tbuckley/cabot-search huggingface dataset:
Risk factors for relapse based on the molecular profiling of Japanese patients with stage II colorectal cancer.
Authors: Shunsuke Kasai, Keiichi Hatakeyama, Akio Shiomi, Hiroyasu Kagawa, Shoichi Manabe, Yusuke Yamaoka, Yusuke Tanaka, Takahiro Igaki, Ken Yamaguchi
Journal: Journal of Clinical Oncology (2025)

215 Background: The association between the molecular profiles and prognosis of Stage II colorectal cancer (CRC) remains unclear. This study aimed to evaluate the long-term outcomes of Stage II CRC based on the molecular profiling and to examine the risk factors for relapse. Methods: We retrospectively enrolled Japanese patients with pStage II CRC without pre- and/or postoperative adjuvant therapy and whose surgically resected specimens were evaluated using gene expression and whole exome analyses from January 2014 to December 2018. We evaluated the 5-year overall survival (OS) and relapse-free survival (RFS), and examined the risk factors for RFS. Results: We evaluated 322 patients with pStage II CRC, including 126 (39.1%) with right colon cancer, 133 (41.3%) with left colon cancer and 63 (19.6%) with rectal cancer. There were 87 patients (27.0%) with pT4, 175 (54.3%) with venous invasion, 120 (37.3%) with lymphatic invasion, and 68 (21.1%) with perineural invasion. Whole exome analyses revealed that there were 48 patients (14.9%) with MSI-High, and the presence of mutations in key genes for colorectal cancer development was as follows: APC , 245 (76.1%); TP53 , 208 (64.6%); KRAS , 134 (6.5%); PIK3CA , 64 (19.9%); FBXW7 , 27 (8.4%); and BRAF , 21 (6.5%). The 5-year OS and RFS rates were 98.0% and 90.7%, respectively. According to the consensus molecular subtype (CMS) classification based on gene expression, 76 patients (23.6%) had CMS4 and a significantly lower RFS than the other patients (5-year RFS: 83.8% vs. 92.9%, p=0.017). The independent risk factors for RFS were perineural invasion (Hazard ratio [HR] 5.316, p&lt;0.001) and CMS4 (HR 2.399, p=0.020). Conclusions: Molecular profiling of Stage II CRC to assess the risk factors for relapse may contribute to the indication and drug selection for postoperative adjuvant chemotherapy and lead to personalized treatment to improve prognosis.
Vascular endothelial growth factor receptor (VEGFR) -tyrosine kinase inhibitors combined with programmed death receptor-1 (PD-1) inhibitors as third- or later-line treatment in patients with microsatellite-stable (MSS) metastatic colorectal cancer (mCRC): A retrospective study.
Authors: Xiaoqian Li, Fang Liu, Bo Liu, Jing Yang, Shumei Han
Journal: Journal of Clinical Oncology (2025)

68 Background: Microsatellite-stable (MSS) metastatic colorectal cancer (mCRC) shows a low response to programmed death receptor-1 (PD-1) inhibitors. Recent studies suggest that combining vascular endothelial growth factor receptor (VEGFR)-tyrosine kinase inhibitors (TKIs) with PD-1 inhibitors may enhance the anti-cancer activity for mCRC patients. Multiple antiangiogenic drugs have been approved by the FDA and NMPA for the treatment of later-line mCRC. Nevertheless, the effects of various anti-angiogenic drugs when used in combination with immunotherapy for mCRC treatment is not yet fully established. Methods: We conducted a non-interventional, retrospective study. Data were compiled from patients with mCRC at Shandong Cancer Hospital. Eligible patients must have received a combination of anti-angiogenic drugs and PD-1 inhibitors following at least two lines of standard treatment. The treatment period spanned from August 2019 to April 2024. The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). Results: At the cut-off date (April 29th, 2024), 79 eligible patients were available for analysis. Of these, 49 patients received fruquintinib in combination with PD-1 inhibitors (F group), 30 patients received investigator-selected other anti-angiogenic agents in combination with PD-1 inhibitors (NF group). The baseline characteristics of the two groups were well balanced. The median overall survival (OS) was significantly longer in the F group compared to the NF group (hazard ratio [HR]: 0.36, 95% CI 0.14-0.96, P=0.042). The median OS was not reached (95% CI 21.1-NA) in the F group, whereas it was 19.1 months (95% CI 12.6-NA) in the NF group. Subgroup analyses of OS were generally consistent with benefit in the whole population across nearly all subgroups. In contrast to NF group, individuals in F group demonstrated a significant enhancement in overall survival (OS) when patients had received prior bevacizumab (HR: 0.26, 95% CI 0.07-0.75, P=0.015), had no prior treatment with cetuximab (HR: 0.23, 95% CI 0.26-0.97, P=0.045), or had experienced surgical resection at baseline (HR: 0.34, 95% CI 0.12-0.95, P=0.041). The median PFS between two groups showed no statistically significant difference (HR: 0.65, 95% CI 0.38-1.13, P=0.127), F group 6.1 months (95% CI 4.6-10.3) versus NF group 4.4 months (95% CI, 3.0-7.5). Conclusions: Fruquintinib demonstrated improved OS over other anti-angiogenic agents when combined with immunotherapy for third or later-line MSS mCRC treatment.
