tbuckley/cabot-search huggingface dataset:
A potent and selective pan-RAS inhibitor, ADT-1004, targeting complex KRAS mutations for pancreatic cancer.
Authors: Gary Piazza, Reddy DS Bandi, Jeremy B Foote, Adam B Keeton, Tyler Ernest Mattox, Xi Chen, Yulia Maxuitenko, Upender Manne, Michael R Boyd, Donald J Buchsbaum, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2024)

90 Background: Pancreatic ductal adenocarcinoma (PDAC) is a challenging cancer with a 5-year survival rate of under 12%. More than 90% of PDAC cases involve KRAS mutations. KRAS G12C inhibitors recently developed have limited use because only 3% of PDAC express this mutation, highlighting the urgent need for pan-RAS inhibitors to address the complex mutation landscape in PDAC while avoiding resistance mechanisms. We synthesized and evaluated a novel pan-RAS inhibitor, ADT-1004, in mouse tumor models transplanted with mouse PDAC cell lines or patient-derived xenografts. ADT-1004 is an orally bioavailable prodrug of ADT-007, a highly potent and selective pan-RAS inhibitor (doi.org/10.1101/2023.05.17.541233). Methods: Human and mouse PDAC cell lines were utilized to evaluate in vitro growth inhibitory potency and selectivity of ADT-007. For in vivo experiments, KPC-Luc (1 × 10 5 ) and 2838C3-Luc (1.5 × 10 5 ) PDAC cells harboring the KRAS G12D mutation were injected into the pancreas of C57BL/6J mice. After one week, the mice were randomly divided into treatment groups (n = 7 per group) and received oral ADT-1004 at a dose of 40mg/kg body weight five times a week for 4 weeks. Tumor burden was assessed weekly by monitoring bioluminescence signals using the IVIS Xenogen imaging system. Four patient-derived xenografts from PDAC patients with KRAS G12C , KRAS G12D , KRAS G12V , KRAS G13Q mutations were subcutaneously implanted in NSG mice by a small incision in the right flank. A week later, when the tumors reached a size of 100mm 3 mice were randomized (n=7 per group) and treated orally with 40mg/kg of ADT-1004 five times a week for 6 weeks. Body weight and tumor size were measured twice weekly. Results: ADT-007 potently and selectively inhibited the growth of human and mouse PDAC cell lines. For example, the IC 50 value pf ADT-007 for KRAS G12C MIA PaCA-2 PDAC cells was as low as 2 nM compared to 2500 nM for RAS WT BxPC3 PDAC cells. Growth inhibition was dependent on activated RAS and associated with reduced GTP-RAS levels and MAPK/AKT signaling. ADT-1004 was well tolerated in mice at a dose up to 175 mg/kg bid orally with sustained plasma levels of ADT-007 far exceeding growth IC 50 values. When administered orally at 40 mg/kg body weight, ADT-1004 displayed robust antitumor activity in mouse tumor models using patient or mouse derived PDAC cell lines with G12D, G12V, G12C, or G13Q KRAS mutations, causing significant inhibitory effects on ERK phosphorylation. Conclusions: ADT-1004 inhibited tumor growth of KRAS mutant PDA tumors by targeting activated RAS to disrupt downstream MAPK/AKT signaling. The results highlight the promise of ADT-1004 as a novel pan-RAS inhibitor and open new strategies for addressing the complex genetic landscape of PDAC and other RAS driven cancers.
Effect of serum diamine oxidase activity derived from response to chemotherapy on adverse events and serum amino acid concentrations for esophageal cancer.
