tbuckley/cabot-search huggingface dataset:
Phase II study of olaparib in patients with advanced pancreatic acinar cell carcinoma.
Authors: Nebojsa Skorupan, Efsun Arda, Serguei Kozlov, Christine Campo Alewine
Journal: Journal of Clinical Oncology (2025)

TPS789 Background: Pancreatic Acinar Cell Carcinoma (PACC) is a rare and biologically distinct subtype of pancreatic cancer, representing 0.5-1% of all pancreatic malignancies, with a median overall survival of 15-20 months. Significant serum CA 19-9 elevation is uncommon, while elevation of serum lipase is observed in at least 50% of patients. Most patients present at advanced stages and treatment with combination chemotherapies extrapolated from other GI malignancies leads to low response rates. No clinical treatment trials specific for PACC have ever been reported. PACC tumors from patients show evidence of high chromosomal instability, a hallmark of DNA repair deficiency. ID3 is ubiquitously downregulated and was recently shown to play a significant role in homologous recombination repair (HRR). Recent genomic profiling of larger PACC patient cohorts has revealed a high prevalence of mutations in HRR genes, including BRCA1, BRCA2, and PALB2. Olaparib is a Poly-ADP ribose polymerase (PARP)-1 inhibitor that has been FDA approved for treatment of BRCA-mutant HRR deficient cancers. We hypothesize that PACC will be sensitive to PARP inhibition with olaparib. Methods: This is an open label, single arm, single center, phase II study of olaparib in patients with advanced previously treated PACC. The primary objective of the trial is to evaluate anti-tumor activity of olaparib (objective response rate). Secondary objectives assess the safety (CTCAE v. 5.0) and alternative measures of efficacy such as clinical outcomes and blood biomarkers (disease control rate, median progression-free survival, median overall survival, best response in serum lipase). Key eligibility criteria include histologic diagnosis of PACC, receipt of at least one line of combination chemotherapy, presence of RECIST measurable disease and adequate organ and bone marrow function. A fixed dose of olaparib at 300 mg will be given orally continuously twice daily during a 28-day cycle, for up to 2 years or until disease progression or intolerable toxicities. In person visits to assess toxicity are required every 4 weeks, and response is determined through serial imaging every 8 weeks (CT or MRI). Exploratory objectives include acquisition of tumor tissue for establishment of new PACC preclinical models, assessment of genetic alterations through genetic mapping technique, assessment of HRR-related gene products as a predictive biomarker, assessment of ID3 protein levels, and assessment of treatment response to tumor profile. Up to 13 evaluable participants will be enrolled. Three participants have been enrolled as of Sep 19, 2024. Clinical trial information: NCT05286827 .
Trends in early onset colorectal cancer–related mortality among adults in the United States from 1999-2020.
Authors: Yousaf Zafar, Adnan Zafar, Arsalan Zafar Iqbal, Marryum Rizwan, Laila Manzoor
Journal: Journal of Clinical Oncology (2025)

42 Background: Colorectal cancer (CRC) has witnessed a decrease in incidence and mortality in the United States (US) for the past few decades likely due to increased screening and improvements in treatment . Despite the overall burden of CRC has declined and survival has been made for older adults, there is a simultaneous and alarming increase in CRCs diagnosed in individuals younger than 50 years of age. These Early Onset CRC (EOCRC) which now account for roughly 10% of new CRC cases in the US. The purpose of this study was to assess the trends and regional differences in EOCRC-related mortality among adults in the United States. Methods: Death certificates from the CDC WONDER (Centers for Disease Control and Prevention Wide-Ranging OnLine Data for Epidemiologic Research) database were examined from 1999 to 2020 for -related mortality in adults &lt;45 years of age. Age-adjusted mortality rates (AAMRs) per 10,000 persons and annual percent change (APC) were calculated and stratified by year, sex, race/ethnicity, and geographic region. Results: Between 1999 and 2020, 32,850 EOCRC-related deaths occurred among adults 25-44 years. The AAMR increased from 2.1 in 1999 to 2.6 in 2020. Men had consistently higher AAMR than women from 1999 (AAMR men: 2.0 vs women: 1.6) to 2020 (AAMR men: 2.6 vs women: 2.0). Non Hispanic (NH) African Americans had the highest overall AAMR (3.1), followed NH White (2.2), NH Asians (1.6) and Hispanics (AAMR 1.5) Caucasians have had a significant increase in mortality over the past 2 decades ( APC 1.4 (95%Cl 1.1-.7)) whereas the Hispanics have shown an APC of 4 (95% Cl 2.3-5.8 from 2012-2020). AAMR also varied substantially by region (overall AAMR: Midwest 2.1; South: 2.4; West: 1.9; Northeast: 2.0). States in the top 90th percentile of EOCRC-related AAMR were Mississippi, Arkansas, Oklahoma, South Carolina, Alabama West Virginia, Louisiana ,Kentucky and Tennessee which had approximately double the AAMRs compared with states that fell into the lower 10th percentile. Conclusions: EOCRC-related mortality in U.S. adults has been steadily increasing over the past two decades . The highest AAMRs were observed among African American adults and men, and among patients living in the Southern , Midwestern regions and those living in the nonmetropolitan United States. Targeted strategies are needed to prevent and treat EOCRC among older adults to curb increasing levels of EOCRC-related mortality.
