tbuckley/cabot-search huggingface dataset:
Valemetostat and trastuzumab deruxtecan (T-DXd) in previously treated advanced or metastatic human epidermal growth factor receptor 2 (HER2)-positive gastric cancer or gastro-esophageal junction (GEJ) adenocarcinoma.
Authors: Kohei Shitara, Peter C. Enzinger, Avani Mohapatra, Yelena Y. Janjigian
Journal: Journal of Clinical Oncology (2025)

TPS508 Background: Valemetostat tosylate (valemetostat), a novel and selective dual inhibitor of enhancer of zeste homolog (EZH)2 and EZH1, has demonstrated clinical efficacy and tolerability in multiple hematologic cancers (200 mg orally [PO] once daily [QD]). EZH2 inhibition by valemetostat is expected to upregulate DNA/RNA helicase Schlafen 11 expression and sensitize tumor cells to DNA damaging agents such as topoisomerase I inhibitor antibody–drug conjugates (ADCs). Topoisomerase inhibitors cause DNA strand breaks, which may synergize with valemetostat. HER2 gene amplification or protein expression has been associated with gastric cancer (GC) and GEJ adenocarcinoma. Patients with HER2+ locally advanced or metastatic gastric adenocarcinoma who progress after first line treatment have poor prognosis and limited therapeutic options. T-DXd is approved globally for HER2+ locally advanced or metastatic GC previously treated with a trastuzumab-based regimen. This study evaluates the clinical activity and safety of valemetostat in combination with T-DXd in patients with GC or GEJ adenocarcinoma as part of a Master Protocol trial evaluating valemetostat in combination with ADCs in solid tumors. Methods: This global, phase 1b, multicenter, open-label Master Protocol study (NCT06244485) will enroll ~ 70 patients per sub-protocol in multiple regions, including the US and Japan. The gastric cohort enrolls patients with previously treated advanced or metastatic HER2+ GC or GEJ adenocarcinoma. The dose-escalation (Part 1) will determine the recommended dose for expansion (RDE), combining valemetostat 50–200 mg PO QD with T-DXd 5.4 or 6.4 mg/kg intravenously every 3 weeks. The dose-expansion (Part 2) will assess the efficacy of valemetostat + T-DXd at the RDE. Primary endpoints include safety and tolerability in Part 1 and the objective response rate in Part 2. Secondary endpoints include response duration, progression-free and overall survival, pharmacokinetics, and HER2 expression by immunohistochemistry and in situ hybridization with clinical response. An interim futility analysis will be performed when 20 patients are enrolled with ≥ 6 months of follow-up. Clinical trial information: NCT06244485 .
The relationship between the tumor microenvironment of hepatocellular carcinoma and apparent diffusion coefficient.
Authors: Yuji Morine, Yu Saito, Shinichiro Yamada, Hiroki Teraoku, Katsuki Miyazaki, Tetsuya Ikemoto, Mitsuo Shimada
Journal: Journal of Clinical Oncology (2025)

616 Background: The tumor microenvironment is critical for the acquisition of tumor malignancy in various cancer types. The objectives of this study were to investigate whether the levels of cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) reflect the prognosis of patients with hepatocellular carcinoma (HCC) after hepatectomy (Hx) and to determine whether the apparent diffusion coefficient (ADC) from diffusion-weighted imaging (DWI) reflects CAF and TAM expression. Methods: The study cohort comprised 109 patients who underwent initial curative resection for HCC. Alpha smooth muscle actin (αSMA) was selected as a CAF marker and CD204 as a TAM marker. Protein expression was immunohistochemically evaluated in the intratumoral regions of resected specimens. Clinicopathological factors, including the long-term prognosis after Hx, were investigated between αSMA-negative and -positive tumors and between CD204-negative and -positive tumors. The correlation between CAF/TAM marker expression and the calculated minimum ADC using DWI was also evaluated. Results: αSMA-positive expression was correlated with tumor number, invasive growth pattern, and advanced stage. CD204-positive expression was correlated with the presence of venous invasion. Both αSMA-positive expression and CD204-positive expression were significant prognostic factors in the univariate analysis of overall survival and disease-free survival. αSMA/CD204 double positivity was associated with an extremely poor prognosis after Hx and was a significant independent prognostic factor for overall survival ( p =0.02, hazard ratio: 3.27). Patients with double positivity also showed a significantly higher ADC low rate (83%). Conclusions: Expression of both CAF and TAM markers reflected a poor prognosis after Hx. Furthermore, the preoperative ADC could be a clinical surrogate marker in the tumor microenvironment in patients with HCC.