Authors: Yuta Sato, Jesse Yu Tajima, Yoshihiro Tanaka, Nobuhisa Matsuhashi
Journal: Journal of Clinical Oncology (2024)

55 Background: The relationship between activity of the small intestinal villi and the effectiveness of chemotherapy remains unclear. This study aimed to investigate how serum diamine oxidase (DAO) activity affects antitumor effects, adverse events, and amino acid absorption. Methods: We performed a single-center prospective cohort study that enrolled 50 patients with esophageal cancer (EC) receiving docetaxel, cisplatin, and 5-fluorouracil therapy. We determined the cut-off value of serum DAO activity contributing to a response to chemotherapy using a generalized additive model. Additionally, we compared adverse events, inflammatory markers, blood amino acid levels, and quality of life between the high and low DAO activity groups during chemotherapy. Results: The cut-off value of serum DAO activity at the first visit that contributed to a chemotherapy response was 6.5 units/L. Leukopenia and neutropenia of Grade ≥3 were significantly higher in the DAO low (&lt;6.5 units/L) group ( p = 0.044, 0.017, respectively). Interleukin-6 was significantly lower in the DAO high (≥6.5 units/L) group at the first visit and at 4 weeks after the end of chemotherapy ( p = 0.039, 0.011, respectively). Glutamine was higher in the DAO high group at all measurement points during chemotherapy. Fatigue was significantly lower in the DAO high group ( p = 0.001). Conclusions: Serum DAO activity may be a predictor of the response to chemotherapy in patients with EC. The absorption capacity of amino acids was maintained in the group with high DAO activity, which may have contributed to the anti-inflammatory effect and provided a background for reducing adverse events. Clinical trial information: UMIN000048273 .
Differences in the expression heterogeneity of ADC-related markers between primary tumors and metastatic lymph nodes in advanced urothelial cancers.
Authors: Xingliang Tan, Zhicheng Liu, Qianghua Zhou, Kai Yao
Journal: Journal of Clinical Oncology (2024)

111 Background: The booming development of antibody‒drug conjugates (ADCs), which represent a novel, effective and low-toxicity therapeutic approach, has dramatically improved clinical outcomes in urothelial cancers, especially those with advanced disease. However, previous studies focused less on the targeted genes expression pattern and heterogeneity in metastatic tissues, which are more critical to inhibit tumor progression. Here, we aimed to explore the expression of potential ADC-related genes, including HER2, HER3, Nectin4 and Trop2 in advanced urothelial cancers between primary tumors and metastatic lymph nodes (mLN) in pairs. Methods: A large cohort of 306 urothelial cancer patients (292 patients, pN+), including 65 renal pelvis, 38 ureter, 179 bladder and 24 urethral cancer patients (10 patients, pN+), from SYSUCC was enrolled. Paraffin-embedded primary tumors and corresponding mLN sections were subjected to immunohistochemistry (IHC) to detect ADC-related gene expression. HER2 IHC scores of 2/3+ were defined as high expression as previously described. HER3, Nectin4 and Trop2 were evaluated by H-scores (range 0-300, rank 0 to 3+) multiplied by the extent and intensity of the staining, and H-scores &gt;15 were considered positive. Results: A total of 74.8% of advanced urothelial cancer patients were HER2 positive (1-3+), and 49.4% had high HER2 expression. High HER2 expression was detected in 33.8%, 42.2%, 56.5% and 50% of renal pelvis, ureter, bladder and urethral primary tumors, respectively. The rate of high HER2 expression in mLNs slightly decreased to 30.1%, 41.7%, 51.9% and 50%, and the concordance rate of HER2 expression between primary and mLNs was 71.9%. Similarly, 27.7%, 42.1%, 52%, and 66.7% of primary tumors were positive for HER3 expression; 72.3%, 89.5%, 77.7%, and 87.5% were positive for Nectin4; and 89.2%, 94.7%, 83.2%, and 95.8% were positive for Trop2 in renal pelvis, ureter, bladder and urethral cancers, respectively. Overall, 71.9%, 50.7%, and 65.3% of patients had consistent expression of HER3, Nectin4 and Trop2 in mLNs, respectively. Survival analysis indicated that the overexpression of HER2, HER3 and Trop2 in advanced urothelial cancers was associated with poor OS (p=0.001, 0.025 and 0.022, respectively). More importantly, we found that patients with higher HER2 expression in mLNs at primary sites had a worse prognosis (p=0.006). Conclusions: We first investigated the heterogeneity of ADC-related marker expression in primary urothelial tumors and mLNs in a large single cohort, especially in patients who underwent radical lymphadenectomy. Therapy targeting HER2-ADCs might show better homogeneity in advanced disease, but it is more recommended to detect IHC staining both in primary and metastatic tissues if possible.
Observational study examining the feasibility of generating real-world evidence (RWE) for new drug applications from the clinical trials database (DB; RELIASE study).
