tbuckley/cabot-search huggingface dataset:
DKN-01 plus bevacizumab and chemotherapy as second-line (2L) investigational therapy in advanced microsatellite stable (MSS) colorectal adenocarcinoma (CRC): DeFianCe trial.
Authors: Meredith Pelster, John H Strickler, Cynthia A. Sirard, Jason Baum, Mike Haas, Craig E. Devoe, Liliana Bustamante, Jeffrey Alan Bubis, Mark Sanders Womack, Ki Y. Chung, Joshua P. Raff, Zev A. Wainberg
Journal: Journal of Clinical Oncology (2024)

104 Background: CRC is characterized by hyperactivation of the Wnt pathway where DKK1 plays a critical regulatory role. DKN-01 is an IgG4 monoclonal antibody that potently neutralizes DKK1. DKN-01 has immunomodulatory activity and stimulates a pro-inflammatory tumor microenvironment. Elevated DKK1 expression has been shown to correlate with fluorouracil (5FU) resistance in CRC tumors. 5FU-based combination therapies have demonstrated promising clinical activity in combination with DKN-01 in gastric cancer. In pre-clinical models of 5FU-resistant CRC, DKN-01 showed potent anti-tumor effects. Methods: DeFianCe (NCT05480306) is a Phase 2 randomized, open-label, two-part, multicenter study to evaluate efficacy and safety of DKN-01 plus FOLFIRI/FOLFOX and bevacizumab versus standard of care (SOC) [FOLFIRI/FOLFOX and bevacizumab] as 2L treatment of advanced MSS CRC patients (pts). The primary endpoint of the single arm Part A (DKN-01 + SOC) was safety and tolerability with secondary endpoints including overall response rate (ORR), progression-free survival (PFS) and overall survival. Retrospective analysis of tumoral DKK1 mRNA expression was measured centrally by in situ hybridization. Results: Thirty-three pts enrolled in Part A between Sept 2022-April 2023. As of 21 Aug 2023, median age 56 years (35, 84); 20 males. 29 pts had tumors with evaluable baseline DKK1 expression; 55% were DKK1-expressing (≥1% tumor cells). All patients had received prior 5FU-based therapies, 30 pts (91%) with oxaliplatin in combination and 17 pts (52%) had prior bevacizumab. 24 pts (73%) had RAS mutations (22 KRAS, 2 NRAS) and 23 pts (70%) had liver metastasis. 30 pts (91%) received DKN-01 + bevacizumab + FOLFIRI. 17 pts (52%) had ≥grade 3 treatment related adverse events (TRAE) with neutrophil count decreased, anemia and fatigue representing the most common. No pt discontinued DKN-01 due to a TRAE. Of the 27 response evaluable pts the ORR was 30% and the DCR was 93%: 8 PR, 17 SD and 2 PD. The median PFS has not been reached. Conclusions: DKN-01 in combination with SOC was well tolerated with promising preliminary activity (ORR 30% and DCR 93%) in the single arm Part A. PFS has not been reached and survival follow up is ongoing. Part B randomized expansion phase has begun and is enrolling an additional 130 pts. Tumoral DKK1 expression and correlation with clinical outcomes will be evaluated as an exploratory efficacy endpoint. Clinical trial information: NCT05480306 .
Prognostic value of minimal residual disease profiling in resectable hepatocellular carcinoma.
