins from immune, inflammatory and metabolic processes, suggesting that for the detection of early stage cancer it may be critical to include both tumor and host specific biomarkers.
Impact of <i>RAS</i> and <i>BRAF</i> heterogeneity on the efficacy of EGFR blockade in patients with metastatic colorectal cancer.
Authors: Nobuhisa Matsuhashi, Takeshi Yamada, Takeshi Nagasaka, Kozo Kataoka, Kazuhiro Sakamoto, Keiji Koda, Kazuhiro Hiramatsu, Hiroshi Matsuoka, Hidekazu Kuramochi, Hideyuki Ishida, Hajime Yokomizo, Yoshinori Kagawa, Mitsukuni Suenaga, Akihisa Matsuda, Jun Nagata, Kei Ishimaru, Chihiro Kosugi, Takao Takahashi, Hiroshi Yoshida, Keiji Hirata
Journal: Journal of Clinical Oncology (2025)

255 Background: Epidermal growth factor receptor (EGFR) blockade can effectively shrink tumors in metastatic colorectal cancer (CRC) patients without RAS nor BRAF mutations. However, some patients without RAS or BRAF mutations in their primary tumors may develop these mutations in metastatic tumors (heterogeneity). Circulating tumor DNA (ctDNA) can reflect this heterogeneity in metastatic tumors. Here, we evaluated the efficacy of EGFR blockade in patients who had no RAS or BRAF mutations in their primary tumors but did have them in ctDNA. Methods: We prospectively enrolled 100 patients with confirmed metastatic CRC without RAS or BRAF mutations in their primary tumors. Patients were treated with first-line systemic chemotherapy including EGFR blockade. We obtained ctDNA from each patient before they started chemotherapy. RAS, BRAF (V600E), and PIK3CA mutations were detected using digital PCR. Results: One of the 100 cases were excluded due to protocol violation. In the ctDNA obtained before starting chemotherapy, RAS, BRAF, and PIK3CA mutations were detected in 12, 4, and 6 patients, respectively. No patients had both RAS and BRAF mutations in their ctDNA; however, one patient had both BRAF and PIK3CA mutations and one had both RAS and PIK3CA mutations. Eighty-nine patients had measurable tumor lesions. Among these, 3 experienced a complete response (CR), 71 had a partial response (PR), 13 had stable disease (SD), and 2 had progressive disease (PD). The response rates for patients with RAS or BRAF mutations and for patients with neither mutation were 81% and 83%, respectively (P=0.73). Median progression-free survival (PFS) for patients with RAS or BRAF mutations and those without mutations were 251 days and 216.5 days, respectively (P=0.82). The presence or absence of PIK3CA mutations did not affect the response rate or PFS. Conclusions: Previously, we reported that the incidence of RAS and BRAF heterogeneity were 10% (1) and 4% (2). In the present study, RAS and BRAF heterogeneity were 12% and 4%, respectively. The heterogeneity of RAS and BRAF mutations had no effect on the response rate and PFS of EGFR blockade as first line chemotherapy. The effect of heterogeneity on the overall survival is of great interest; however, about half of the patients are still alive. 1. Yamada T, et al. Cancer Science 2016. 2. Ueda K, et al. Eur J Surg Oncol 2022. Clinical trial information: UMIN000031177 .
Q-TWiST analysis of pembrolizumab plus trastuzumab and chemotherapy for patients with metastatic HER2-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma in the KEYNOTE-811 trial.
