bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinicopathological characteristics and survival in metastatic colorectal cancer with short-form APC mutations.
Authors: Osumi Hiroki , Ooki Akira , Fukada Ippei , Yoshino Koichiro , Tamba Mikako , Udagawa Shohei , Fukuoka Shota , Wakatsuki Takeru , Ogura Mariko , Takahari Daisuke , Chin Keisho , Nakamura Yoshiaki , Bando Hideaki , Yoshino Takayuki , Hayashi Naomi , Takahashi Shunji , Yamaguchi Kensei , Seimiya Hiroyuki , Shinozaki Eiji 
Published: June 2024

3555 Background: Wnt/β-catenin signaling is activated by loss-of-function mutations in the adenomatous polyposis coli ( APC) gene and plays a key role in tumorigenesis in colorectal cancer (CRC). Tankyrase inhibitors, which cause degradation of β-catenin, are expected to have a promising therapeutic effect for CRC, and the short-form APC mutations predict the sensitivity of CRC cells to tankyrase inhibitors (Tanaka et al. Mol Cancer Ther 2017; Chen et al. Br J Cancer, in press).However, clinicopathological characteristics and survival in metastatic CRC (mCRC) with short-form APCmutations remain unclear. Methods: Patients with mCRC who were treated with chemotherapy between 2010 and 2021 and have tissue or circulating tumor DNA-based next-generation sequencing results were enrolled. Short-form APC mutations were defined as those truncated at amino acid 1,256 or shorter, lacking all seven 20-amino acid repeat (20-AAR) regions. Non-short-form APC mutations were defined as those possess more than one 20-AAR. Short-form and non-short-form heterozygous mutations were classified as non-short-form APC mutations. We confirmed incidence of mCRC with short-form APC mutations and compared clinicopathological characteristics and overall survival (OS) between mCRC patients with short-form and non-short-form APCmutations. Results: Of 177 patients (median age, 56.0 years) included in this study, 44 (25%) and 79 (45%) had short-form and non-short-form APC mutations, respectively. Patients with short-form APC mutations were not likely to have lung metastasis (P = 0.15). Logistic regression multivariate analysis, lung metastasis was related to mCRC patients with short-form APC mutations (Odds ratio: 0.46, P = 0.047). Patients with short-form APC mutations had significantly shorter overall survival (OS) than did those without (n = 133), with a median OS of 34.7 vs 50.5 months ( P Log-rank= 0.035, hazard ratio (HR), 1.59; 95% confidence interval (CI), 1.03-2.45). In multivariate analysis, short-form APC mutation was independent factor related to OS (hazard ratio (HR): 1.68, P = 0.02), as well as the BRAF V600E mutation, liver metastasis and peritoneal metastasis. Conclusions: Short-form APC mutation is more common in mCRC patients without lung metastases and is independently associated with a short prognosis.
Tumor microbiome differences in early-onset versus average-onset pancreatic adenocarcinoma.
Authors: Jayakrishnan Thejus , Sangwan Naseer , Nair Kanika G. , Kamath Suneel Deepak , Patel Mehrie , Joyce Daniel , Walsh Matthew , Simon Robert , Vadehra Deepak , Iyer Renuka V. , Fountzilas Christos , Khorana Alok A. 