Authors: Jie Hu, Jian Zhou, Haoran Tang, Cancan Jia, Feng Xie, Yue Zhang, Shidong Jia
Journal: Journal of Clinical Oncology (2024)

530 Background: Detecting post-surgical residual disease is a critical clinical requirement in resectable hepatocellular carcinoma (HCC). Previous studies focused on specific genomic regions have indicated that ctDNA holds promise as a tool for prognostic assessment. Nevertheless, these methods exhibited limited sensitivity and failed to meet the minimal residual disease (MRD) threshold. Here we report the prognostic value of MRD profiling in HCC patients who have undergone hepatectomy. Methods: This retrospective study involved 88 HCC patients who underwent surgical resections in China, from January to May in 2016. During surgery, tumor and normal tissue specimens were collected. Plasma samples were obtained 7 days post-surgery. PredicineBEACON, a baseline tissue- or blood-informed MRD assay, was used for MRD profiling. This entailed identifying tumor-specific mutations through whole exon sequencing of tissue samples. Subsequently, a personalized MRD panel, selecting up to 50 mutations via bioinformatics pipelines merged with a fixed panel featuring 500 tumor actionable hotspots, was created for each patient. To detect MRD in post-surgery plasma samples, we employed ultra-deep sequencing at a coverage of 100,000X, utilizing the designed panel. Results: In the cohort of 88 patients, the distribution based on Barcelona Clinic Liver Cancer (BCLC) staging was as follows: 79.5% stage A (N=70), 12.5% stage B (N=11), and 8.0% stage C (N=7,). The MRD assay identified 36 patients as MRD+ and 52 patients as MRD-. We observed significant correlations between MRD status and both relapse-free survival (RFS) and overall survival (OS). For MRD+ patients, the median RFS was 17.1 months, while it was not reached for MRD- patients (p=0.0013). Likewise, the median OS for MRD+ patients was 40.1 months, in contrast to it not being reached for MRD- patients (p=0.0012). The MRD positivity rate stood at 100% in stage C patients, a significantly higher percentage compared to the rates observed in stage B (36.4%, p=0.0256) and stage A (36.2%, p=0.0042). Significantly, MRD status emerged as a pivotal prognostic differentiator among clinically low-risk patients in stage A: among MRD+ patients, the median RFS was 23.3 months, whereas it was not reached for MRD- patients (p=0.05). Additionally, the median OS of both MRD+ and MRD- was not reached but their survival curves showed significant differences (p=0.038). Conclusions: This study demonstrated the clinical utility of ctDNA MRD assay in patients with resectable HCC, as notably evident in the robust detection of MRD using plasma samples collected 7 days after surgery. Furthermore, the assessment of post-surgical MRD status provided valuable prognostic insights into both patient survival and the risk of disease relapse. ctDNA MRD status played a pivotal role as a prognostic differentiator, particularly among clinically low-risk patients.
Genomic analysis of oesophageal carcinoma (EC) to identify recurrent mutations in histone methyltransferases as a distinctive subset.
Authors: Jingyuan Wang, Joanne Xiu, Matthew James Oberley, Francesca Battaglin, Hiroyuki Arai, Shivani Soni, Wu Zhang, Richard M. Goldberg, Anthony F. Shields, Axel Grothey, Jimmy J. Hwang, John Marshall, Igor A. Astsaturov, Benjamin Adam Weinberg, Emil Lou, Michael J. Hall, Rachna T. Shroff, Moh'd M. Khushman, Davendra Sohal, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2024)

379 Background: Histone-lysine N-methyltransferase 2 (KMT2) family proteins methylate lysine 4 on the histone H3 tail at important regulatory regions in the genome and thereby impart crucial functions through modulating chromatin structures and DNA accessibility, which is associated with tumorigenesis and immune tolerance, indicating its possible correlation with the efficacy of immunotherapy. Recurrent mutations of KMT2 have been identified in EC, but data addressing the molecular features of KMT2 mutated (MT) EC are lacking. We aimed to understand the molecular profile of KMT2 -MT EC. Methods: A total of 787 oesophageal carcinoma [adenocarcinoma (EAC), N=604; squamous cell carcinoma (ESCC), N=183] were analyzed using next-generation sequencing (NGS) and immunohistochemistry (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was calculated based on somatic nonsynonymous mutations, and mismatch repair deficiency (dMMR)/microsatellite instability-high (MSI-H) status was evaluated by a combination of IHC, Fragment analysis and NGS. Results: The mutation spectrum of KMT2A/C/D was significantly different between ESCC and EAC ( KMT2A, 2.7% vs. 1.2%; KMT2C, 3.8% vs. 1.2%; KMT2D, 14.2% vs. 2.0%, P &lt;0.05). KMT2-MT EAC tumors showed significantly higher mutation rates in CIC (13% vs 1.1%), NF1 (12.5% vs 2.2%), FBXW7 (12% vs 3.4%), ATM (11.5% vs 2.6%) and BRCA1 (11.5% vs 1%, all q&lt;0.05), compared to KMT2-WT tumors. However, in ESCC there were no significant differences in gene mutations between the KMT2-MT and WT groups. Significantly higher rates of dMMR/MSI-H (19.2% vs 1.0% in EAC, 5.4% vs. 0% in ESCC, both p&lt;0.01) were seen in both KMT2-MT ESCC and EAC, compared to KMT2-WT cohorts, respectively. TMB was significantly higher in both KMT2-MT ESCC (median: 10 vs 8.6 mut/Mb, P=0.042) and EAC (23.9 vs 8.0 mut/Mb, P&lt;0.0001), compared to KMT2-WT cohorts, respectively. A numerically longer immune-related overall survival was observed in KMT2 -MT EC patients, compared to KMT2 -WT EC patients (9.05 vs 6.98 months, HR=0.744, 95%CI: 0.52-1.07, P =0.11). Conclusions: This is the largest study to investigate the distinct genomic landscapes between KMT2 -MT and WT EC to date. Our data showed the KMT2 -MT EC has a distinctive genetic profile, indicated by higher TMB, and higher frequency of dMMR/MSI-H and gene mutations involved in DDR and epigenetic regulation. Understanding these molecular characteristics may be informative in the development of effective treatment strategies in KMT2 -MT EC.
Feasibility of functional evaluation in older adults with gastroesophageal cancer using fitness trackers.
Authors: Lauren Laderman, Caitlin R. Meeker, Elizabeth A. Handorf, Kelly A. Filchner, Mohamedtaki Abdulaziz Tejani, Grant Richard Williams, Arthur Winer, Sukeshi Patel Arora, Namrata Vijayvergia, Efrat Dotan
Journal: Journal of Clinical Oncology (2024)

298 Background: With advances in treatment and an aging population, gastroesophageal cancer (GEC) in older adults (OA) is increasing. Geriatric assessment (GA) is recommended as part of treatment decision in patients ≥ 65. Unfortunately, due to the complex nature and multiorgan effects of GEC, it is often difficult for oncologists to discern whether GA abnormalities are secondary to aging or the GEC itself. Because of their objectivity, fitness trackers are becoming increasingly popular in the functional evaluation of cancer patients. While fitness trackers have shown feasibility and validity in some cancers, data for their use in OA is currently limited. Objective: Evaluate the feasibility of functional status assessment via Fitbit activity tracker (FB) in comparison to traditional geriatric assessments in OA with GEC. Methods: Patients age ≥65 with any stage of GEC completed a GA and were given a FB to wear for 3 days in line with the battery life of the device. GA included a comprehensive evaluation of all geriatric domains with functional status assessed by performance status (PS), falls, Timed Up and Go (TUG), Activities of Daily Living (ADLs), and Instrumental Activities of Daily Living (IADLs). FB collected total steps per day (SPD), and patients’ mean SPD was calculated. We compared patient characteristics and outcomes using Fisher’s exact and Wilcoxon tests grouped by below and above median SPD. Results: 82 patients completed GA, of which 69 (84%) wore FB for ≥8 hours. Mean SPD for all patients was 2827 (38 – 11032), median SPD was 2264. Patients with ≤ median SPD were older (75 vs 72 p=0.034), female (32% vs 14% p=0.093), Black (24% vs 9% p=0.068), and living alone (29% vs 14% p=0.153). Patients SPD below and above the median had similar distributions of education level (≤12 yrs 35% vs 31% p=0.802) and Stage (&gt;2 82% vs 80% p=0.99). Patients with SPD below the median were more likely to have ≥ 2 abnormalities on GA (68% vs. 40%, p=0.03), self-reported PS &gt;2 (24% vs 0% p=0.013), and impaired IADL (33% vs 9% p=0.064). Patients with lower SPD had higher rates ≥Gr 3 toxicity (47% vs 20% p=0.022) and hospitalization (32% vs 6% p=0.006). The rate of abnormal TUG was similar in both groups (21% vs 17%, p=0.285). Conclusions: FB use for short objective evaluation functional status is feasible among OA with GEC and provides data which correlates with other GA abnormalities and treatment tolerance. Additional research is warranted to further incorporate this assessment tool into clinical care.