Authors: Sun Young Rha, Cedric Revil, Adriana Valderrama, Liya Wang, Manon Andre, Grant McCarthy, Kate Young
Journal: Journal of Clinical Oncology (2025)

354 Background: In the phase 3 KEYNOTE-811 trial (NCT03615326), first-line pembrolizumab plus trastuzumab and chemotherapy (pembrolizumab group) statistically significantly improved PFS and OS versus placebo plus trastuzumab and chemotherapy (placebo group), with manageable safety, in patients with metastatic HER2-positive G/GEJ adenocarcinoma, while maintaining HRQoL, specifically in patients with PD-L1 combined positive score (CPS) ≥1 tumors. The objective of this analysis was to assess quality-adjusted time without symptoms of disease progression or toxicity (Q-TWiST) for patients treated in the KEYNOTE-811 trial. Methods: Q-TWiST is a measure of survival weighted by health states utility values. The analysis categorized survival time into 3 health states: time with grade ≥3 adverse events (toxicity [TOX]) and time without symptoms or toxicities (TWiST)—both before disease progression or death—and relapse (REL), defined as time from disease progression to death. Q-TWiST was calculated as the restricted mean survival time spent in each state, with a weighted health state utility for that state. Average utility weights were derived based on pooled EQ-5D-5L scores using the US mapping algorithm and standardized base case utility weights. Relative gains in Q-TWiST of ≥10% and ≥15% were “clinically important” and “clearly clinically important,” respectively, as reported in the literature. Treatment difference 95% CIs were generated using the nonparametric bootstrapping method. Data are reported for patients with PD-L1 CPS ≥1 tumors. The data cutoff date was March 20, 2024. Results: At the maximum follow-up of 63 months, patients in the pembrolizumab group had a 2.36-month (95% CI, −0.24 to 4.56) longer restricted mean time in TOX (6.98 vs 4.63 months), a 3.40-month (95% CI, −0.44 to 7.45) longer restricted mean time in TWiST (12.03 vs 8.62 months), and a 1.45-month (95% CI, −5.84 to 3.09) shorter restricted mean time in REL (8.87 vs 10.32 months) versus the placebo group. For the restricted mean Q-TWIST at month 63, based on the US mapping algorithm, the difference between the pembrolizumab and placebo groups favored the pembrolizumab group by 3.90 months (95% CI, 1.30 to 6.72), representing a 16.57% relative Q-TWiST gain. Based on the standardized base case utility weights, the difference also favored the pembrolizumab group by 3.86 months (95% CI, 1.47 to 6.67), representing a 16.38% relative Q-TWiST gain. Conclusions: Pembrolizumab plus trastuzumab and chemotherapy produced a clearly clinically important improvement in quality-adjusted survival time based on Q-TWiST analyses compared with placebo plus trastuzumab and chemotherapy in patients with previously untreated metastatic HER2-positive G/GEJ adenocarcinoma with PD-L1 CPS ≥1. Clinical trial information: NCT03615326 .
Intra-arterial gemcitabine versus intravenous gemcitabine: Pharmacokinetic sub-study of the TIGeR-PaC phase 3 clinical trial.
Authors: Paula M. Novelli, Amer H. Zureikat, Michael J. Pishvaian, Kenneth Lee Meredith, Hassan Hatoum, Emmanuel E. Zervos, Reza Nazemzadeh, Sandeep Laroia, Ramtin Agah
Journal: Journal of Clinical Oncology (2025)

719 Background: Localized, dual balloon catheter-mediated, intra-arterial delivery of gemcitabine (IAG) targeted to tumors/tissue can provide higher local drug potency (1). Furthermore, IAG may result in a decreased systemic drug concentration and associated side effects. In patients with locally advanced pancreatic cancer (LAPC), this approach is currently being tested in the TIGeR-PaC Phase 3 clinical trial. Herein we report the results of a 19-patient pharmacokinetics (PK) sub-study analysis within TIGeR-PaC. Methods: PK analyses were performed for a total of 19 participants across 6 TIGeR-PaC study sites; 11 participants received IAG with the RenovoCath dual balloon catheter at 1000 mg/m 2 over 20 minutes and 8 participants received intravenous gemcitabine (IVG) (5 at 1000 mg/m 2 , 2 at 800 mg/m 2 , 1 at 500 mg/m 2 ) over 30 minutes. IAG target treatment arteries were either the superior mesenteric artery (SMA) (n=5) or branches of the celiac axis (n=6). At