More isn't always better: Expanding and refining prognostic methylation signatures for pancreatic ductal adenocarcinoma.
Authors: Deepak Sherpally, Sravan Jeepalyam, Harshitha Puram, Ashish Manne
Journal: Journal of Clinical Oncology (2025)

769 Background: In our previous study, we developed protein-informed methylation signatures from a chemoresistance gene panel (RGp, n=122) curated from the literature, identifying 28 signatures with strong prognostic value in The Cancer Genome Atlas (TCGA) pancreatic ductal adenocarcinoma (PDA) database. To enhance the clinical utility of this panel, we incorporated methylation changes from genes with known prognostic (PGp) and diagnostic (DGp) significance in PDA to form a composite gene panel (CGp-PDA) and repeated our analysis. We hypothesized that epigenetic changes in these genes reflect protein expression and that deriving signatures from them could help identify patients at risk of treatment failure. Methods: We assembled a composite gene panel (CGp-PDA) of 206 genes (122 RGp + 26 PGp + 82 DGp) through a literature review spanning from January 1970 to April 2024. These PGp and DGp genes are unique, as cell-free DNA methylation changes in them have established prognostic and diagnostic value, respectively in PDA. The same cohort of pancreatic ductal adenocarcinoma (PDA) patients (n=184) from our previous study was analyzed. We applied elastic net multivariate analysis to calculate survival outcomes and generated Kaplan-Meier plots using our gene panel, optimizing values for 𝛼 and λ over 100 iterations. Results: Our analysis identified 20 signatures with cytosines followed by a guanine residue (CpG) site in genes from our panel. The number of CpG sites in these signatures ranged from 3 to 4248. The most effective signature featured 17 CpG sites (22 months [m] vs. 67m, p=0.03), followed by signatures with 3 (16m vs. 49m, p=0.009) and 12 (17m vs. 36m, p=0.02) CpG sites. The 4248 CpG site signature demonstrated the poorest prognostic value among the signatures (17m vs. 21m, p=0.01). Some signatures included multiple CpG sites within a single gene. Notably, KCNH2 reappeared in several signatures, as in the prior study. Expanding our RGp to CGp-PDA did not produce more (20 vs. 28) signatures or improved prognostic value. Conclusions: Targeted methylation signatures, supported by robust preclinical or translational evidence of their impact on treatment resistance, can be clinically valuable for informing treatment selection and prognosis. We may need to shift our focus from machine learning-based broad methylation or transcriptomic analyses to more targeted investigations.
Demographic predictors of multi-target stool DNA test completion in an underserved primary care population: A retrospective analysis.
