tbuckley/cabot-search huggingface dataset:
Treatment sequences in patients with metastatic colorectal cancer in Japan: Real-world evidence of 1 <sup>st</sup> - to 5 <sup>th</sup> -line treatments.
Authors: Yoshinori Kagawa, Tsuyoshi Osaka, Toshiki Imamura, Hiroyo Kuwabara
Journal: Journal of Clinical Oncology (2025)

76 Background: The development of later-line drugs for metastatic colorectal cancer (mCRC) has expanded treatment options for systemic chemotherapy in patients with mCRC. However, few studies have investigated patients who received later-line treatment in a real-world setting, and available information on treatment sequences and transition rates from early- to later-line treatments is limited. Methods: This was a retrospective study using hospital administrative data collected by MDV (Medical Data Vision, Tokyo, Japan) from April 2008 through February 2023 in Japan. Treatment regimens were derived from standard treatments recommended in the Japanese guidelines. The study population was determined using an algorithm from a similar study previously conducted in Japan. Our analysis focused on patients who started CRC surgery or 1 st -line treatment after January 2017 to reflect recent late-line real-world practice. Transition rates from 1 st - to 5 th -line treatment were calculated, and treatment sequences were summarized using a Sankey diagram. Logistic regression was performed to identify the factors associated with the transition from 2 nd - to 3 rd -line treatment. Results: A total of 722,005 patients with a CRC diagnosis record were identified in the MDV database. Of these, 26,456 patients were included in the study population. The median age was 69 years and 61.4% of patients were male. The rates of transition to subsequent lines from 1 st to 5 th line ranged from 65.7% to 70.4% (1 st to 2 nd 68.3%; 2 nd to 3 rd 70.4%; 3 rd to 4 th 69.9%; 4 th to 5 th 65.7%). Among 8528 patients who received 2 nd -line treatment, ~70% of patients (6006) continued 3 rd -line treatment, and 30% of patients (2522) received best supportive care. Comparing these 2 patient groups, younger age (&lt;65 years, OR: 1.50, 95%CI: 1.35-1.67; p&lt;0.001) and longer treatment durations of 1 st (≥180 days, OR: 1.26, 95%CI: 1.14-1.39; p&lt;0.001) and 2 nd (≥120 days, OR: 1.67, 95%CI: 1.52-1.84; p&lt;0.001) lines were significant factors for 3 rd -line treatment continuation. Prior therapy with oxaliplatin or irinotecan plus molecular targeted drugs was also associated with a higher likelihood of proceeding to 3 rd -line treatment (OR: 1.42, 95%CI: 1.28-1.58; p&lt;0.001). Conclusions: In this study, ~70% of patients were able to transition to subsequent lines at the time of each line transition. However, 30% of patients were unable to continue treatment in real-world practice. To increase treatment continuation rates and maintain patient quality of life, new treatment options and further research are necessary to meet patients’ treatment needs, especially in the later-line treatment setting where unfavorable effects from previous treatments are accumulated.
Analysis of lipogenic and metabolic subtypes and survival outcome in patients with pancreatic adenocarcinoma.
Authors: Madappa N. Kundranda, Nischal Mahaveer Chand, J. Carl Barrett, James Moser, Eric M. Grund, Poornima K. Tekumalla, Gregory M. Miller, Niven R. Narain, Vijay Modur, Michael A. Kiebish, Ramesh K. Ramanathan
Journal: Journal of Clinical Oncology (2025)

775 Background: Delayed diagnosis and rapid progression are major drivers of poor survival outcomes for Pancreatic Ductal Adenocarcinoma (PDAC). In previous studies, molecular profiling in tumor tissue has identified Cholesterogenic, Classical, or Exocrine-Like pathological subtypes associated with improved prognosis. Herein, in a clinical trial called Project Survival, we molecularly and clinically characterized a prospective PDAC biomarker cohort. This multicenter (n=6) clinical trial (NCT 02781012) of PDAC combined with high-fidelity longitudinal phenotypic characterization and multi-omic profiling was utilized to identify biomarkers with diagnostic and therapeutic utility. The study included assessment of plasma, serum, buffy coat, urine, saliva, and tumor tissue samples and followed 269 PDAC subjects for up to 7 years (Median survival was 700 days, with IQR of 822 days). Methods: We assessed plasma samples to identify circulating biomarkers using proteomics, metabolomics, and lipidomics profiling. Multi-omic comparison of patients with Overall Survival (OS) above the 75th percentile (improved survival) against those with OS below the 25th percentile (poor survival) was performed. Results: We identified distinct panels of proteins, metabolites, and lipids that were associated with patient survival outcomes. Protein biomarkers that were increased in improved survival outcomes were associated with cholesterol metabolism (7/14, p-value = 0.00085) and glycolysis/gluconeogenesis (5/12, p-value = 0.00089), however, protein markers associated with immune surveillance and inflammation were associated with poorer survival. For metabolite biomarkers, 19 metabolites were increased in poorer survivors of which 13/19 were carnitine metabolites, and 42 metabolites were increased in patients with improved survival. Interestingly, only two lipid molecular species of the diacylglyceride family were increased in patients with poorer survival. Conclusions: Project Survival, a prospective biomarker-driven clinical trial identified distinct metabolic and molecular subtypes of patients which characterize survival outcome in PDAC. These subtypes go beyond tumor genomic characterization and align with distinct cholesterogenic and glucogenic phenotypes associated with survival outcomes, which can potentially be leveraged for therapeutic intervention strategies.