T = -5, 10, 15, 20, 30, 40, 60, and 90 minutes from the onset of infusion, 2 mL of blood was collected in heparinized tubing containing 25 mcg/mL of tetrahydrouridine. Plasma from each sample was frozen and shipped to a reference lab for gemcitabine assays. Maximum plasma drug concentration (C max ) and the area under the drug plasma concentration curve (AUC) based on the terminal phase were compared between the two groups; for these dose-dependent parameters, only participants who received 1000 mg/m 2 gemcitabine (IAG, N=11; IVG, N=5) were included in the comparison analysis. Results: As shown in the table, AUC was significantly lower with IAG (4.99) compared to IVG (9.97) ( P = 0.019). Peak plasma gemcitabine concentrations were also lower with IAG (12.9 mcg/mL) vs. IVG (14.6 mcg/mL) despite a 50% higher drug concentration during IAG vs. IVG (1000 mg/m 2 infused over 20 minutes vs. 30 minutes, respectively). There was no difference in plasma levels between IAG treatment sites (SMA vs. celiac axis). Conclusions: In this analysis, localized, dual-balloon catheter-mediated IAG resulted in decreased systemic levels of gemcitabine compared to IVG. Thus, in addition to providing increased local potency, the IAG approach may also be beneficial in decreasing gemcitabine-related systemic side effects. 1. Farsad K, et al. 2024. JVIR 35:1043-48 e3. Clinical trial information: NCT03257033 . Effects of treatment mode on mean pharmacokinetic parameters for gemcitabine. PK parameter IAG Group(N=11) IVG Group(N=5) C max (mcg/mL), Mean (SE) 12.9 (±2.4) 14.6 (±1.2) AUC (hr ⋅ mcg/mL), Mean (SE) 4.99 (±0.96) 9.97 (±1.9) AUC = area under the curve; C max = maximum serum concentration; IAG = intra-arterial gemcitabine; IVG = intravenous gemcitabine; PK = pharmacokinetic; SE = standard error.
A protocol for pretreatment testing for antibodies to galactose-alpha-1,3-galactose to mitigate the risk of cetuximab hypersensitivity reactions.
Authors: Nicholas Della Marta, Alexander Yuile, Claire Mok, Joe Wei, Meredith Oatley, Tracey Skinner, Samuel Miller, Sheryl van Nunen, Stephen John Clarke, Connie Irene Diakos, Madhawa De Silva, David Chan, Gavin M. Marx, Nick Pavlakis
Journal: Journal of Clinical Oncology (2025)

115 Background: Cetuximab has been shown to improve survival in patients with KRAS wildtype metastatic colorectal cancer. However, high rates of hypersensitivity reactions (HSRs) limit its use, with HSR rates up to 10-20%. A major driver of cetuximab HSR is from pre-formed antibody response to galactose-1,3-alpha-galactose (alpha-gal). Evidence from retrospective studies supports alpha-gal pre-screening in this setting. We are the first to report on the impact of prospective alpha-gal antibody screening on cetuximab HSR. Methods: Records were reviewed across three medical oncology centres that have adopted alpha-gal antibody screening measures. Data for patients with metastatic colorectal cancer treated with cetuximab were retrieved. All centres assessed alpha-gal antibody status using the ImmunoCAP ELISA assay. Due to lack of a shared screening approach across study sites, a pre-determined protocol was retrospectively applied to all cases. This protocol allowed cetuximab administration if alpha-gal levels were ≤0.1 kUA/L, but prohibited it if alpha-gal levels were &gt;0.1 kUA/L in favour of panitumumab administration. Patients were allocated to either the Protocol Applied or Protocol Not Applied cohorts based on protocol requirements being met. The primary outcome between these patient groups was the incidence of cetuximab HSRs. Results: Of 254 assessable patients, 39 underwent the pre-treatment screening protocol. Of the Protocol Applied group, 3% (n=1/38) experienced a cetuximab HSR compared to 16% (n=35/215) in the Protocol Not Applied group (Odds ratio (OR) 7.16; 95% CI 1.13–299.61, p =0.02). Patients with alpha-gal antibody titres &gt;0.1 kUA/L were more likely to experience a cetuximab HSR (OR 69.71; 95% CI 5.18–4296.81, p =0.0001). Conclusions: Pre-treatment screening for alpha-gal antibodies significantly reduces the incidence of cetuximab HSRs. A testing threshold of 0.1 kUA/L is effective in identifying patients at risk. Implementing this protocol can improve the safety of cetuximab therapy in high-risk populations.