Authors: Hideaki Bando, Toshihiro Misumi, Yasutoshi Sakamoto, Yuriko Takeda, Yoshiaki Nakamura, Kazuya Mizuguchi, Yoshihiro Aoyagi, Izumi Miki, Takayuki Yoshino, Atsushi Ohtsu
Journal: Journal of Clinical Oncology (2024)

TPS100 Background: The extraction of the data that contributes to regulatory approval from real-world data (RWD) are difficult due to the lack of standardized data format as well as the extraction methodology. In addition, when RWE is used as an external control group, the similarity between internal and external control data has not been evaluated. Methods: In our ‘REALISE’ study, we will investigate the data extraction methodology as external control data of rare molecular subtype. We also elucidate the 'quality' and 'reliability' of RWD/RWE necessary for regulatory submissions. In addition, as most databases are not designed for regulatory use in the creation phase, we will investigate the retrospective methodologies to ensure reliability of RWD/RWE. We compare ‘data quality’ and ‘data reliability’ of ARCAD global DB (N=45,224), SCRUM-Japan registry (N=546), SCRUM-Japan observational study (N=14,325), and the Flatiron health RWD in Japan (N=650) and statistically analyze the differences and similarities among 4 databases. All analyses will be summarized descriptively. Similarity of patient characteristics and efficacy endpoints such as response rate, progression-free survival, overall survival, and all available endpoints will be evaluated by cancer type, treatment line, and standard treatment. For colorectal cancer, data extracted from the SCRUM-Japan registry, SCRUM-Japan observational study, and the Flatiron health RWD will be compared with data extracted from randomized controlled trials in the ARCAD global DB to examine the availability as an external control of RWD. The Kaplan-Meier method will be applied to estimate the survival distribution of time-to-event data. No imputation method for missing data will be used, and the frequency of missing data will also be summarized. We will also examine the methodology for extracting data with sufficient quality from the SCRUM-Japan observational study. In addition, if the reliability of RWD/RWE does not reach the required level, we will also examine the methodologies to retrospectively assure the reliability of the SCRUM-Japan observational study for regulatory submissions. [Table: see text]
Updated efficacy of anti-TROP2 ADC ESG401 for first-line metastatic TNBC in phase 1b study.
Authors: Fei Ma, Fuming Qiu, Zhongsheng Tong, Yehui Shi, Guohua Yu, Xinhong Wu, Hong Wang, Jiani Wang, Hua Yang, Anwen Liu, Yan Zhang, Hongmei Zheng, Qiongyu Lan, Yongqiang Zhang, Ying Cheng, Qing Zhou, Xiaoyan Xing, Xiaomei Chen
Journal: Journal of Clinical Oncology (2024)

2 Background: ESG401, a novel ADC comprising a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to SN-38, with a Drug-Antibody Ratio of 8 and a stable cleavable linker, demonstrated preliminary efficacy and tolerability in the Phase Ia trial (Ma, ASCO 2023). This report presents updated results from the first-line mTNBC cohort of the Phase Ib trial and results from patients with brain metastases. Methods: Patients (pts) aged ≥18 years with confirmed local advanced/unresectable or metastatic TNBC, without prior metastatic treatment, received ESG401 (16 mg/kg IV on Day 1,8, and 15, with a 28-day cycle) until unacceptable toxicity, progressive disease, or consent withdrawal. Results: As of the cutoff date (Apr 7 th , 2024), 24 pts in the cohort received ≥1 dose of ESG401. Median age was 53 years (range: 33-73), 33.3% were ECOG 0, 25.0% were de novo stage IV, 70.8% had visceral disease (8.3% brain, 33.3% liver, 50.0% lung). Updated efficacy results are shown in the Table. Thirteen pts (68.4% of 19 efficacy evaluable pts) remained on treatment, with the longest on-treatment duration being 10.3 mons. Median PFS has not been reached. Two pts in this cohort had brain metastases, with one achieving a complete intracranial response and an overall response of PR, and the other demonstrating overall PR with a -13.8% reduction in brain lesion size. Totally 16 pts with brain metastases were enrolled in the entire Phase Ia/1b trials, for these pts, the best overall intracranial response rate was 31%, with an intracranial disease control rate of 75%, while the corresponding overall response rate and disease control rate were 50% and 69%, respectively. The response of intracranial lesions to the treatment is consistent with that of extracranial lesions. The safety profile of ESG401 remained consistent with previous reports, showing no new or unexpected safety signals. Conclusions: ESG401 monotherapy demonstrates promising antitumor activity in 1L mTNBC pts, characterized by a high response rate and durable response. The ORR numerically exceeded that reported in the BEGONIA Study arm 7 in which pts with the same indication were treated with TROP-2 ADC and PD-L1 combination therapy. Additionally, ESG401 shows clear potential for treating HER2-negative breast cancer with brain metastases, including mTNBC and HR+/HER2- BC. These results support further clinical investigation of ESG401. Clinical trial information: NCT04892342 . [Table: see text]
Longitudinal tracing of on-treatment plasma Epstein-Barr virus DNA as a biomarker for real-time dynamic risk monitoring in patients with nasopharyngeal carcinoma: The EP-SEASON study.