Comparison of palliative treatment modalities among patients with colon cancer: A review of NCDB Database.
Authors: Baqir Jafry, Munir Buhaya, Syed Mohammad Ali Kazmi
Journal: Journal of Clinical Oncology (2024)

220 Background: Among colon cancer patients some patients present with significant symptom burden needing upfront palliation-directed therapies, aimed to improve the quality of life of patients with severe illnesses. These include palliation-directed surgery, chemotherapy, radiation, pain management, or a combination of these. The extent to which these palliation-directed therapies are utilized in colon cancer remains under-explored. This study's purpose was to understand the trends in utilization and factors associated with palliation-directed treatment modalities among patients with colon cancer. Methods: From the National Cancer Database, we identified patients with colon cancer who received first-line palliation-directed therapies from 2004 to 2016 without an intent to give definitive therapy. We evaluated the use of these treatments over time and compared frequencies of categorical variables using Chi square tests. A multivariate logistic regression was also used to evaluate patient characteristics associated with the use of these treatments. Results: We identified a total of 21,516 patients receiving palliation-directed therapy among patients with colon cancer – 19,506 received single palliation-directed therapy, 908 received a combination of palliation-directed treatments without pain management and 1102 received a combination of palliation-directed treatments with pain management. Of the 21,516 patients who received single palliation-directed treatments, 50.6% and 49.4% were male and female, respectively. The mean age was 67 years. Most patients had no existing comorbidities (68.7%), lived in metropolitan areas (81.6%), had grade 2 (59.4%) and AJCC Clinical stage 4 colon cancer (32.6%). Overall, most patients received chemotherapy (50.7%) as a palliative treatment, followed by surgery (25.2%), pain management (14.4%) and radiation (9.7%). The utilization of chemotherapy (39.6% in 2004 to 63.1% in 2016) and pain management (9.7% in 2004 to 12.7% in 2016) increased over time while the utilization of surgery (37.1% in 2004 to 16.9% in 2016), and radiation (13.6% in 2004 to 7.3% in 2016) decreased over time. The type of facility, readmission rates, and proportion of individuals who were whites, elder (age&gt;50), resided in metropolitan areas and had insurance were significantly different between groups. Male patients, patients without existing comorbidities, and patients with grade 2 tumors had higher odds of receiving surgery, radiation, or chemotherapy as palliative therapy compared to pain management. Conclusions: Utilization of first-line palliation-directed chemotherapy has increased significantly from 2004 to 2016 whereas surgery and radiation therapy use has decreased in that period. Notably, patient characteristics such as gender, absence of existing comorbidities and grade 2 tumors influence the choice of therapy.
ARC-8: Phase 1/1b randomized study of quemliclustat + gemcitabine/nab-paclitaxel ± zimberelimab in patients with treatment-naive metastatic pancreatic adenocarcinoma.