Correlation between PD-L1 CPS and clinical outcomes in patients treated with first-line nivolumab plus chemotherapy for advanced gastric or gastroesophageal junction cancer: A multi-center retrospective study in Japan.
Authors: Misa Onishi, Nozomu Ogura, Rin Inamoto, Yosuke Kito, Kengo Nagashima, Naoki Takahashi, Mitsuhiro Furuta, Hirokazu Shoji, Nozomu Machida
Journal: Journal of Clinical Oncology (2025)

364 Background: The CheckMate 649 trial showed the superiority of first-line nivolumab plus chemotherapy (Nivo-CT) compared with chemotherapy alone for advanced gastric and gastroesophageal junction (GEJ) cancer with a programmed cell death ligand 1 (PD-L1) combined positive score (CPS) &gt;5, while survival benefit was poor in PD-L1 CPS &lt;1 and &lt;5. However, there were few studies on correlation between PD-L1 CPS and efficacy of first-line Nivo-CT for advanced gastric or GEJ cancer in real world data. Methods: This multi-center retrospective study included patients with histologically confirmed advanced gastric or GEJ cancer who were started on first-line Nivo-CT between December 2021 and December 2023. PD-L1 CPS was assessed before the start of Nivo-CT by classified into three groups at each center: &lt;1, 1~5 and &gt;5, using the Dako PD-L1 immunohistochemistry 28-8 pharmDx assay. The efficacy was evaluated by overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Results: A total of 271 patients were included (median age, 70 [range 18–85] years; male/female, 64/36%; performance status (PS) 0/1/2, 47/49/4%; primary tumor site gastric/GEJ, 90/10%; status unresectable/recurrent, 81/19%; histology intestinal/diffuse, 30/70%). PD-L1 CPS status were evaluated 234 (86%) patients and PD-L1 CPS &lt;1, 1~5 and &gt;5 was found in 35 (15%), 76 (33%) and 123 (53%) patients, respectively. Median follow-up time was 11.3 (range 1-30) months. The median PFS was 9.7 (95%CI, 5.9-16.3), 8.8 (95%CI, 7.2-13.0) and 6.3 (95%CI, 5.3-9.0) months in the patient with PD-L1 CPS &lt;1, 1~5 and &gt;5, respectively. The median OS was 18.7 (95%CI, 17.4-NA), 23.4 (95%CI, 17.7-NA) and 18.3 (95%CI, 13.3-22.5) months, and the ORR were 30.8, 66.7 and 61.3% (p = 0.075) in the patient with PD-L1 CPS &lt;1, 1~5 and &gt;5, respectively. Liver metastases were found in 43 (35.0%) of the patients with PD-L1 CPS &gt;5, significantly more than in the patients with PD-L1 CPS &lt;5 (p &lt; 0.001). Multivariate analysis indicated that PD-L1 CPS status was not associated with prognosis (PD-L1 CPS ≥5 vs. &lt;1, HR 1.18 [95%CI, 0.75-1.86], p = 0.48). In the overall population, grade ≥3 adverse events were observed in 102 (37.6%) patients and grade ≥3 immune-related adverse events were observed in 26 (9.6%) patients. Conclusions: There were no significant differences in prognosis and response between PD-L1 CPS in first-line Nivo-CT for advanced gastric or GEJ cancer in real world data.
Preclinical analysis and clinical validation to identify biomarkers for trifluridine/tipiracil (FTD/TPI) efficacy with or without bevacizumab in patients with metastatic colorectal cancer.