The Oncopig hepatocellular carcinoma model: An innovative large animal platform for evaluating treatment effects.
Authors: Ian Chau, Lobna Elkhadragy, Ron C. Gaba, Lawrence B Schook, Kyle Schachtschneider
Journal: Journal of Clinical Oncology (2025)

619 Background: Hepatocellular carcinoma (HCC) is an aggressive disease associated with poor prognosis and limited treatment options. Systemic therapies for advanced HCC include sorafenib, lenvatinib, and atezolizumab plus bevacizumab. However, given the limited efficacy of systemic treatment options, novel treatment approaches including combination of systemic and locoregional therapies (LRTs) is required to improve patient outcomes. These approaches require advanced large animal models to prove effectiveness. Pigs represent an ideal platform that provide both regulatory acceptable and clinically relevant large animal cancer models due to their similar physiology, size, genetics, immunity, and metabolism in relation to humans. The Oncopig HCC model is an ideal tool for testing LRT and other oncolytic based treatments. Methods: The Oncopig cancer model develops tumors following induced expression of KRAS G12D and TP53 R167H driver mutations utilizing an adenoviral vector encoding Cre recombinase (AdCre). Oncopig HCC cell lines were developed by isolating hepatocytes from Oncopig liver biopsies and transformed in vitro via exposure to AdCre. Transgene expression and hepatocyte cell origin were validated by RT-PCR and arginase-1 staining, respectively. Comparison of in vitro Oncopig, human, and murine HCC cell line phenotypes (proliferation, migration, and chemotherapeutic response) was performed. Oncopig HCC tumor formation was performed via autologous intrahepatic injection of Oncopig HCC cells. Tumor formation was evaluated using ultrasound and CT imaging. Results: Oncopig and human HCC cell lines displayed similar cell cycle lengths and migration rates. Oncopig HCC cells were consistently more predictive of human HCC responses than murine cells when treated with standard chemotherapeutic agents (doxorubicin, cisplatin, mitomycin C, and sorafenib). Importantly, consistent with human HCC, Oncopig HCC cells were non-responsive to 5-fluorouracil, while murine HCC cells were responsive. Intrahepatic injection of Oncopig HCC cells resulted in tumors visible on ultrasound and CT scan within 2-4 weeks. Resulting tumors were consistent with human tumors on imaging. Histological analysis of tumor biopsies confirmed the identity of the resulting masses as HCC tumors based on positive arginase-1 and KRAS G12D staining. Conclusions: The Oncopig HCC model may be more predictive of human HCC chemotherapeutic responses than currently employed murine models. Tumors develop rapidly (within 2-4 weeks) and are readily identified on ultrasound and CT imaging, making this an ideal model for evaluation of novel therapeutic approaches. Further exploration and development of additional tumor models including further translational characterization will be important for broader utility.
Sensitizing K-Ras G12D mutant colorectal patient-derived organoids via ferroptosis pathway.
Authors: Dechokyab De, David Cohen, Yosuke Mitani, Tianxia Li, Casidhe-Nicole Bethancourt, Joel Gabre
Journal: Journal of Clinical Oncology (2025)

211 Background: Colorectal cancer remains the third most fatal form of cancer for males and females combined, with K-Ras mutations present in approximately 40% of all cases. These mutations drive cancer progression and confer resistance to conventional therapies, underscoring the need for novel treatment strategies. Ferroptosis, a regulated non-apoptotic form of cell death characterized as iron-dependent lipid peroxidation, has emerged as a target for cancer therapy. A study published in 2023 found that K-Ras mutant pancreatic ductal adenocarcinoma and non-small cell lung cancer cells lack ferroptosis induced lipid peroxidation and concurrently upregulated ferroptosis suppressing protein (FSP-1). It is unknown if K-Ras mutant colorectal tumors also evade ferroptosis-induced cell death as a method of cancer progression and therapy resistance. This study aims to measure the effects of inhibiting K-Ras G12D, the most common K-Ras