Prognosis of signet ring cell (SRC) gastric carcinoma (GC) compared with other histological subtypes.
Authors: Rafael Torosian, Sergey Nered, Nikolay Kozlov, Henian Sun, Pavel Kononets, Ivan Stilidi
Journal: Journal of Clinical Oncology (2025)

357 Background: Signet ring cell (SRC) gastric cancer (GC) has its unique clinicopathological features with poor tissue differentiation, high invasiveness, diffuse growth pattern and poor prognosis. Survival rates and clinicopathological characteristics of patients with SRC GC regardless of the stage of the disease has not been well studied. Methods: The retrospective analysis was undertaken of 993 patients with diagnosed gastric cancer. These patients received surgical resection in period from January 2013 to December 2018 in N.N. Blokhin National Medical Research Center of Oncology. We compared clinical and pathological features as well as prognostic factors between these groups. Results: For early SRC carcinoma, the median survival rates weren’t reached; 3- and 5-year survival rates were 100% and 89.0 %; for non-SRC carcinoma 91.4 and 85.3 % (HR=0.73; 95 % CI 0.22–2.42, р = 0.6) respectively. For locally advanced/metastatic SRC carcinoma, the median survival rates, 3- and 5-year survival rates were 38 months, 53.0 and 38.4 %; for non-SRC carcinoma 51.1 months, 59.2 and 48.0 % (HR=1.2; 95 % CI 0.91–1.54, р = 0.2). At univariate analysis SRC morphology was found as independent risk factor for overall survival (HR=1.19; CI 95% 0.94 – 1.50; p&lt;0.0001). Multivariate analysis did not reveal SRC morphology to be significant and independent risk factor for overall survival (HR=1.00; CI 95% 0.72 – 1.38; p=0.98). Conclusions: Overall survival rates in patients with early (mucosal and submucosal tumor regardless of lymph nodes status) SRC gastric cancer did not show any significant differences in comparison with other histological types of GC. Thus, the prognosis of early SRC GC is equivalent or better than that of other histological subtypes of GC. Overall survival rates of locally advanced/metastatic SRC gastric cancer are worse than non-SRC cancer, but the differences are not statistically significant.
A phase I, single-center, open label, dose de-escalation and expansion study of Ivosidenib + mFOLFIRINOX in patients with resectable pancreatic adenocarcinoma.