Authors: Mitsukuni Suenaga, Tetsuo Mashima, Naomi Kawata, Shingo Dan, Hiroyuki Seimiya, Kensei Yamaguchi
Journal: Journal of Clinical Oncology (2025)

230 Background: We previously identified candidate biomarkers for FTD/TPI efficacy through preclinical and translational studies in patients with metastatic colorectal cancer (mCRC). Recent studies reported that FTD/TPI plus bevacizumab (BEV) improved survival compared to FTD/TPI alone. This study evaluated the clinical significance of these biomarkers in patients with refractory mCRC receiving either FTD/TPI plus BEV or FTD/TPI alone. Methods: Candidate biomarkers were selected based on our transcriptomic and cell biological analyses. We validated these biomarkers in mCRC patients treated with FTD/TPI plus BEV (cohort A) or FTD/TPI alone (cohort B). Blood samples were collected at baseline (BL), before the second cycle (2nd), and progressive disease (PD), with serum biomarker levels measured using ELISA. Change patterns were classified as ‘increased’ or ‘decreased’ from BL. To address the unbalanced distribution of baseline characteristics between cohorts, propensity score matching (PSM) was performed. Results: A total of 112 patients were included, with 34 in each cohort after PSM. Cohort A showed significantly longer overall survival (OS) (14.4 vs 6.2 months, HR 0.53, 95%CI: 0.30-0.93) and higher disease control (DC) (58.8 vs 34.4%, P=0.047) compared to cohort B. In univariate analysis, increased IL-8 or AREG at 2nd and increased IFI16 at PD were associated with poorer clinical outcomes. Grade ≥3 neutropenia (NEU) was linked to better survival in both cohorts. Multivariable analysis identified decreased AREG and Grade ≥3 NEU as better markers for progression-free survival and OS. OS was significantly longer in cohort A compared to B (12.8 vs 5.8 months, HR 0.43, 95%CI: 0.21-0.89) when IL-8 increased at 2nd. Cohort A also had longer OS compared to cohort B when EREG (12.8 vs 6.2 months, HR0.27, 95%CI: 0.11-0,65) or AREG (14.2 vs 9.7 months, HR 0.40, 95%CI: 0.17-0.95) decreased at 2nd. There was no significant interaction between the regimen and biomarkers (IL-8, EREG, and AREG) for OS. Conclusions: Our data suggest that AREG may serve as a prognostic marker for FTD/TPI efficacy. Changes in IL-8, EREG and AREG potentially contribute to the extended survival benefit of combining BEV with FTD/TPI.
Impact of tislelizumab + chemotherapy versus placebo + chemotherapy on patient-reported symptoms and disease progression by programmed death-ligand 1 expression in gastroesophageal adenocarcinoma: A post hoc analysis of the RATIONALE-305 trial.
Authors: Marcia Cruz-Correa, Do-Youn Oh, Rui-Hua Xu, Markus H. Moehler, Ken Kato, Frederick Barnes, Yaling Xu, Tao Sheng, Gisoo Barnes, Timothy Victor
Journal: Journal of Clinical Oncology (2025)

365 Background: The relationship between patient-reported outcome (PRO)-based symptom scores, recurrent PRO-based symptomatic deterioration events (RDEs), and terminal events such as progression-free survival (PFS) are rarely examined in the oncology therapeutic domain. Thus, we applied a 3-component joint model (JM) framework aiming to illuminate more clinically interpretable associations between PRO-based treatment effects, RDEs, and PFS among subgroups of patients with programmed death-ligand 1 (PD-L1) expression of ≥1%, ≥5%, and ≥10%. Methods: The final analytic sample included 378 patients in the tislelizumab + chemotherapy arm (T+C) vs 401 in the placebo + chemotherapy arm (P+C) for the PD-L1 ≥1% subgroup, 238 in the T+C arm vs 237 in the P+C for the PD-L1 ≥5% subgroup, and 118 in the T+C arm vs 125 in the P+C arm for the PD-L1 ≥10% subgroup. Symptom domain scores from the EORTC QLQ-C30 and QLQ-STO22 symptom were modeled. Change from baseline (CFBL) in each domain was analyzed every cycle up to cycle 6, then every other cycle thereafter (up to cycle 25). The joint model was applied to all PD-L1 subgroups and comprised three components: 1) linear mixed model (LMM) predicting CFBL symptom scores, 2) Cox proportional hazard (CPH) model for disease progression (PFS as terminal event), and 3) frailty (random effects for RDEs) CPH model for time to PRO-based RDEs. Osoba’s 10-point threshold was used to define RDEs. Results: In the LMM, significant treatment efficacy for the T+C arm compared with the P+C arm was observed for the GHS/QoL ( P =0.0080) and dietary restriction scores ( P =0.0475) in the PD-L1 ≥5% subgroup. In the PD-L1 ≥1% subgroup, compared with the P+C arm, the T+C arm was associated with less worsening in pain/discomfort ( P =0.0376), upper gastrointestinal symptoms ( P =0.0088), and dietary restrictions ( P =0.0352). In the CPH model, the average hazard ratio indicated that compared with the P+C arm, the T+C arm was associated with a reduction in risk of disease progression across all PRO domains and PD-L1 subgroups. Lastly, the PRO-based RDE frailty predictions were strongly associated with PFS risk in the PD-L1 ≥1% and ≥5% subgroups for GHS/QoL, and in the PD-L1 ≥1% subgroup for physical functioning, fatigue, dysphagia-odynophagia, pain/discomfort, and dietary restrictions, as well as for pain/discomfort and dietary restrictions in the PD-L1 ≥5% subgroup. Conclusions: Through the 3-component JM, PRO-based effects were detected and demonstrated strong associations between PRO-based RDEs, and investigator-assessed PFS among varying PD-L1 expression levels. This framework may be a promising alternative for analyzing and interpreting PRO data in the context of PFS.