Authors: Zev A. Wainberg, Gulam Abbas Manji, Nathan Bahary, Susanna Varkey Ulahannan, Shubham Pant, Nataliya Volodymyrivna Uboha, Paul Eliezer Oberstein, Lawrence H Lu, Jennifer R. Scott, Wilson Wu, Joon Rhee, Dimitry S. A. Nuyten, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2024)

665 Background: Metastatic pancreatic ductal adenocarcinoma (mPDAC) remains a challenging cancer to treat, with median survival of &lt;1 year. In PDAC, extracellular adenosine (eADO) produced from ATP is released from tumor cells and suppresses antitumor immune responses. Quemliclustat (Q) is a potent and selective small-molecule inhibitor of soluble and cell-bound CD73, a key enzyme involved in the production of eADO within the tumor microenvironment. Elevated CD73 expression is found in 40-60% of PDAC and correlates with poor clinical outcome. ARC-8 evaluated Q ± anti-PD-1 antibody zimberelimab (Z) in combination with gemcitabine/nab-paclitaxel (G/nP). Methods: ARC-8 (NCT04104672) is a phase 1b dose escalation and expansion study in patients (pts) with treatment-naive mPDAC. Q 100mg was previously determined as the recommended dose for expansion (Manji et al., 2021). Q 100 mg is administered with standard doses of G/nP with Z (240 mg IV Q2W) in the dose expansion (Cohort A; QZ+G/nP) and in randomized (2:1) cohorts either with Z (Cohort A1; QZ+G/nP) or without Z (Cohort A2; Q+G/nP). Adverse events (AEs) are recorded and graded per NCI CTCAE 5.0. Clinical activity is assessed every 8 weeks per RECIST v1.1. Endpoints include measures of safety and median overall survival (OS). Results: As of June 19, 2023, 122 patients with untreated mPDAC were treated with Q 100mg, including 93 pts treated with QZ+G/nP (dose escalation, n=6; cohort A, n=26; and randomized cohort A1, n=61) and 29 pts treated with Q+G/nP (Cohort A2). Median age was 66 years, 66% ECOG of 1, and 65% had liver metastasis at baseline. Median survival follow-up was 21 months (mos). Efficacy is summarized in Table 1. All patients reported AE, 85% Grade 3+ AE, and 23% discontinued study treatment due to AE. Most common Grade 3+ AE was neutrophil count decreased (31%) and anemia (25%). Conclusions: Results from ARC-8 demonstrate the addition of Q 100 mg ± Z to G/nP was safe and tolerable, with no significant added toxicity to GnP. Modulation of eADO with Q may confer benefit beyond radiographic measures of disease. The OS is promising and supports further development of Q in mPDAC. Clinical trial information: NCT04104672 . [Table: see text]
Does routine clinical assessment of older adults with gastroesophageal cancer tell the whole story?
Authors: Meghan Connors, Caitlin R. Meeker, Elizabeth Handorf, Kelly A. Filchner, Mohamedtaki Abdulaziz Tejani, Grant Richard Williams, Arthur Winer, Sukeshi Patel Arora, Namrata Vijayvergia, Efrat Dotan
Journal: Journal of Clinical Oncology (2024)

297 Background: Geriatric Assessment (GA) can help oncologists determine fitness of their older patients (pt) for anti-cancer therapy. Our objective was to compare routine provider assessment (PA) and GA of older adults with gastroesophageal cancer (GEC). Methods: Patients ≥65 with any stage of GEC completed a GA. The pt’s provider completed a PA and abnormalities detected by both assessments were centrally reviewed and compared. GA and PA assessed functional status, nutrition, comorbidities, psychological distress, cognition, social support, and chemotherapy toxicity risk. Validated assessment tools were used for the GA. Data collected 3 months post-enrollment included hospitalization, ≥ grade 3 toxicities, and treatment delays. We compared the proportions detected/not detected abnormalities by PA vs GA using McNemar’s test for paired data, and we measured agreement using Kappa statistics (1=full, 0=no, -1=disagreement). Results: 82 pts were