The role of immunotherapy for real-world patients with HER2-negative advanced gastric cancer between 2011-2023.
Authors: Keitaro Shimozaki, Akira Ooki, Koichiro Yoshino, Mikako Tamba, Shohei Udagawa, Hiroki Osumi, Takeru Wakatsuki, Mariko Ogura, Eiji Shinozaki, Keisho Chin, Kensei Yamaguchi
Journal: Journal of Clinical Oncology (2025)

404 Background: Although the appearance of immunotherapy has apparently brought benefits for all patients (pts) with advanced gastric cancer (AGC), the magnitude of the benefit in real-world pts with HER2-negative AGC has not been fully investigated. Methods: We conducted a retrospective study on pts with HER2-negative AGC who received first-line platinum-based chemotherapy between 2011 and 2023. We evaluated the clinical outcomes across different periods of immunotherapy approval in Japan: Group A (pre-immunotherapy approval): 2011-2017, Group B (approved for third-line treatment or later): 2018-2021, and Group C (approved for first-line treatment): 2022-2023. Results: A total of 949 pts were enrolled (A: n = 477; B: n = 344; C: n = 128). Patient's characteristics were comparable except for the proportion of those with age ≥75 years (P = 0.002), prior gastrectomy (P = 0.03), and liver metastases (P &lt; 0.001). The median overall survival (OS) was 16.2, 15.2, and 21.3 months in group A, B, and C, respectively, with no significant difference between groups (log-rank P = 0.50). Pts who had received first-line immunotherapy plus chemotherapy (n = 173) showed significantly improved OS compared with pts without having received any immunotherapy-containing treatment at 2011-2017 (n = 382) (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.61-0.99; P = 0.04). In the multivariate analysis, the use of immunotherapy at first-line treatment was not significantly associated with worse OS, whereas the use of immunotherapy at any lines was prognostic (HR, 0.54; 95% CI, 0.41-0.71; P &lt; 0.0001). The proportion of pts who had received any second-line treatment was comparable among groups: 76%, 80%, and 71%, respectively. Conclusions: Our study suggests that the immunotherapy might partially have an impact on the survival improvement of real-world pts with HER2-negative AGC, which calls for the need for appropriate treatment strategies, including other agents.
Exploring Nectin-4 expression in hepatocellular carcinoma.