Published: June 2024

4016 Background: The rise in early-onset gastrointestinal cancers includes an increased risk of pancreatic adenocarcinoma (PDAC), but the underlying pathogenesis is incompletely understood. The tumor microbiome is an increasing focus of research given its impact on tumor pathogenesis and outcomes. We evaluated microbiome profiles in resected specimens from early-onset PDAC (eoPDAC) and average-onset PDAC (aoPDAC). Methods: PDAC specimens were selected consecutively from Cleveland Clinic and Roswell Park Cancer Institute biorepositories and categorized on age at diagnosis ( < 50 years defined as eoPDAC, and > 50 years as aoPDAC). The tissue microbiome was characterized using shotgun metagenomic sequencing. Alpha diversity, denoting the richness and evenness of microbial species within a specific sample, was compared using the Wilcoxon rank-sum test. The differential test of Beta-diversity distances (Bray Curtis distance), representing microbial taxonomic differences between the specimens was performed using Permutational MANOVA. All p-values were adjusted for multiple testing. Results: The study comprised 44 individuals with resected PDAC (24 eoPDAC and 20 aoPDAC). After quality checks, 63 tissue specimens were selected for analysis (13 tumor and 10 adjacent normal specimens for eoPDAC, 20 each of tumor and adjacent normal specimens for aoPDAC). eoPDAC tumor demonstrated significantly higher alpha diversity compared to adjacent normal tissue (P = 0.02) and aoPDAC (P = 0.0062) while aoPDAC did not (tumor vs normal alpha diversity P = 0.31). Beta diversity analysis demonstrated significantly different diversity of genera between all the groups (P < 0.05). Consistent with this finding, the majority of the species - 259/302 (85.8%) in eo vs aoPDAC comparison and 262/366 (71.6%) for eoPDAC vs normal comparison did not overlap. Differential abundance analysis revealed a significant variation of tumor microbiome in eoPDAC vs aoPDAC (P < 0.05). Prevalent bacterial genera (tumor specimens) are listed in the Table. eoPDAC tumor tissues were enriched in Enterobacter, Neisseria,and Escherichia genera, while aoPDAC tumor tissues were enriched in Klebsiella and Bacillus genera. Conclusions: eoPDAC has a distinct microbiome profile compared to aoPDAC. The correlation with several microbial genera associated with pancreatic diseases is a significant finding and warrants further exploration. This is relevant considering the rising incidence of eoPDAC of unknown etiology, and ongoing efforts to develop microbiome-based biomarkers for screening and treatment. [Table: see text]
Trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing biliary tract cancer (BTC) and pancreatic cancer (PC): Outcomes from DESTINY-PanTumor02 (DP-02).
Authors: Oh Do-Youn , Lugowska Iwona A. , Stroyakovskiy Daniil , Jung Kyung Hae , Dumas Olivier , Penkov Konstantin , Dechaphunkul Arunee , Oaknin Ana , Kim Seung Tae , Starling Naureen , Chewaskulyong Busyamas , Charonpongsuntorn Chanchai , Doroshow Deborah Blythe , Hsiao Sheng-Yen , Hung Yi-Ping , Jung Lindsey , Kuptsova-Clarkson Nataliya , Michelini Flavia , Puvvada Soham D. , Meric-Bernstam Funda 
Published: June 2024

4090 Background: Existing late-line treatment (Tx) options for BTC and PC offer limited long-term benefit. In DP-02, T-DXd showed tumor-agnostic potential, with an objective response rate (ORR) of 37.1% (95% CI 31.3, 43.2) and clinically meaningful survival outcomes in 267 pts with HER2-expressing tumors. Here we report subgroup analyses in the BTC and PC cohorts and characterize pts with an objective response (OR). Methods: This open-label Phase 2 study (NCT04482309) evaluated T-DXd (5.4 mg/kg Q3W) in pts with HER2-expressing (immunohistochemistry [IHC] 3+/2+ by local or central testing) locally advanced/metastatic disease after ≥1 systemic Tx, or without Tx options. The primary endpoint was confirmed ORR by investigator (INV). Secondary endpoints included progression-free survival (PFS) and safety. Exploratory endpoints included efficacy outcomes by HER2 expression. Results: At data cutoff (June 2023), 41 pts with BTC and 25 pts with PC had received T-DXd (median [m] follow up [range]: 6.01 [0.7–29.1] and 4.99 [1.1–27.2] months [mo], respectively); 27 (65.9%) and 18 (72.0%) pts had ≥2 prior Tx regimens, 7 (17.1%) and 2 (8.0%) pts had prior anti-HER2 Tx, and 8 (19.5%) and 18 (72.0%) pts had prior topoisomerase 1 inhibitor Tx, respectively. In pts with BTC and IHC 3+ expression, 9 pts (56.3%; 95% CI 29.9, 80.2; primary tumor locations: n=2 ampulla of Vater; n=2 extrahepatic; n=4 gallbladder; n=1 intrahepatic) had confirmed OR by INV; of these pts, 6 had received ≥2 prior Tx regimens and 4 had PD-L1 immune cell status ≥1%. The Table shows efficacy outcomes in all pts and by central HER2 expression. In pts with BTC and PC, Grade (G) ≥3 drug-related adverse events occurred in 16/41 (39.0%) and 7/25 (28.0%) pts, respectively; adjudicated drug-related interstitial lung disease / pneumonitis occurred in 7/41 (17.1%; n=5 G2; n=1 G3; n=1 G5) and 1/25 (4.0%; n=1 G1) pts, respectively. Conclusions: T-DXd showed clinically meaningful benefit in pts with BTC across primary tumor locations. Low pt numbers limit interpretation of the PC cohort; however, data support further exploration of T-DXd in this population. Safety was consistent with the known profile. These data support T-DXd as a potential Tx for pts with HER2-expressing BTC. Clinical trial information: NCT04482309 . [Table: see text]
Avutometinib/defactinib and gemcitabine/nab-paclitaxel combination in first-line metastatic pancreatic ductal adenocarcinoma: Initial safety and efficacy of phase 1b/2 study (RAMP 205).