mutation found in CRC, on ferroptosis through a patient derived colorectal cancer organoid (PDO) model. We hypothesize that blocking K-Ras G12D using a MRTX-1133, a K-Ras G12D specific inhibitor, can induce ferroptosis and synergistically work with ferroptosis inducers. Methods: As a pilot study, two patient derived organoid lines were established. Surveillance screening and whole exome sequencing was performed to verify K-Ras mutation. CRC9T has wild-type and CRC30T has mutant K-Ras. Additionally, Columbia Pathology Core confirmed tissues used to generate organoids were moderately differentiated colorectal adenocarcinoma. CTG-3D assays were performed to measure IC50 using ferroptosis inducers RSL3, iFSP, and K-Ras inhibitor MRTX-1133. Organoids were cultured in standard gut media for 72 hours, treated, and collected after 72 hours. After treatment, organoids were imaged and stained with BODIPY-C11, a lipid peroxidation fluorescence dye. Flow cytometry was performed, and results were analyzed using FlowJo to show ferroptosis-induced lipid peroxidation in stained organoids. Results: Inhibiting K-Ras G12D and inducing ferroptosis showed a synergistic effect on ferroptosis-induced lipid peroxidation. CRC9T was more sensitive (IC50 RLS3: 2.96 uM, iFSP 3.46 uM) to ferroptosis inducers than CRC30T (IC50: RSL3: 5.68 uM, iFSP: 8.6 uM). Blocking K-Ras in was only efficacious in CRC30T (IC50: MRTX1133: 9.73 uM). Cells from the mutant line showed greatest lipid peroxidation when combining ferroptosis inducers with K-Ras G12D inhibitors in flow cytometry analysis. Conclusions: These findings demonstrate a synergistic effect when blocking K-Ras G12D and inducing ferroptosis and align with previous studies that showed a connection between ferroptosis suppression and oncogenic KRAS expression. We plan to validate these findings in other patient derived organoid model systems and to assess the effects of pan-KRAS inhibition and ferroptosis inducer on non-K-Ras G12D PDOs.
MRI imaging and machine learning based radiomics for detection of mixed HCC and CCA tumors: Still a need for liver biopsy?
Authors: Yuquan Qian, Qiaoyuan Lu, Isaac Rodriguez, Michael Vácha, Xiangde Min, Muzaffer Reha Ümütlü, German A Castrillon, Andreas Schreyer, Michael Haimerl, Stefan O. Schoenberg, Matthias Philip Ebert, Abhinay Vellala, Carlos Romero Alaffita, Juan Alberto Garay Mora, Zhiqiang Guo, Jürgen Hesser, Christel Weiss, Matthias Froelich, Yingshi Sun, Andreas Teufel
Journal: Journal of Clinical Oncology (2025)

531 Background: Primary liver cancer (PLC), comprising hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is a leading cause of cancer mortality globally. The combined hepatocellular cholangiocarcinoma (cHCC-CC) subtype may be less common but is relevant to treatment efficacy. We therefore evaluated the diagnostic accuracy of various approaches in distinguishing these liver cancers. Methods: Patients diagnosed with HCC, CCA, and cHCC-CC at Beijing University Cancer Hospital and Institute, China were included. Radiologists of varying expertise independently assessed MRI scans, and we measured their diagnostic consistency. Radiomic features were extracted from MRI scans, and machine learning was applied to differentiate the cancer types. Results: Standard imaging was insufficient to reliably characterize cHCC-CC. Abdominal imaging experts (AIEs) had a higher mean sensitivity for HCC and CCA, 88% and 84% respectively, while non-experts (NIEs) had a lower sensitivity of 50% for HCC and 38% for CCA (HCC: p=0.03, CCA: p=0.008). Radiomic analysis found ‘Sphericity’ and ‘ClusterShade’ as the most relevant features. However, radiomics algorithms were also not sufficient to distinguish cHCC-CC from either HCC or CCA. Regarding sensitivity, the radiomic-based model was not better than radiologists for any of the three classes (p=0.065 for HCC, p=0.426 for CCA, and p=1.0 for cHCC-CC). The random forest algorithm yielded an accuracy of 76% in the test set, since it correctly classified most HCC and CCA, while only one quarter of cHCC-CC tumors. Conclusions: Until improved diagnostic tools are available, biopsy of liver cancer remains critical to the detection, diagnosis, and effective treatment of these cancers.