Authors: Arup Ganguly, Ruchir Paladiya, Cunegundo Vergara
Journal: Journal of Clinical Oncology (2025)

30 Background: Colorectal cancer screening remains crucial for early detection, with multi-target stool DNA(Exact Sciences, Madison, WI, USA) serving as a non-invasive option. However, adherence to test completion may vary across different demographic groups. This study aims to assess the association between patient demographics and the completion of Cologuard testing in an underserved primary care population in order to further explore the disparities that exist. Methods: We conducted a retrospective analysis of 12071 eligible patients, aged 45-75, across Hartford Healthcare Primary Care Clinics across Connecticut, USA, between November 2022 and April 2024 for whom an order for this test was placed. Demographic data including gender, age, English proficiency, and insurance status(public/private vs no insurance) were analyzed. The outcome of interest was whether patients had results available within 120 days of placing the order. Logistic regression was used to examine the relationship between these variables and the likelihood of Cologuard test completion. Results: 11704(96.9%) of all patients were insured. Among insured patients, 6945 (59.9%) had results available, while 4759 (41.1%) did not have results at the 120 day mark. Among uninsured patients, 46 (12.5%) had results, while 321 (87.5%) did not. Insured patients were more likely to have test results available compared to uninsured patients (OR = 10.184, 95% CI: 7.460-13.901, p &lt; 0.01). 10977(90.9%) patients were English proficient. They were more likely to have results compared to Non-English proficient patients (OR = 3.474, 95% CI: 3.038-3.972, p &lt; 0.01). Gender was not a significant predictor of test completion (OR = 0.964, 95%CI: 0.895-1.039, p = 0.341), and older age demonstrated a small, non-significant effect (OR = 1.004, p = 0.094), with a test for non-linearity confirming a linear relationship between age and test completion (p = 0.162). Conclusions: Insured status and English proficiency are significant predictors of Cologuard test completion in this primary care cohort and are more likely complete testing. These findings underscore the need for targeted interventions to increase colorectal cancer screening adherence, particularly among this population.
Bragg peak proton irradiation and ATM inhibition for rectal cancer.
Authors: Cameron Matthew Callaghan, Sonja Dragojevic
Journal: Journal of Clinical Oncology (2025)

259 Background: Rectal cancer patients with a complete response (CR) after chemotherapy and radiotherapy may opt for non-operative management. Currently only 20-40% of patients reach a CR. Escalating the dose of radiation may increase the risk of toxicity. ATM inhibitors (ATMi) are potent radiosensitizers in colorectal cancer (CRC). Proton irradiation exhibits an entrance portion of the beam (ENT) where dose is deposited sparsely and a Bragg Peak (BP) with virtually no ‘exit dose’ thereafter. ATMi renders cells uniquely hypersensitive to proton BP, and BP+ATMi may increase the response of Mismatch Repair proficient (pMMR) rectal cancer to immunotherapy. Methods: Tumor efficacy and immunogenicity was assessed using clonogenic survival, γH2AX foci, micronuclei, and cytoplasmic cGas assays after indicated IR modalities +/-ATMi. Normal tissue toxicity was assessed via murine models of non-tumor bearing BALB/c after whole-abdominal irradiation (WAI) after indicated IR modalities +/- ATMi via acute weight loss, FITC/Dextran assay, and Radiation Injury Score (RIS, Scale 0-18) in jejunal and rectal samples at 4 days post-IR. Results: ATMi decreased clonogenic survival across all types of radiation, but the effect was most pronounced with BP protons. BP+ATMi also significantly increased unresolved γH2AX foci, micronuclei, and cytoplasmic cGas compared to ENT+ATMi. Normal tissue toxicity studies demonstrated that BP+ATMi did not significantly increase acute weight loss, RIS in jejunal or rectal tissue; but did increase FITC/Dextran intestinal permeability. Conclusions: Inhibition of ATM preferentially radiosensitized BP protons compared to x-rays or ENT protons in CRC but not in normal tissue based on weight loss and histopathological evaluation. Differential tumor efficacy and normal tissue toxicity after x-ray, entrance and Bragg Peak Protons +/- ATM inhibitor. A B C D E F G H I J DMSO 1 1 1 2.9 1.5 8764 96.4 10 0.3 0.2 ATMi 0.873 0.842 0.723 8.2 3.0 16300 98.5 5.8 0.7 0.8 x-ray 0.615 0.751 0.109 82.4 6.2 4.8 1.0 x-ray+ATMi 0.123 0.344 0.011 80.0 14.4 5.2 1.5 ENT protons 0.293 0.515 0.080 10.2 5.8 10429 78.5 6 2.9 1.5 ENT+ATMi 0.091 0.066 0.013 15.1 7.2 12274 73.0 23.8 5.2 3.8 BP protons 0.213 0.340 0.032 12.0 12.6 7192 75.6 24.6 4.1 3.7 BP+ATMi 0.074 0.038 0.004 22.7 16.2 43677 73.6 310.4 5.3 4.3 Clonogenic survival of pMMR colorectal cancer cell lines after IR (4 Gy) +/- 10nM AZD1390 (ATM inhibitor) ofA) HT29, B) CT26, and C) SW480 cell lines. D) γH2AX foci at 24 hours post-IR in HT29. E) Micronuclei, and F) cytoplasmic cGas integrated density per cell via immunofluorescence in SW480 72 hours post-IR. WAI (10Gy/1 fraction) was delivered to non-tumor bearing BALB/c mice which were followed for G) acute weight loss (% from baseline), and H) FITC/Dextran permeability assay. Tissue samples were graded for Radiation Injury Score in I) jejunal, and J) rectal samples at 4 days post-IR (n=5 per cohort, 3 samples per mouse). Figures are means of triplicate data.