Authors: Ho Jun Lee, Lauren E. Henke, Jennifer Anne Dorth, Melissa Amy Lumish, Madison Conces, AMR Mohamed, Sakti Chakrabarti, Amit Mahipal, J. Eva Selfridge, John Brian Ammori, Jeffrey Hardacre, Jordan Michael Winter, David L. Bajor
Journal: Journal of Clinical Oncology (2025)

TPS794 Background: Pancreatic ductal adenocarcinoma (PDA) carries a dismal prognosis, with a 34% 5-year survival rate for patients with localized disease. Guidelines recommend consideration of neoadjuvant approaches in localized PDA with the goals of controlling microscopic metastatic disease and increasing rates of microscopically margin-negative resections. One of the hallmark characteristics of PDA is a micronutrient poor, highly stromal microenvironment. Surviving in this environment requires enhanced mitochondrial function, which utilizes isocitrate dehydrogenase 1 (IDH1). In pre-clinical studies, ivosidenib, an FDA approved medication for IDH1 mutant AML, induced high levels of reactive oxygen species in PDA cells with wild-type IDH1, and caused tumor regressions and extended survival in implanted KPC mouse models. Here, we investigate the addition of ivosidenib to standard of care neoadjuvant mFOLFIRINOX in patients with resectable PDA to determine safety, pharmacodynamics, and early efficacy signals. Methods: This is a phase I, single-center, open label, dose de-escalation and expansion study in patients with resectable PDA. Eligible patients must have histologically confirmed and resectable right-sided PDA based on CT or MRI imaging. Patients receive approximately 10 weeks of neoadjuvant treatment composed of 2 weeks of ivosidenib monotherapy, followed by 6 weeks (3 cycles) of mFOLFIRINOX with ivosidenib, followed by up to 4 weeks of ivosidenib monotherapy until the day of surgery. Ivosidenib is administered once daily at 500mg; it is to be de-escalated to 250mg based on Bayesian Optimal Interval Design with Informative Prior and a target dose limiting toxicity (DLT) rate of 30%. The primary endpoint is to determine the safety and tolerability of ivosidenib in combination with mFOLFIRINOX. Secondary endpoints include RECIST version 1.1 response rates, major pathologic response rates, and biochemical (CA19-9, CEA) response rates. Correlative studies will be performed on surgical samples to evaluate metabolomic profiles. At the time of submission, 10 out of 16 planned patients have been enrolled. There have been no DLT at 500mg of ivosidenib. Clinical trial information: NCT05209074 .
Phase 1/2 study of the HER3-directed antibody-drug conjugate patritumab deruxtecan (MK-1022) as monotherapy in patients with gastrointestinal cancers.
Authors: Do-Youn Oh, Tae Won Kim, Ariel Aguilo, Naimin Jing, Rishi Jain, David E. Adelberg, Michael J. Pishvaian
Journal: Journal of Clinical Oncology (2025)

TPS321 Background: A significant medical need exists for more effective and tolerable therapeutic options for patients with advanced gastrointestinal cancers (colorectal cancer [CRC], biliary tract cancer [BTC], and hepatocellular carcinoma [HCC]). Human epidermal growth factor receptor (HER3) expression is high in CRC and BTC, and low-to-intermediate in HCC. Patritumab deruxtecan (HER3-DXd; U3-1402/MK-1022) is a HER3-directed antibody-drug conjugate (ADC) comprising a fully human anti-HER3 immunoglobulin G1 monoclonal antibody (patritumab), which includes a plasma-stable, selectively cleavable linker, and a potent topoisomerase I inhibitor payload (DXd; released payload) that leverages the clinically validated deruxtecan (a derivative of exatecan) technology. DXd is cell membrane permeable and enables a bystander antitumor effect after DXd ADC internalization and linker cleavage, resulting in elimination of both target and neighboring tumor cells. Patritumab deruxtecan has shown antitumor activity in phase 1 and 2 studies of EGFR-mutated advanced non–small cell lung cancer and advanced breast cancer and in preclinical studies of CRC. This nonrandomized, open-label, phase 1/2 study (NCT06596694) will examine the safety and efficacy of patritumab deruxtecan in select gastrointestinal cancers. Methods: Approximately 130 adults (aged ≥18 years) will be allocated to 1 of 3 cohorts based on their disease. Patients in cohort 1 (CRC; n = 40) must have previously treated unresectable or metastatic colorectal adenocarcinoma. Patients in cohort 2 (BTC; n = 40) must have previously treated locally advanced or metastatic BTC. Patients in cohort 3 (HCC; n ≤50) must have previously treated advanced HCC. Prior topoisomerase I inhibitor therapy is not allowed. Patients in cohorts 1 and 2 will receive patritumab deruxtecan intravenously (IV) as monotherapy. Cohort 3 includes a dose-escalation phase to determine the recommended phase 2 dose of patritumab deruxtecan monotherapy and an efficacy phase. In the efficacy phase, patients will receive the recommended phase 2 dose of patritumab deruxtecan. The primary objectives are to evaluate safety and tolerability of patritumab deruxtecan and to evaluate the confirmed objective response rate per RECIST v1.1 assessed by blinded independent central review (BICR) for each cohort. Secondary objectives are to evaluate duration of response and progression-free survival per RECIST v1.1 by BICR and overall survival, and to characterize the pharmacokinetics of patritumab deruxtecan. Clinical trial information: NCT06596694 .
Spatially resolved protein profiling in pancreatic adenosquamous carcinoma.