Authors: Lim Kian-Huat , Spencer Kristen Renee , Safyan Rachael A , Picozzi Vincent J. , Varghese Anna M. , Siolas Despina , Perez Kimberly , Clift Sheena , Denis Louis J. , Bhambhani Vijeta , Hill Stacey , Pachter Jonathan A. , Pultar Philippe , Hidalgo Manuel 
Published: June 2024

4140 Background: More than 90% of pancreatic ductal adenocarcinomas (PDAC) harbor an activating KRASmutation .Avutometinib (avuto) is an oral RAF/MEK clamp. Defactinib (defact) is an oral selective FAK inhibitor. Avuto/defact combined with gemcitabine/paclitaxel have shown synergistic antitumor activity in preclinical PDAC models. RAMP 205 (NCT05669482) is a Phase 1b/2 study assessing the safety and efficacy of avuto/defact + gemcitabine/nab-paclitaxel (GnP) in first-line metastatic PDAC. Methods: Eligible patients (pts) were enrolled and treated in 3+3 cohorts with escalating doses of avuto orally (PO) twice weekly (BIW) and defact PO twice daily (BID), both 3 out of 4 weeks, in combination with GnP dosed intravenously (IV) on a D1, D8, D15 or D1, D15 (modified) 4wk schedule (Table 1). Key eligibility criteria include histologically confirmed newly diagnosed metastatic PDAC with measurable disease, ECOG performance status (PS) ≤1, adequate organ function, and no prior treatment. Results: At the 24Jan2024 data cutoff, 18 pts were enrolled, 44% were male, 65 y median age, and 61% ECOG PS 1. Pts were enrolled to DL-1 (n=3), DL1 (n=6), DL1a (n=6), and DL2a (n=3). No dose-limiting toxicities (DLTs) were reported and the majority of treatment related adverse events (TRAEs) were mild to moderate. The most frequently reported TRAEs of any grade in the safety population (N=18) were nausea (50%), alopecia (44%), fatigue (39%), maculo-papular rash (33%), and peripheral edema (28%). The most common grade ≥3 TRAEs included alanine aminotransferase increase (17%), neutropenia (17%), peripheral edema (11%), anemia (11%), and sepsis (11%). Four patients experienced serious AEs (SAEs). Grade ≥3 treatment emergent SAEs included pulmonary embolism (n=2; unrelated), sepsis (n=2), febrile neutropenia (n=1; did not meet DLT criteria), and neutropenia (n=1). One patient discontinued treatment due to TRAE (febrile neutropenia and blood bilirubin increased). All efficacy evaluable pts (n=8) experienced a reduction in target lesions (100% disease control rate) and partial responses were observed in 6/8 (75%), 3 being confirmed at data cutoff. All efficacy evaluable pts with an elevated CA19-9 at baseline (n=7) had a ≥60% CA19-9 reduction from baseline. Conclusions: Avuto/defact and GnP are combinable and show notable preliminary efficacy in first-line metastatic PDAC based on RECIST v.1.1 criteria and CA19-9 levels. No DLTs were reported across the 4 dosing cohorts/schedules and safety signals were consistent with previous clinical data. Updated safety and efficacy will be reported. Clinical trial information: NCT05669482 . [Table: see text]
Quality indicators in the care of patients with rectal cancer in social security in Guatemala: Results of a retrospective population study.
Authors: López Pedro Luis , Castro-Salguero Hugo Raul , Ranero Meneses Jorge Luis , Peralta de León Stefany Jerusa 
Published: June 2024

e15518 Introduction: Rectal cancer is a serious condition affecting a significant number of patients worldwide. However, in the Guatemalan population, the epidemiology and clinical characteristics of this disease have not been widely studied. This study aims to address this knowledge gap by retrospectively analyzing patients with rectal cancer treated at the Guatemalan Social Security Institute between 2013 and 2018. Methods: A retrospective analysis of eighty-eight patients with rectal cancer treated at the Guatemalan Social Security Institute during the mentioned period was conducted. Descriptive statistical techniques, such as chi-square, as well as survival analysis using Cox regression and Kaplan-Meier, were employed to assess the relationship between clinical stages, treatments, and overall survival. Results: The mean age at diagnosis was 70 years +/- 20 years, and 71% of the patients were male. At the time of diagnosis, 14.28% of the patients had localized disease, 58.86% had regional spread, and 26.86% had metastatic disease. Patients in clinical stage I showed a 5-year survival rate of 100%, with a p-value < 0.001 and an HR of 0.01. Additionally, the combination of chemotherapy, radiotherapy, and surgery was found to be significantly associated with improved survival, with a p-value of 0.03 and an HR of 0.82. Conclusions: This study provides crucial information on the clinical characteristics and survival of Guatemalan patients with rectal cancer. The findings underscore the importance of early detection and multimodal treatment, including chemoradiotherapy followed by surgery, to improve outcomes in these patients. Sharing these results is essential to promote access to standard treatment and enhance survival outcomes in patients with rectal cancer in Guatemala.