Authors: Ling-Xin Xu, Zhi-Xuan Li, Li Lin, Chen-Fei Wu, Guan-Qun Zhou, Ying Sun, Jiawei Lv, Jun Ma
Journal: Journal of Clinical Oncology (2024)

136 Background: Plasma Epstein-Barr virus (EBV) DNA is a biomarker for nasopharyngeal carcinoma (NPC). However, whether longitudinal on-treatment EBV DNA tracing would inform real-time recurrence risk in NPC remains to be elucidated. To address this issue, we conducted EP-SEASON (NCT03855020), a prospective cohort study of longitudinal on-treatment EBV DNA in EBV-positive NPC patients. Methods: Non-metastatic NPC with detectable pretreatment EBV DNA that received standard sequential chemo-radiotherapy were recruited. Serial EBV DNA in blood specimens were collected across pretreatment, 3-week after each induction chemotherapy (IC), every-week during radiotherapy (RT), within 1-week and 1-3 months upon RT completion. EBV DNA extracted from plasma was quantified by a real-time quantitative polymerase chain reaction assay targeting the BamHI-W region of the EBV genome. Longitudinal changing patterns of EBV DNA and their clinical relevance were analyzed. Results: Between May 2019 and April 2021, a total of 1000 patients underwent per-protocol EBV DNA assessments and treatment; 248 and 752 patients received concurrent chemoradiotherapy (CCRT, subcochort no-IC ) and IC plus CCRT (subcochort IC ), respectively. Longitudinal changes and clearance rates of EBV DNA displayed unique patterns during IC and RT phases. Throughout IC and RT phases, the rate of EBV DNA clearance decreased with repeated IC cycles; interestingly, the rate re-rose upon the introduction of RT, and then dropped to low levels (&lt;10%/week) after the 4 th week of RT (post-RT4w). Patients in subcochort no - IC and subcochort IC also exhibited differential clearance patterns during RT, with the rate of clearance being higher in subcochort no-IC before the 2 nd week of RT (post-RT2w). Notably, despite the prognostic significance of EBV DNA at each timepoint ( P all &lt; 0.05), longitudinal EBV DNA displayed a linkage changing map with dynamic recurrence risks: 3-year disease-free survival (DFS) rate steadily dropped with delayed EBV DNA clearance during IC; it re-rose at the 2 nd RT week upon EBV DNA clearance, followed by a sharp decrease at the 4 th RT week in subcochort IC . In contrast, 3-year DFS rate continuously decreased with delayed EBV DNA clearance in subcochort no-IC . Finally, we identified different phenotypes of whole-course circulating tumor DNA changing dynamics that showed distinct prognosis ( P &lt; 0.05). Conclusions: Longitudinal on-treatment EBV DNA tracing could forecast real-time risks and facilitate risk-adapted decision-making in NPC.
Systemic treatment post curative-intent intervention based on tumor-informed circulating tumor DNA result for oligometastatic colorectal cancer.