Authors: Chien Huai Chuang, Chang-Tsu Yuan, Ching-Cheng Chang, Tsung-Hao Liu, Ying-Chun Shen, Li-Chun Lu, Da-Liang Ou, Chih-Hung Hsu, Ann-Lii Cheng
Journal: Journal of Clinical Oncology (2025)

632 Background: Nectin cell adhesion protein 4 (Nectin-4) is overexpressed in various malignancies, contributing to cancer progression and poor prognosis. We aimed to assess Nectin-4 expression in hepatocellular carcinoma (HCC). Methods: Patients who underwent primary liver tumor resection for HCC upon initial diagnosis at National Taiwan University Hospital in 2019 were included. Exclusion criteria consisted of prior systemic or loco-regional therapy, or death within three months post-surgery. Immunohistochemical (IHC) staining for Nectin-4 (EPR15613-68, Abcam) was conducted and independently reviewed by two pathologists. Nectin-4 expression patterns (membranous, cytoplasmic, and nuclear) and intensity were scored on a 0–3 scale, with normal eccrine glands (2+) serving as a positive control. Nectin-4 expression was further assessed in primary and paired progressive or metastatic tissue samples from patients with available paired samples. Results: Of the 193 patients, 175 had specimens available for IHC analysis. Nectin-4 expression was detected in 22.9% of these patients, with intensity scores of 0 in 77.1%, 1 in 22.3%, and 2 in 0.6%. The majority of staining pattern was cytoplasmic (94.3%), with membranous staining observed in 5.1% of cases. Nectin-4 expression was significantly associated with higher pathological grades ( p = 0.005) but showed no correlation with recurrence-free survival ( p = 0.771) or overall survival ( p = 0.396) after surgery. Importantly, Nectin-4 expression intensity significantly increased in paired progressive or metastatic samples compared to initial HCC specimens ( p = 0.046; n = 27). Conclusions: Nectin-4 expression is associated with higher pathological grades but not related to clinical outcomes in HCC. Increased Nectin-4 expression in progressive or metastatic disease highlights its potential as a therapeutic target.
Neoadjuvant immunotherapy and nonoperative management of dMMR gastroesophageal adenocarcinoma (GEA): A retrospective case series.
Authors: Oudai Sahvan, Fares Jamal, Mitesh J. Borad, Tanios S. Bekaii-Saab, Christina Wu, Daniel H. Ahn, Mohamad Bassam Sonbol
Journal: Journal of Clinical Oncology (2025)

451 Background: Perioperative chemotherapy with surgery is the standard of care for patients (pts) with resectable gastric or gastroesophageal junction adenocarcinoma (GEA). However, recent studies have shown more favorable responses after neoadjuvant immunotherapy (NIO) in patients with mismatch repair deficient (dMMR) cancers. Herein, we present the outcomes of 10 cases with dMMR GEA. Methods: We retrospectively reviewed patients with GEA at Mayo Clinic Arizona who met the following criteria: have dMMR disease by IHC, nonmetastatic operable disease, and received NIO +/- chemotherapy. Patient demographics, disease characteristics, and clinical outcomes were extracted. The primary endpoint was clinical complete response (cCR) in patients treated with non-operative management (NOM) defined as complete radiological response and no residual disease on endoscopic ultrasound (EUS) and biopsy. Results: 10 pts with dMMR GEA with a median age of 70 (43-85) were identified. 6 pts had T2N0, 1 had T4N0, 3 had N+ disease. 8 pts received NIO monotherapy upfront, 1 received NIO after progressing on chemotherapy, and 1 concurrently with chemotherapy. No grade 3/4 toxicities were reported, however, 2 pts discontinued therapy due to arthralgia and colitis. After NIO, 9/10 pts had significant or complete resolution of FGD avidity on PET/CT, while 1/10 had stable disease. 3/10 pts underwent surgical resection, with 2 achieving pathological complete response (pCR) and the third showing T1N0 disease with no recurrence 1 year after surgery. Notably, one of the pts with pCR passed away due to surgical complications. 7/10 patients had NOM, of whom, 4 had cCR and 3 had radiological response only, as no EUS data was available. 4/7 NOM pts had follow up data at 6 months with no evidence of progression, of whom one pt remained progression-free at 33 months. ctDNA testing was performed in 6/10 pts: 2 had undetectable ctDNA at baseline, while 3 became MRD-negative after NIO, consistent with radiological and/or pathological response, and 1 had persistent ctDNA both before and after NIO, despite cCR. Conclusions: This study demonstrates exceptional and prolonged response, along with good tolerability to NIO in pts with dMMR GEA, supporting the feasibility of non-operative management in such patients.
Longitudinal ctDNA measurements for treatment response monitoring in patients with metastatic colorectal cancer undergoing systemic therapy: The ORCA trial.