Triplet chemotherapy combined with anti-EGFR treatment in RAS wild-type colon cancer: A network meta-analysis.
Authors: Di Nardo Paola , Giudici Fabiola , Basile Debora , de Scordilli Marco , Torresan Sara , Bortolot Martina , Rota Simone , Foltran Luisa , Guardascione Michela , Fumagalli Arianna , Noto Claudia , Guglielmi Alessandra , Ongaro Elena , Puglisi Fabio 
Published: June 2024

e15592 Background: The optimal first-line treatment for RAS wild-type (wt) metastatic colorectal cancer (mCRC) remains undetermined. Recently, several studies have explored the efficacy of first-line treatment regimens, including triplet chemotherapy (CT) combined with an anti-EGFR antibody, in comparison to either doublet CT combined with an anti-EGFR antibody, triplet CT combined with an anti-VEGF treatment, or triplet CT alone. However, none of these trials yielded conclusive results. Hence, we conducted a systematic review and an explorative network meta-analysis (NMA) of the available data. Methods: A systematic review was conducted, encompassing all phase II/III randomized clinical trials (RCTs) that compared a regimen consisting of triplet CT associated with an anti-EGFR treatment against different first-line systemic regimens for RAS-wt mCRC patients. Both pairwise and NMA were performed to establish direct and indirect comparisons of overall response rate (ORR) using a random effects model within the frequentist framework. Results: 7 RCTs (TRIPLETE, VOLFI, TRICE, PANIRINOX, AIO-CELIM2, FOCULM, DEEPER), involving a total of 1283 patients, were included in the analysis. Overall, 4 arms were identified, encompassing all possible combinations of CT, anti-EGFR treatment, and anti-VEGF treatment: arm A (triplet + anti-EGFR), arm B (doublet + anti-EGFR), arm C (triplet alone), and arm D (triplet + anti-VEGF). A benefit was demonstrated for all treatments associated with targeted therapy when compared to triplet alone; no difference was observed among groups A, B and D. Results of selected NMA comparisons are shown in the table 1. Additionally, we conducted a pairwise meta-analysis for ORR, which, due to available comparisons, was only feasible for groups A vs. B, A vs. C, and A vs. D; the results of this analysis confirmed the NMA findings (group A vs. group C, pooled OR: 4.23 (2.06 – 8.68)). Conclusions: Through indirect comparisons, no significant ORR benefit was found for triplet CT associated with anti-EGFR treatment compared to doublet CT combined with anti-EGFR treatment or triplet CT combined with anti-VEGF. All regimens incorporating targeted treatment demonstrated superior performance compared to triplet CT alone. Our findings do not advocate for the routine use of triplet CT associated with anti-EGFR treatment in this patient population; however, we await mature OS data from a few of the trials included in our analysis. [Table: see text]
A first-in-human, phase 1/2 trial of FOG-001, a β-catenin:TCF antagonist, in patients with locally advanced or metastatic solid tumors.
Authors: Papadopoulos Kyriakos P. , Rodon Ahnert Jordi , Khushman Moh'd M. , Sharma Sunil , Pelster Meredith , Cecchini Michael , Kummar Shivaani , Choi Minjung , Akella Lalith V , Garofalo Amanda , Yu Ziyang , Iyer Varsha , Nguyen Marie Huong , Orford Keith W. , Klempner Samuel J. 