Authors: Adel Kardosh, Rosalie C. Sears, Zheng Xia, Eizabaru M Sasatomi, Brian Mau, Jonathan R Brody, Melissa Wong, Charles D. Lopez, Emerson Yu-sheng Chen, Guillaume Joe Pegna, Cristiane M Franca, John Muschler, Joanna Pucilowska, Shaun M. Goodyear
Journal: Journal of Clinical Oncology (2025)

760 Background: Pancreatic adenosquamous carcinoma (PASC) is a rare histopathological type of pancreatic cancer that is more aggressive than pancreatic ductal adenocarcinoma (PDAC). Although PASC has a unique tumor biology and poorer prognosis, there are no guidelines for differentially treating PASC patients, and its rarity makes it significantly understudied. We used Nanostring GeoMX digital spatial profiling (DSP) to provide a targeted proteomic characterization of key tumor-promoting proteins in PASC and PDAC. Methods: FFPE tissue from PASC (n=10 primary, n= 4 met) and PDAC (n=21 primary, n=5 met) cases were analyzed using the DSP platform. Sections were stained with an 82-protein cocktail of antibodies conjugated to UV-photocleavable DNA barcodes. A pan-cytokeratin morphology marker was used to select tumor regions of interest (ROI) and inferred surrounding stromal (i.e., pan-CK negative) ROIs. UV excitation of the defined ROIs was used to release the DNA barcodes and were quantified on the NanoString nCounter system. For PASC, squamous enriched ROI were inferred from corresponding p40 IHC. Corresponding clinical and mutational status for all cases were abstracted from medical records. Results: TP53 (PDAC, 80%; PASC, 83%) and KRAS (PDAC, 76%; PASC, 100%) were the most prevalent mutations . In comparing the tumor ROIs of PASC and PDAC (all cases), DSP-assessed global expression and activation of EGFR-MAPK signaling is significantly increased in PASC, whereas PI3K-AKT signaling is significantly decreased. Compared to PDAC, EGFR expression and phosphorylation (p-EGFR), as well as p-MEK1, are significantly increased in PASC. PASC showed significantly lower levels of PLCG1 and INPP4B, while the majority of other AKT signaling effectors were unchanged. For DNA damage response signaling, PASC showed significantly higher levels of p-ATM, p-CHK2, and p21, but not p-ATR. Likewise, expression of oncoproteins c-MYC and BCL6 were significantly increased in PASC (vs. PDAC). Conclusions: Given that the normal pancreas lacks squamous cells, their histological presence is a uniquely aberrant feature that can be used to guide deep spatially-resolved interrogation of complex cellular and molecular programs. Our preliminary findings show that regions of squamous cell differentiation within PASC have intrinsically higher levels of active EGFR signaling. With emerging RAS-targeted agents poised to alter the treatment landscape, high EGFR signaling in PASC suggest a possible compensatory resistance mechanism that may require additional targeting. Likewise, reliance on ATM signaling highlights this as preferential target for DDR-directed therapies. Building on these results with additional multiomic assays will inform strategies for improving the management of patients with PASC.
Clinical and genomic features of the morphological subtypes in advanced pancreatic cancer.
Authors: Eugenia Flores-Figueroa, Yuanchang Fang, Maryam Monajemzadeh, Ayah Elqaderi, Tom Ouellette, Amy Zhang, Gun Ho Jang, Karen Ng, Milena Gallucci, Zhen-Mei Liu, Nikolina Radulovich, Nhu An Pham, Anna Dodd, Julie Wilson, Erica S Tsang, Steven Gallinger, Jennifer J. Knox, Grainne M. O'Kane, Faiyaz Notta, Robert C Grant
Journal: Journal of Clinical Oncology (2025)

765 Background: In resected pancreatic cancer (PDA), morphology from routine histopathology slides provides a rapid inexpensive biomarker that predicts overall survival and correlates with transcriptomic subtypes. In this study, we evaluated clinical and genomic associations of morphological subtypes in resected and advanced disease and validated the consistency of subtypes in patient-derived organoids (PDO) and mouse xenografts (PDXs) during in vitro and in vivo modeling. Methods: Our cohort included PDA tumor tissues from 152 resectable (stage I/II) and 228 advanced cases (Stage III/IV). Hematoxylin and eosin-stained slides were blindly reviewed by two pathologists and classified into subtypes based on Kalimuthu (1). Morphological subtypes were correlated with clinical and genomic data from whole-genome and transcriptome sequencing. Histological preparations from PDOs and PDXs obtained from pancreatic resections and metastases were reviewed using the same criteria. Results: Morphological subtypes were significantly associated with clinical patterns. Locally advanced PDA exhibited the highest proportion of glandular tumors. Metastatic tumors were enriched for non-glandular morphologies. The non-glandular morphologies were significantly associated with lower survival rates in both resected and advanced tumors. Furthermore, morphological subtypes were significantly associated with unique genomic alterations. Compared to glandular tumors, non-glandular tumors were associated with increased KRAS copy number, KRAS imbalances, and polyploid genomes. In advanced settings, glandular and non-glandular tumors mostly exhibited classical and basal-like transcriptional subtypes, respectively. Squamous tumors had the highest mutation burden and the highest proportion of Basal A signature (2). Using differential gene expression, we identified transcriptional signatures of the morphological subtypes. PDOs and PDXs maintained the morphological subtypes, although non-glandular tumors had a lower success rate for PDO establishment. Conclusions: Morphological subtypes have distinct clinical and genomic associations across all stages of pancreatic cancer, which can be consistently modeled both in vitro and in vivo . These results demonstrate that morphological subtyping offers a rapid and biologically-relevant classification of PDA that could be used for drug development and stratification to predict therapy selection. 1. Gut; 69:317-328 (2020). 2. Nat Gen; 52:231-240 (2020).