Authors: Denise van Steijn, George Laliotis, Erik Anthony Spickard, Suzanna J. Schraa, Frederieke H van der Baan, Cornelis J. A. Punt, Daan van den Broek, Shruti Sharma, Himanshu Sethi, Minetta C. Liu, Adham A Jurdi, Niels FM Kok, Miriam Koopman, Geraldine R Vink, Remond Fijneman
Journal: Journal of Clinical Oncology (2025)

220 Background: Precise monitoring of treatment response may support and improve treatment decision-making in patients with metastatic colorectal cancer (mCRC). The PLCRC-ORCA study aimed to explore the clinical applicability of personalized ctDNA testing for treatment response monitoring in patients with mCRC. Methods: The prospective, observational ORCA study is a substudy of the Prospective Dutch ColoRectal Cancer cohort (PLCRC). After informed consent, blood samples were collected before initiating first line of treatment (baseline) and subsequently every 8-9 weeks during routine clinical care. ctDNA levels were analyzed using a clinically validated, personalized, tumor-informed 16-plex PCR NGS assay (Signatera™, Natera, Inc). Results: The majority of patients (45/49) had blood samples collected at both baseline and the first on-treatment time point. At baseline, 43/45 (95.6%) patients were ctDNA-positive with a median concentration of 63.5 mean tumor molecules per mL (MTM/mL; range 0.08 to 16,200). In a multivariate linear regression model including metastatic site at baseline and resection status of the primary tumor, ctDNA levels at baseline were lower in patients with metastatic disease limited to the lung (n = 4; p &lt; 0.001) or peritoneum (n = 6; p = 0.002) compared to patients with liver-limited metastases. Moreover, primary tumor resection was independently associated with lower levels of ctDNA at baseline (p = 0.05). At the first measurement on-treatment, 13/45 patients (28.9%) were ctDNA-negative and 32/45 (71.1%) patients were ctDNA-positive with ctDNA levels ranging from 0.04 to 318 MTM/mL. Reduction in ctDNA levels relative to baseline was observed in 42/45 (85.7%) patients while two patients exhibited increased ctDNA levels. One patient had undetectable ctDNA levels at baseline and on treatment. Among the 30 patients with detectable but reduced ctDNA levels on treatment, the median ctDNA levels decreased 55-fold (95% CI: 26–600). Conclusions: The levels of ctDNA in patients with mCRC are influenced by the metastatic site and are lowest among patients with metastases limited to the lung and peritoneum. Our data suggest that clinical applications of ctDNA testing for treatment response monitoring should take the baseline ctDNA levels into account when interpreting ctDNA dynamics. Correlation of ctDNA status with radiological treatment response is underway and will be reported during the conference.
Exploring the link between liver cirrhosis and liver metastasis in colorectal cancer.
Authors: Chaula Desai, Suriya Baskar, Davin Turku, Sweta Lohani, Anush Vasikaran
Journal: Journal of Clinical Oncology (2025)

301 Background: Colorectal cancer (CRC) is the third most common cancer and the second most common cause of cancer mortality in the world. Although it is now associated with improved outcomes due to advancements in treatment modalities, CRC continues to be the most common source of liver metastasis. Previous studies have shown cirrhotic livers to be at reduced risk of metastatic disease. Our study aims to investigate the association between colorectal cancer and liver metastasis in the presence of concomitant liver cirrhosis. Methods: The National Inpatient Sample (NIS) was queried to identify all hospitalizations with colorectal cancer utilizing ICD-10 codes C18.x, C19.x, and C20.x from 2016 to 2020 and were further classified based on the presence or absence of cirrhosis. Demographic and clinical data were analyzed using chi-squared tests, independent sample t-tests, and binary logistic regression (adjusted for age, gender, and Charlson comorbidity index or CCI). The primary outcome studied was liver metastasis. Secondary outcomes were hepatic encephalopathy, portal hypertension, and spontaneous bacterial peritonitis. Statistical significance is indicated by a p-value less than 0.05. Results: A total of 255,599 hospitalizations with colorectal cancer were identified. Out of these, 5,370 (2.1%) had liver cirrhosis and 250,229 (97.9%) did not. Hospitalizations with CRC and concomitant cirrhosis had higher comorbidities as per the Charlson Comorbidity Index (10.5 vs 8.1, p-value&lt;0.001) and higher mortality rates (8.5% vs 4.2%, p-value&lt;0.001). Higher rates of liver metastasis (26.5 vs 23.4, p &lt;0.001) and portal hypertension (26.1% vs 0.3%, p&lt;0.001) were observed in the cirrhosis subgroup. This subgroup also has a significantly higher risk of SBP (2.8% vs 0.2%, p &lt;0.001). Conclusions: This is a large retrospective study analyzing the impact of cirrhosis on liver metastasis in patients with colorectal cancer. Patients with concomitant cirrhosis consistently have increased liver metastasis and worse outcomes. The results of this study imply that diligent CRC screening is of utmost importance in patients with cirrhosis. Patients with CRC and coexisting cirrhosis would benefit from routine surveillance such as carcinoembryonic antigen (CEA) screening or CT scans to allow early detection of liver metastases which could potentially improve outcomes. Colorectal Cancer Patients No Cirrhosis (N=250,229) Cirrhosis (N=5,370) p-value Age (in years) 65.79 ± 13.8 65.04 ± 10.9 &lt;.001 Sex (Female) 47.3% 36.8% &lt;.001 Charlson Comorbidity Index 8.1 ± 3.6 10.5 ± 3.7 &lt;.001 Mortality 4.2% 8.5% &lt;.001 Length of Stay 6.6 ± 7.2 7.4 ± 7.2 &lt;.001 Liver Metastasis 23.4% 26.5% &lt;.001 Hepatic Encephalopathy 0.0% 0.2% &lt;.001 Portal hypertension 0.3% 26.1% &lt;.001 Spontaneous Bacterial Peritonitis (SBP) 0.2% 2.8% &lt;.001
Efficacy, safety and DNA methylation analysis of cadonilimab combined with taxane and cisplatin as first-line treatment for advanced esophageal squamous cell carcinoma (ESCC): Updated results from an open-label, multicenter phase II trial (AK104-IIT-014).