Authors: Teerada Siripoon, Conor O'Donnell, Nikolas Naleid, Patrick Starlinger, Thomas D. Atwell, Cornelius A Thiels, Susanne Warner, Jessica L. Mitchell, Krishan Jethwa, Christopher Leigh Hallemeier, Kellie Leanne Mathis, Sherief Shawki, Amit Mahipal, Zhaohui Jin
Journal: Journal of Clinical Oncology (2024)

84 Background: Local therapies potentially offer a curative approach for patients with oligometastatic colorectal cancer (CRC). The effectiveness of systemic chemotherapy following definitive local treatment in this setting is not well-defined. Tumor-informed circulating tumor DNA (ctDNA) might guide management strategies after curative-intent local treatment. Methods: This is a single institution retrospective study of patients with CRC who underwent curative-intent local therapy to an isolated site of metastatic disease and had post-intervention tumor-informed ctDNA (Signatera) testing. The study was approved by the institutional review board. Clinical characteristics, including ctDNA results, were collected and evaluated. Kaplan-Meier method and log-rank test were used to calculate and compare disease-free survival (DFS). Factors associated with DFS were analyzed using multivariate Cox proportional hazards model. Results: 45 patients were included with median age of 59 years, 62% being male, 91% white, and 53% with stage IV disease at diagnosis. 37% of the patients had RAS mutations, no patient had BRAF mutation, and 2.2% patient had mismatch repair deficient disease. Isolated liver metastases were present in 80% of patients, lung metastases in 11% and other sites in 9%. 44 patients received chemotherapy prior to definitive treatment, with a median treatment duration of 16 weeks. ctDNA tests were done prior to local therapy in 23 patients, with 14 cases (61%) testing positive. Definitive treatment included resection (58%), ablation (13%), radiotherapy (4%), and multimodality (25%). Post-definitive treatment chemotherapy was administered to 24 (53%) patients. ctDNA positivity following definitive therapy was observed in 10 patients (22%), which was associated with a poorer prognosis, with a median DFS of 5.3 months compared to 21.3 months for the ctDNA-negative group (p&lt;0.001). These findings were confirmed on multivariate analysis. In patients who had negative ctDNA after definitive local treatment, median DFS was 14.9 months for those who received post-intervention chemotherapy versus 21.3 months for those without post-intervention chemotherapy (p=0.835). Conclusions: Patients with negative ctDNA results following definitive local therapy for isolated metastatic CRC have better prognosis. Post-intervention chemotherapy in this group of patients was not associated with improved DFS. ctDNA guided omission of post-intervention chemotherapy following curative-intent local treatment of oligometastatic CRC warrants further study. [Table: see text]
Reduced cardiovascular disease risk after gastrectomy for gastric cancer: Unexpected treatment benefits.
Authors: Yeongkeun Kwon, Dohyang Kim
Journal: Journal of Clinical Oncology (2024)

51 Background: The relationship between gastrectomy for gastric cancer and subsequent cardiovascular risk modifications has been noted, yet the direct consequences of such surgeries on cardiovascular incidences are not fully established. This study evaluated cardiovascular event rates among patients who received gastrectomy versus a matched general cohort. Methods: In a nationwide retrospective cohort analysis, we examined individuals diagnosed with gastric cancer who underwent gastrectomy (n=18,698), and a control group matched for demographics (n=81,787) from 2004 to 2008. Criteria for inclusion were patients devoid of any previous cancer diagnosis (except gastric cancer), myocardial infarction, or ischemic stroke. The primary outcome was the incidence of major adverse cardiovascular events (MACE) such as acute myocardial infarction (MI) or acute ischemic stroke, in patients with gastric cancer. Results: Within a seven-year observational window, 2.7% of the gastrectomy group (or 4.29 events per 1000 person-years) experienced new MAC). The gastrectomy group showed a significantly lower incidence rate of MACE compared to the matched control subjects (hazard ratio [HR] 0.65; 95% confidence interval [CI] 0.63–0.71; P&lt;0.001), MI (HR, 0.68; 95% CI, 0.60–0.78; P &lt; 0.001), and stroke (HR, 0.73; 95% CI, 0.66–0.79; P&lt;0.001). In the subgroup analyses, no significant interactions were identified between the study groups and baseline variables. Conclusions: The study indicates a decreased risk of developing cardiovascular diseases post-gastrectomy for gastric cancer, as opposed to the general population. Beyond their significance for public health strategies aimed at cardiovascular risk management in gastric cancer patients, these findings empower both patients and healthcare providers with enhanced knowledge for making decisions about gastric cancer surgical options. Furthermore, this study lays the groundwork for future investigations into the metabolic effects of gastric cancer surgeries, notably their potential in lowering cardiovascular risk.