Optimal preoperative treatment strategy for conversion surgery in unresectable locally advanced pancreatic cancer: A project study by the Japanese Society of Hepato-Biliary-Pancreatic Surgery.
Authors: Satoshi Yasuda, Sohei Satoi, Hideki Takami, Satoshi Hirano, Hirofumi Akita, Yu Takahahshi, Ippei Matsumoto, Michiaki Unno, Riki Ninomiya, Manabu Kawai, Yuichi Nagakwa, Teiichi Sugiura, Naoto Yamamoto, Minako Nagai, Kenichiro Uemura, Masafumi Imamura, Naoki Ozu, Masafumi Nakamura, Masayuki Ohtsuka, Masayuki Sho
Journal: Journal of Clinical Oncology (2025)

718 Background: Conversion surgery (CS) for unresectable locally advanced pancreatic cancer (UR-LAPC) has been widely accepted when feasible. However, optimal preoperative treatment strategies remain unclear. To determine the most effective preoperative approach for UR-LAPC in the current treatment landscape, we conducted a project study in the Japanese Society of Hepato-Biliary-Pancreatic Surgery. Methods: We analyzed 465 UR-LAPC patients who underwent CS following chemotherapy with FOLFIRINOX (FFX), gemcitabine plus nab-paclitaxel (GnP), or modified regimens between 2015 and 2020 across 84 Japanese board-certified training institutions. Overall survival (OS) was the primary endpoint. We used the Kaplan-Meier method for estimating survival analyses, the Cox proportional hazards model for multivariate analyses, and Maximally Selected Rank Statistics to determine the optimal preoperative treatment duration. Results: Median OS was 43.8 months, with a 5-year survival rate of 37.2%. The optimal preoperative treatment duration was 6.1 months. Patients receiving &gt;6 months of preoperative treatment (n=350) showed significantly better median OS and recurrence-free survival (RFS) compared to ≤6 months (n=115) (50.4 vs 29.7 months and 15.6 vs 9.1 months, respectively; both P&lt;0.001 ). FFX-based regimens (n=116) showed better OS and RFS than GnP-based regimens (n=349) (65.0 vs 36.5 months and 19.3 vs 12.4 months, respectively; both P&lt;0.01 ). Multivariate analysis identified preoperative treatment &gt;6 months (HR 0.53, 95% CI 0.407-0.697, P&lt;0.001 ) and initial FFX-based regimens (HR 0.63, 95% CI 0.464-0.843, P=0.002 ) as independent prognostic factors. Additional favorable factors included normal CA19-9 and CEA levels, PNI&gt;45 before CS, adjuvant chemotherapy, R0 resection, and Evans grade III/IV. Conclusions: This large-scale retrospective study has demonstrated that preoperative treatment duration &gt;6 months and the use of FFX-based regimens as initial treatment were associated with improved survival outcomes in UR-LAPC patients undergoing CS. These findings provide critical information for considering CS in UR-LAPC patients, especially in current clinical practice.
Rate of gene fusion/rearrangement identification in GI cancers as sequencing evolved from limited panels to whole exome sequencing.