Authors: Wang Qu, Jing Gao, Bo Zhang, Yun Liu, Yijia Guo, Mudan Yang, Jing Huang
Journal: Journal of Clinical Oncology (2025)

463 Background: Immune checkpoint inhibitors combined with chemotherapy had become the first-line standard treatment for advanced ESCC and cadonilimab, as a bispecific antibody simultaneously targeting PD-1 and CTLA-4, may further boost anti-tumor activity with a satisfied safety profile. Here, we present the updated data for the safety and efficacy of cadonilimab combination therapy as the first-line treatment in advanced ESCC. The correlation between DNA methylation and clinical response was also investigated. Methods: Treatment-naïve patients (pts) with unresectable locally advanced or metastatic ESCC were enrolled. Cadonilimab (10mg/kg, iv, d1, q3w) combined with paclitaxel or nab-paclitaxel (175 mg/m 2 , iv, d1, q3w) and cisplatin (65 to 75 mg/m 2 , iv, d1, q3w) were administrated for up to 6 cycles, then Cadonilimab (10mg/kg, iv, d1, q3w) monotherapy continued as maintenance until progressive disease or unacceptable toxicity, with a maximum of 24 months. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), disease control rate (DCR) and safety. Plasma cell-free DNA samples were collected before and after treatment and prepared for methylation level sequencing. Results: As of September 20, 2024, 43 pts were enrolled with a median age of 61 years (range 44-75), 81.4% were male, 39.5% had PD-L1 CPS≥10 and 95.3% had metastatic diseases. All pts were evaluable for safety and efficacy. The ORR was 81.4% (95%Cl: 66.1%-91.1%) and DCR was 97.7% (95%Cl: 86.2%-99.9%). The median PFS (mPFS) was 7.05 months (mo) (95%Cl: 5.86-8.24) and OS analysis was immature. In the PD-L1 CPS≥10 pts, the ORR was 100.0% (95%Cl: 77.1%-100.0%) and mPFS was 7.05 mo (95%Cl: 5.19-8.91). In the PD-L1 CPS＜10 pts, the ORR was 77.3% (95%Cl: 54.2%-91.3%) and mPFS was 7.05 mo (95%Cl: 5.87-8.24). Six hyper-methylated CpG sites, EPTIN9、PKNOX2、DLEU7、SOX7、CNRIP1 and LINC00554 might be the candidate biomarkers as the mean pretreatment methylation levels were signiﬁcantly higher in the PR pts than those in the non-PR pts (p=7.8×10 -7 ). Grade 3-4 treatment-related adverse events (TRAEs) were reported in 44.2% (19/43) pts, mainly including neutropenia (25.6%), leukopenia (9.3%) and hyponatremia (7.0%). The infusion-related reactions (IRR) occurred in 14.0% (6/43) and grade ≥3 IRR occurred in 4.7% (2/43) pts. 7 pts discontinued cadonilimab administration due to TRAEs. Conclusions: The updated results suggested that bispecific antibody cadonilimab combined with taxane and cisplatin as first-line treatment continued to show encouraging anti-tumor activity and manageable safety in pts with advanced ESCC. DNA methylation level might be a potential biomarker for guiding patient outcomes. Clinical trial information: NCT05522894 .