enrolled, majority male (74%), median age 73 (65-91), stage III/IV (82%) disease on first line therapy (79%). Cancer sites included gastric (32%), esophageal (43%), GEJ (26%). Pts’ demographic and clinical characteristics did not predict for the identification of GA abnormalities. GA detected 196 abnormalities and PA detected 86. Majority of pts (84%) had ≥ 1 unidentified abnormality by PA. Providers identified more pts with clinically significant comorbidities as compared to GA. However, the GA identified more abnormalities compared to PA in all other evaluated domains (Table). Low agreement was found between PA and GA in any of the domains. Pts scoring high on the CARG chemotherapy toxicity prediction tool (p=0.004) and pts with evidence of psychological distress (p=0.049) had more ≥ grade 3 toxicity. Pts with abnormalities in functional status, nutrition, psychological distress, and a high CARG score were more likely to be hospitalized during therapy. Conclusions: Clinical characteristics of older pts with GEC are not predictive of GA abnormalities. While providers were better at identifying comorbidities, the GA resulted in a comprehensive evaluation of all domains and identified significant abnormalities that affect treatment outcomes in this population. [Table: see text]
Multicenter clinical validation of GutSeer: A cost-effective, blood-based assay for early detection and localization of major gastrointestinal cancers.
Authors: Wanqing Chen, Changfa Xia, Chengcheng Ma, Yiying Liu, Minjie Xu, Wei Li, Jin Sun, Chengxiang Gong, Qiye He, Yunzhi Zhang, Zhixi Su, Rui Liu
Journal: Journal of Clinical Oncology (2024)

739 Background: Gastrointestinal (GI) cancers account for over one-third of cancer-related deaths. We have previously developed GutSeer, a non-invasive assay utilizing cell-free DNA (cfDNA) methylation and fragmentation signatures, to cost-effectively detect and localize five major GI cancers, including colorectal (CC), gastric (GC), liver (LC), esophageal (EC), and pancreatic cancer (PC). Methods: GutSeer was initially developed and validated in a large retrospective cohort of 1844 plasma samples, demonstrating excellent performance with specificity, sensitivity, and tissue of origin (TOO) accuracy at 96.7%, 86.2%, and 82%, respectively. In this study, we conducted a blind, multi-center clinical test for further validation. Participants were recruited from two centers, Beijing (BJ) and Shanghai (SH). Cohort BJ included 42 participants (20 healthy, 22 cancer), and Cohort SH comprised 403 participants (105 healthy, 123 benign, 175 cancer). Over half of the cancer samples in Cohort SH were in early-stage disease (TNM stages I and II). Results: In Cohort BJ, GutSeer showed 100% specificity, 68.2% sensitivity, and 86.7% TOO accuracy. Individual cancer type sensitivities within Cohort BJ were 100% for CC, 57.1% for EC, 75% for GC, 40% for PC, and 100% for LC. In Cohort SH, GutSeer exhibited 94.6% specificity for healthy samples and 86.2% for benign conditions. For cancer samples in Cohort SH, the overall sensitivity achieved 78.9%, with specific sensitivities of 92.3% for CC, 81.0% for EC, 78.4% for GC, 52.9% for PC, and 86.4% for LC. Moreover, GutSeer also efficiently detected early-stage cancers, with stage-wise sensitivities ranging from 64.7% (stage I) to 96.3% (stage IV). TOO accuracy in Cohort SH was 79.0%, with individual cancer types achieving accuracies from 71.7% to 94.7% (72.2% for CC, 71.7% for EC/GC, 94.7% for LC, and 77.8% for PC). Conclusions: GutSeer demonstrates promising potential as a cost-effective, non-invasive test for early detection and localization of major GI cancers. Its consistently high performance in both retrospective and multi-center blind clinical tests implies its potential to revolutionize the screening and diagnosis paradigm for GI cancers.