Authors: Hilary Chan, Sachdev P. Thomas, Chen Jiang, Elaine Chung, Amit Arora, Grace Li, Laurel A. Habel
Journal: Journal of Clinical Oncology (2025)

809 Background: Gene fusion/rearrangements occur at a frequency of 0-15% in GI system cancers. Detection and treatment of fusion genes such as NTRK, FGFR2, NRG1 and RET fusions are included in NCCN guidelines and are commonly detected using next generation sequencing (NGS). NGS panels have continued to expand over time, which should result in increases in the identification of gene fusions. The aims of this study were to describe the percent of patients with advanced GI tumors undergoing NGS with identified gene rearrangements across time as panels expanded. Methods: The study included 7237 patients in the Kaiser Permanente Northern California Integrated Health System receiving care for advanced GI cancers from 2017 to Aug 2024, whose tumors samples were evaluated using NGS (Stomach=926, Colorectal=2792, Gallbladder=569, Esophagus=761, liver=218, Pancreas=1971). Results: A total of 231 patients (3.2%) were identified with a gene rearrangement, including 4.6% in stomach(N=43), 2.8% in colorectal(N=78), 8.9% in gallbladder(N=24), 5.3% in esophagus(N=40), and 1.9% in pancreatic (N=38 ). Rearrangements included NTRK1/2/3, FGFR2/3, NRG, ALK, ROS, CLDN18-ARHGAP, RSPO2/3, DNAJB1-PRKACA, BRAF, MET and RET. The numbers per year were (see table). Conclusions: The use of more comprehensive NGS panels such as WES did not appear to increase the detection rate for fusion/rearrangements. In resource limited settings, limited panels may suffice. The number of GI cancer patients getting NGS testing has increased over time. Gene rearrangements/fusions identified per year. YEAR 2018 2019 2020 2021 2022 2023 2024 (Jan – Aug) Gene Rearrangement identified 29 37 43 55 54 62 38 TOTAL GI Cancer Samples Sequenced 610 858 900 1047 1249 1181 785 Percentage 4.75% 4.31% 4.78% 5.25% 4.32% 5.25% 4.84%
Short-course radiation(SCRT) followed by 6 cycles of cadonilimab plus mFOLFOX6 as neoadjuvant therapy for patients with locally advanced rectal cancer (LARC): A multicenter, single arm, phase II trial (NeoCaCRT).
Authors: Wan He, Jun Huang, Guixiang Liao, Wenwen Li, Jing Shen, Yuxiang Fu, Na Tang, Fang He, Yandong Zhao, Zhimin Liu, Lishuo Shi, Fengyun Pei, Qijun Yao, Xiaoling Zhong, Keli Zhong
Journal: Journal of Clinical Oncology (2025)

LBA210 Background: Preoperative chemoradiotherapy (CRT) followed by total mesorectal excision (TME) is recommended for mismatch repair-proficient (pMMR) or microsatellite stability(MSS) LARC. Recent studies have shown that anti-PD-1/PD-L1 in combination with CRT can improve pathological complete response (pCR) compared to CRT in the neoadjuvant setting. This trial aims to investigate the efficacy and safety of SCRT followed by cadonilimab, a first-in-class anti-PD-1/CTLA-4 bispecific antibody, plus mFOLFOX6 in patients (pts) with LARC. Methods: Eligible pts aged 18-79 years with pMMR/MSS, nonmetastatic, stage cT3-4N0 or cT1-4N1-2 rectal adenocarcinoma located below the peritoneal reflection were enrolled and given SCRT (25Gy/5F) followed by 6 cycles of cadonilimab (6mg/kg, q2w) plus mFOLFOX6. The primary endpoint was pCR. Secondary endpoints included clinical complete response (cCR), major pathological response (MPR), disease-free survival (DFS), overall survival (OS), safety and quality of life. The exploratory endpoint explored potential biomarkers related to response. Results: From April 2023 to May 2024, 27 pts were enrolled and received at least 1 dose of treatment. As of data cutoff date of October 20, 2024,median follow-up was 9.7 months (IQR 5.4–18·8)，and all pts received study treatment, and 24/27(88.9%) underwent R0 resections (one delayed surgery due to