Development of a methylation-based, tissue-agnostic test for the detection of molecular residual disease by circulating tumor DNA.
Authors: John Paul Y.C. Shen, Johannes Reiter, Joshua Babiarz, Preethi Srinivasan, Fei Lu, Ehsan Haghshenas, Tzu-Chun Chen, Nathan Liang, Jayashree Joshi, Hsiao-Yun Huang, Liliana Cerna, Spenser Alexander, Boris Gutman, Garima Kushwaha, Vasily N. Aushev, Marcia Cruz-Correa, Matthew Rabinowitz, Trupti Kawli, Alexey Aleshin, Stacey A. Cohen
Journal: Journal of Clinical Oncology (2025)

266 Background: Clinical validation studies support tumor-informed molecular residual disease (MRD) as a prognostic biomarker for disease recurrence across multiple solid tumor types. However, these tests are not always feasible due to the occasional lack of tumor tissue. Here, we discuss the design of a test for tissue-agnostic MRD detection and its application to a cohort of patients with colorectal cancer (CRC). Methods: A targeted panel composed of differentially methylated regions was developed. A machine-learning model was trained on differential methylation patterns in order to classify plasma samples as MRD-positive or MRD-negative. Performance of the independently trained classifier was assessed in a cohort of 247 patients enrolled in the Bespoke CRC trial (NCT04264702). These patients had MRD results available using a tumor-informed circulating tumor DNA (ctDNA) assay (Signatera), of whom 163 were persistently MRD-negative without clinical progression and 84 had MRD-positive results. Tissue-agnostic MRD results were compared to the tumor-informed results by calculating the percent positive agreement (PPA). Additionally, the differentially methylated allele fraction (DMAF) from the tissue-agnostic test was compared with variant allele frequencies (VAFs) from the tumor-informed test. Results: In the Bespoke CRC clinical cohort (72% non-Hispanic White, 54% male, mean age 61.4±12.3 years), 71 (28%) patients had stage II CRC, and 147 (60%) had stage III CRC. Overall, PPA was 86% (95% CI: 70-100%) and specificity was 97% (95% CI: 93-100%). When categorizing based on tumor-informed MRD VAF levels, PPA was 97% for VAF &gt;0.2%, 100% for VAF 0.1-0.2%, 89% for VAF 0.04-0.1%, and 68% for VAF &lt;0.04%. The DMAFs strongly correlated with the VAFs from the tumor-informed test and the correlation was independent of disease stage, histology, age, and sex. Conclusions: This is the first study of its kind demonstrating high concordance between a tissue-agnostic MRD test and a clinically validated tumor-informed ctDNA assay. These findings demonstrate that in cases where tissue is not available or of inadequate quality, a methylation-based tissue-agnostic assay may serve as a potential alternative for MRD detection.
A first-in-human phase I trial with antibody drug conjugate ADCT-701 in neuroendocrine tumors and carcinomas.