Meta-analysis of randomized controlled trials (RCTs) to evaluate the incidence of hemorrhage and venous thromboembolism (VTE) events in patients with gastrointestinal (GI) cancers treated with fruquintinib.
Authors: Daniel Thomas Jones, Hazem Aboaid, Rishi Kumar Nanda, Ramaditya Srinivasmurthy, Kevin Nguyen, Jason Ta, Kyaw Zin Thein
Journal: Journal of Clinical Oncology (2025)

118 Background: Fruquintinib is a novel cancer therapy that was recently approved by the US FDA as a third-line treatment for metastatic colorectal cancer (mCRC). It works by inhibiting the vascular endothelial growth factor receptors, that leads to blocking of angiogenesis which is essential for the tumor proliferation. Close monitoring is always crucial in order to promptly detect and manage any adverse events. This study aims to assess the risk of hemorrhagic and VTE events in patients with GI cancers treated with fruquintinib. Methods: A comprehensive literature search was conducted using MEDLINE, EMBASE, and COCHRANE databases from inception through August 12th, 2024. Phase II/III RCTs utilizing fruquintinib in GI cancers reporting hemorrhage or VTE events as an adverse event were included. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran’s Q-statistic. Random effects model was applied. Results: A total of 1872 patients were included. Data were pooled from three phase III RCTs (FRESCO, FRESCO-2, FRUTIGA) and one phase II RCT, all reporting VTE events including deep vein thrombosis and pulmonary embolism and hemorrhage. FRESCO, FRESCO-2, and the phase II trials involved patients with mCRC, comparing fruquintinib to placebo. FRUTIGA trial incorporated patients with gastric or gastroesophageal junction adenocarcinoma, comparing fruquintinib + paclitaxel to placebo + paclitaxel. High-grade hemorrhage incidence was higher in the fruquintinib arm compared to the control arm (29.00% vs 21.18%, RR 1.62; 95% CI: 1.26-2.08, P=0.0001). In the mCRC subgroup, high-grade hemorrhage rate was also higher and statistically significant in the fruquintinib arm 20.87% vs 11.22% (RR 1.84; 95% CI: 1.25-2.70; P=0.002). Incidence of any grade or high grade VTE events was neither statistically significant in GI cancer population or mCRC subgroup. Incidence of any grade VTE events in GI cancer group and mCRC subgroup was 2.74% vs 2.15% (RR, 1.23; 95% CI: 0.53-2.88; P=0.63) and 2.68% vs 1.53% (RR, 0.95; 95% CI: 0.09-9.67; P=0.97), respectively. Rate of high grade VTE events in GI cancer cohort was 1.67% vs 0.67% (RR, 1.96; 95% CI: 0.52-7.36; P=0.32), while in mCRC subgroup was 1.79% vs 0.76% (RR, 1.08; 95% CI: 0.06-19.98; P=0.96). Conclusions: This meta-analysis demonstrates that patients with GI cancers, including mCRC, treated with fruquintinib have higher incidence of high-grade hemorrhage. These findings underscore the importance of individualized risk assessment, especially for patients predisposed to hemorrhagic complications. No increased risk of VTE events was noted in patients treated with fruquintinib compared to placebo.