chemotherapy-related pneumonia, while the other two were assessed unresectable). The primary endpoint was met with a pCR of 37%(10/27)(95% CI, 19.4%–57.6%) and MPR of 55.6%. A cCR of 22.2%(6/27) was observed, and among them, 83.3%(5/6) still received local excisions. The T downstaging was observed in 59.3%(16/27) while N downstaging in 66.7%(18/27). Grade 3–5 adverse events occurred in 5 (18.5%) of 27 pts; the most common were diarrhea (ten [37%]),nausea (ten [37%]) and fatigue (ten [37%]), and neutropenia (seven [26%]). Drug-related serious adverse events occurred in eight (30%) of 27 patients. No new safety signal was identified. Conclusions: In pts with pMMR/MSS LARC, neoadjuvant SCRT with cadonilimab plus mFOLFOX6 resulted in promising pCR rates with intolerable toxicities. Follow up continues. These data deserve further investigations in a phase III randomized trial. Clinical trial information: NCT05792735 .
An exploratory phase II trial of low-dose decitabine and sintilimab combined with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma.
Authors: Yunyi Du, Xiaoling Zhang, Ning Ma, Wei Yang, Bo Yang, Fei Su, Liang Zong, Wenqing Hu, Jun Zhao
Journal: Journal of Clinical Oncology (2025)

390 Background: Combining epigenetic modulator with PD-1 inhibitor may enhance treatment outcomes in cancer patients. This study aimed to evaluate the efficacy and safety of epigenetic drug decitabine, sintilimab (a PD-1 inhibitor), and chemotherapy in gastric cancer. Methods: In this single-arm, exploratory phase II trial, patients with HER2-negative, locally advanced or metastatic gastric or gastroesophageal junction (G/GEJ) adenocarcinoma were enrolled between August 12, 2021, and October 22, 2022. Treatment included low-dose decitabine (10 mg/m² for 5 days), sintilimab (a PD1 inhibitor, 200 mg every 21 days), and XELOX. The primary endpoint was objective response rate (ORR) and second endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and safety. The protocol was approved by the ethics committee of the Changzhi Medical College Affiliated Changzhi People's Hospital (No. 2021K002). All patients provided written informed consent form before study participation. The trial is registered with Chinese Clinical Trial, number ChiCTR2100043312. Results: Sixteen patients were initially enrolled, with a median follow-up of 14.8 months. Eleven patients exhibited a PD-L1 combined positive score (CPS) &lt; 5. In the per-protocol sets, 11 patients remained eligible for efficacy analysis. In the intention-to-treat analysis of all 16 patients, 9 achieved partial response and 2 had stable disease, resulting in an ORR of 69% and a DCR of 56%. As of the data cutoff on November 4, 2023, the median PFS was 11.1 months (95% CI, 5.1-not reached) and the median OS was 13.2 months (95% CI, 5.1-not reached). Treatment-related adverse events were generally well-tolerated, with most being grade 1-2. Three patients experienced severe AEs, including one fatal case of grade 4 immune-related pneumonia. Conclusions: The combination of low-dose decitabine, sintilimab, and chemotherapy appears promising strategy for locally advanced or metastatic G/GEJ adenocarcinoma, especially in patients with negative HER2 and low PD-L1 expression. These preliminary findings support further investigations to confirm the benefits and explore the underlying mechanisms. Clinical trial information: ChiCTR2100043312. Objective response and disease response. Full analysis set (n=16) Efficacy analysis set (n=11) Complete response 0 0 Partial response 9 9 Stable disease 2 2 Progressive disease 0 0 Non-evaluable* 5 NA Objective response 9 (56%) 9 (81.8%) Disease control 11 (69%) 11 (100%) NA=not applicable. *Included patients without any post-baseline response assessment.