Authors: Jaydira Del Rivero, John Glod, Tamika Magee, Kimberley Cooper, Anna Rivero, Tea Lanfranconi, Rashmika Patel, W Douglas Figg, Yves Pommier, Brigitte C. Widemann, Nitin Roper
Journal: Journal of Clinical Oncology (2025)

TPS672 Background: Neuroendocrine neoplasms (NENs) consist of neuroendocrine tumors (NETs) and neuroendocrine carcinomas (NECs), which are rare malignancies found in various anatomical sites, including the gastrointestinal tract, pancreatic islets, lungs, and adrenal glands. Poorly differentiated NECs are classified as high-grade carcinomas that bear resemblance to small-cell lung cancer (SCLC). Treatment for poorly differentiated NECs typically follows small-cell carcinoma guidelines, utilizing platinum-based regimens; however, these patients experience a high risk of relapse and demonstrate a limited response to additional systemic therapies. Adrenocortical carcinoma (ACC) is another rare malignancy associated with a median survival of approximately 14.5 months post-diagnosis, and advanced disease management options show limited efficacy. Currently, no targeted therapies have demonstrated significant effectiveness for this condition. Preclinical investigations have indicated that Delta-like non-canonical notch ligand 1 (DLK1) is expressed in various neuroendocrine neoplasms, including ACC, SCLC, neuroblastoma, pheochromocytoma, and paraganglioma. ADCT-701, a humanized antibody targeting DLK1, has shown potential in suppressing tumor growth and enhancing survival across multiple cancer models expressing this marker. Methods: This Phase I dose escalation study (NCT06041516) aims to enroll adult patients with histologically or cytologically confirmed neuroendocrine neoplasms or malignant ACC with evaluable disease, as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Participants will be part of a dose-finding trial. A 3+3 design is utilized to assess up to ten different dose levels of ADCT-701. Dose escalation continues unless dose-limiting toxicities occur, the maximum tolerated dose (MTD) is reached, or an optimal dose is established. The primary endpoint of the study is to ascertain the recommended phase 2 dose of ADCT-701 in patients with neuroendocrine neoplasms or malignant adrenocortical carcinoma. Secondary endpoints will assess safety, preliminary tumor activity, response rate, overall survival, pharmacokinetics, and the immunogenicity profile of ADCT-701. The trial aims to enroll up to 70 evaluable patients across a maximum of 10 dose levels. For further details, please refer to clinical trial information NCT06041516. Clinical trial information: NCT06041516 .
Correlation of tumoral collagen width with overall survival and tumoral collagen straightness with distant recurrence-free survival in patients with pancreatic ductal adenocarcinoma.
Authors: Alexander Marwaha, Kriti Dhamija, Rachel Kim, Rachel Dileo, Yue Yin, Abdulahi Hassan, Dulabh K. Monga, Michael Landau
Journal: Journal of Clinical Oncology (2025)

779 Background: Quantitative measurements of fibrillar collagen characteristics has been shown to correlate with survival in several types of malignancy. The aim of this study was to determine whether these characteristics correlate with survival in pancreatic ductal adenocarcinoma. Methods: Patients who underwent pancreatic resection for pancreatic ductal adenocarcinoma at an Allegheny Health Network hospital between 1/1/2019 and 12/31/2023, and for whom archived formalin-fixed paraffin-embedded tumor tissue was available, were included in the study. Clinical and pathologic characteristics were collected from the patient's electronic medical record. Survival data included overall survival (OS), local recurrence-free survival (RFS), and distant RFS. One section of tumor per patient was stained with Picrosirius Red and a representative digital image was obtained with a camera attached to a microscope at 100x magnification. Each image was analyzed with CT-FIRE software to determine averages of collagen fiber width, length, straightness, and angle. Descriptive statistics were initially computed. Log-rank tests were also conducted to compare the OS rate and RFS rate between four different groups (width, length, straightness, angle). Each group was divided into high and low groups, using the mean as cutoff. In the end, multivariate Cox regression was conducted by controlling the confounders including sex, perineural invasion, lymphovascular invasion, and presence of lymph node metastasis to examine the hazard ratios of OS, local RFS, and distant RFS for the four collagen fiber metrics. All statistical analyses were performed via SAS 9.4 under alpha level .05. Results: One hundred three patients met the inclusion criteria. Based on the results of log-rank test, OS was significantly different between high and low collagen width groups, p = .0251. The lower width group had higher survival rate than the upper width group. Also, distant recurrence-free survival was significantly different between high and low collagen straightness groups, p = .0053. The lower straightness group had higher distant RFS rate than upper group. The results of multivariate Cox regression were consistent with the Kaplan-Meier curves. Compared to the high collagen width group, the low collagen width group had a 57% lower chance of dying, hazard ratio = 0.43, 95% CI [0.23, 0.78], p = .0056. The low collagen straightness group had a 60% lower chance of distant recurrence than the high collagen straightness group, hazard ratio = 0.40, 95% CI [0.19, 0.85], p =.0163. Conclusions: Quantitative collagen fiber metrics could help identify patients with resected pancreatic adenocarcinoma who are at risk of earlier death and distant recurrence.