Published: June 2024

TPS3175 Background: The Wnt/β-catenin pathway is a frequently activated oncogenic pathway and a well-described driver of many cancers. FOG-001 is designed to be a first-in-class direct inhibitor of β-catenin that blocks β-catenin’s interaction with the T-cell factor (TCF) family of transcription factors. Preclinical studies have indicated FOG-001 can cause tumor growth inhibition and regression by disrupting β-catenin-dependent signaling. FOG-001 is unique from previously reported Wnt/β-catenin pathway modulators as it is designed to directly inhibit TCF transcription factor and β-catenin interaction, the most downstream node in the Wnt pathway. It is hypothesized FOG-001 will abrogate the hyperactivation of the Wnt pathway that is driven by most known pathway mutations. Methods: This first-in-human, Phase 1/2, multicenter, open-label, dose escalation (Parts 1a and 1b) and dose-expansion (Part 2) study is evaluating the safety/tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of FOG-001 in patients with advanced or metastatic solid tumors. Patients with the following tumor types are eligible: microsatellite stable (MSS) colorectal cancer (CRC) or any solid tumor with documented Wnt pathway activating mutation (WPAM) (Part 1a), MSS CRC only (Part 1b) and MSS CRC, gastric/gastroesophageal (GEJ) cancer, non-small cell lung cancer (NSCLC), and any solid tumors with documented WPAM in Part 2. Patients must have received ≥1 prior systemic anticancer therapy(ies) and be ineligible for curative surgery or curative chemoradiation. In Part 1, FOG-001 is administered at escalating doses via intravenous (IV) infusion on Days 1, 8, 15, and 22 of each 4-week cycle; additional dosing regimens may be explored. After selection of the preliminary recommended Phase 2 dose(s) (pRP2D) and regimen(s) in Part 1, the following cohorts will be enrolled to receive FOG-001 at the pRP2D in Part 2: (2a) MSS CRC; (2b) NSCLC with documented WPAM in adenomatous polyposis coli (APC) or β-catenin; (2c) gastric/GEJ cancer with documented WPAM in APC or β-catenin; and (2d) solid tumors with ≥1 documented WPAM in any predefined Wnt pathway genes. The primary endpoints are safety/tolerability (Parts 1 and 2), and also preliminary antitumor activity (objective response rate) (Part 2). Secondary endpoints are PK, PD, and additional antitumor activity assessments. Enrollment in Part 1 is ongoing. Clinical trial information: NCT05919264 .
Pilot study of CBX-12 pharmacodynamics in patients with advanced solid tumors.
Authors: Shin Sarah , O'Sullivan Coyne Geraldine Helen , Rubinstein Larry V. , Takebe Naoko , Wright John Joseph , Wilsker Deborah , Ferry-Galow Katherine V. , Karlovich Chris Alan , Anderson Larry , Kuhlmann Laura , Parchment Ralph E. , Doroshow James H. , Chen Alice P. 
Published: June 2024

TPS3187 Background: Topoisomerase 1 (TOP1) inhibitors effectively kill a diverse range of tumor cells but have limited clinical utility due to severe off-target toxicities. Targeted therapeutic strategies have been developed to circumvent these limitations, although there remains an unmet need for antigen-agnostic tumor targeting. CBX-12 is a peptide conjugate that uses a novel pH-low insertion peptide (pHLIP) linked to TOP1 inhibitor exatecan to selectively target the low-pH tumor microenvironment and deliver the payload intracellularly. Recently published results of the first-in-human study of CBX-12 (NCT04902872) demonstrated single-agent activity in 4 patients, including a complete response in a patient with ovarian cancer. The predominant reported toxicity was myelosuppression with the most common grade 3/4 treatment-related adverse event being neutropenia in 28.6% of patients. Here we report our new pharmacodynamic (PD) biomarker-driven pilot study of CBX-12 in patients with advanced solid tumors. The primary objective of this study is to assess the effects of CBX-12 on biomarkers of DNA damage response (DDR) in biopsy specimen to establish the degree and duration of CBX-12 target engagement. The secondary objectives are to assess the effects of CBX-12 on TOP1 molecular response; determine any association between tumor TOP1 levels, DDR modulation, and plasma exatecan levels; evaluate the effect of CBX-12 on CD8+ T cell infiltration and activation in the tumor microenvironment; assess the objective response rate using RECIST v 1.1; and assess safety and tolerability of CBX-12. The planned PD endpoints aim to confirm and further enrich knowledge of the mechanisms underlying response or resistance to CBX-12 treatment, and guide future complementary treatment combination strategies. The study results may also help identify future patient populations likely to benefit from CBX-12 treatment. Methods: CBX-12 will be administered intravenously once weekly in 28-day cycles at the recommended phase 2 dose. Mandatory biopsies will be collected at baseline, 24-36 hours post first dose, and on cycle 3 day 1 to assess both short- and long-term effects of CBX-12 on the tumor. Mandatory research blood samples will be collected at specified timepoints for pharmacokinetic, circulating tumor cell, and cell-free DNA analyses. Clinical trial information: NCT05691517 .