tbuckley/cabot-search huggingface dataset:
Real-world treatment patterns, testing patterns, and clinical outcomes of first-line (1L) therapy for metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma (mGC/GEJC/EAC).
Authors: Sumie Kakehi, Keith A. Betts, Xiaoyu Nie, Sophie A. Kitchen, Saurabh Ray
Journal: Journal of Clinical Oncology (2024)

275 Background: GC/GEJC/EAC are among the leading causes of cancer-related morbidity and mortality worldwide. Nivolumab + fluoropyrimidine- + platinum-containing chemotherapy (NIVO+chemo) has demonstrated superior efficacy in patients with advanced non-HER2-positive (HER2-) GC/GEJC/EAC versus chemo alone in the CheckMate 649 trial. The objective of this study was to characterize real-world treatment and PD-L1 testing patterns in the 1L setting for mGC/GEJC/EAC since the FDA approval of NIVO+chemo on April 16, 2021. Methods: This retrospective observational study used the electronic medical record data from the ConcertAI Patient360 database. Adult patients with HER2- mGC/GEJC/EAC and 1L initiation date (index date) between April 16, 2021 and October 31, 2022 were included. PD-L1 testing patterns and 1L regimens were described overall and stratified by PD-L1 testing. The analyses of clinical outcomes are currently ongoing. Results: A total of 161 patients with mGC/GEJC/EAC met the inclusion criteria. The median age at index was 67.0 years, 76.4% were male, and the median follow-up time from index date was 6.7 months. 81 (50.3%) patients had evidence of receiving at least one PD-L1 test (median [interquartile range] time from first test to 1L initiation: 0.4 [-0.1, 1.0] months) among whom 28 (34.6%) had the first test documented after 1L initiation. Overall, 1L immunotherapy-based regimens were received by 63 (39.1%) patients, with NIVO+chemo being the most common (n = 47; 29.2%). 1L fluoropyrimidine- + platinum-containing chemotherapy and other chemotherapies were received by 51 (31.7%) and 42 (26.1%) patients, respectively. Among patients with evidence of PD-L1 testing, 31 (38.3%) received NIVO+chemo, and 37 (45.7%) received chemotherapy alone. Among those without evidence of PD-L1 testing, 56 (70.0%) received chemotherapy alone, and 16 (20.0%) received NIVO+chemo. Conclusions: These preliminary findings show an early uptake of NIVO+chemo in the advanced or metastatic GC/GEJC/EAC patient population. With a majority of PD-L1 untested patients receiving chemotherapy only as 1L therapy, there is an opportunity for these patients to potentially benefit from immuno-oncology containing regimens. Further analyses are needed to characterize the chemotherapy only treated patient population.
Prediction of resistance to bevacizumab plus FOLFOX in metastatic colorectal cancer using a multi-marker panel and a machine-learning approach: Final results of the prospective multicenter PERMAD trial.
Authors: Hans A. Kestler, Thomas Jens Ettrich, Alexander Stein, Dirk Arnold, Gerald W. Prager, Stefan Kasper, Michael Niedermeier, Lothar Müller, Stefan Kubicka, Alexander Koenig, Petra Buechner-Steudel, Andreas Berger, Kai Wille, Angelika Kestler, Johann M. Kraus, Silke Werle, Lukas Perkhofer, Ludwig Lausser, Thomas Seufferlein
Journal: Journal of Clinical Oncology (2024)

204 Background: Anti-vascular endothelial growth factor (VEGF) monoclonal antibodies (mAbs) are widely used for tumor treatment, including metastatic colorectal cancer (mCRC). So far, there are no biomarkers that reliably predict resistance to anti-VEGF mAbs like bevacizumab. A biomarker-guided strategy for early and accurate assessment of resistance could avoid the use of non-effective treatment and improve patient outcomes. We hypothesized that repeated analysis of multiple cytokines and angiogenic growth factors (CAFs) before and during treatment using machine learning could provide an accurate and earlier, i.e., 100 days before conventional radiologic staging, prediction of resistance to first-line mCRC treatment with FOLFOX plus bevacizumab. Methods: 15 German and Austrian centers prospectively recruited 154 mCRC patients receiving FOLFOX plus bevacizumab as first-line treatment. Plasma samples were collected every two weeks until radiologic progression (RECIST 1.1) as determined by CT scans performed every 2 months. 102 pre-selected CAFs were centrally analyzed using a cytokine multiplex assay (Luminex, Myriad RBM). Results: Using random forest machine learning, we developed a predictive model that discriminated between the situations of ”no progress within 100 days before radiological progress” and ”progress within 100 days before radiological progress”. Into this we incorporated a combination of ten out of the 102 CAF markers, which fulfilled this task with 81% accuracy, 72% sensitivity, and 88% specificity. Conclusions: Using artificial intelligence we identified a CAF marker combination that indicates treatment resistance to FOLFOX plus bevacizumab in patients with mCRC within 100 days prior to radiologic progress. Further studies are required to show its clinical value. Clinical trial information: NCT02331927 .
Utility of gene expression–based cancer classification in diagnosis of malignant peritoneal mesothelioma (MPeM): Filling in the gaps in standard pathologic work-up for a rare cancer.
Authors: Joelle Allam, Li Ma, Jeannelyn Estrella, Anneleis Willett, Karen A. Beaty, Aurelio Matamoros, Elizabeth A Lano, Keith F. Fournier, Kai Treuner, Kanwal Pratap Singh Raghav, Ryan W Huey
Journal: Journal of Clinical Oncology (2024)

728 Background: Malignant peritoneal mesothelioma (MPeM) is a rare cancer (incidence of 0.12 per 100,000) and an arduous diagnostic challenge, requiring skillful evaluation by expert pathologists. Subjective and experiential immunophenotyping coupled with inattention to this rare entity causes delayed or misdiagnosis and leads to suboptimal treatment and outcomes. Gene-expression-based cancer classification offers an objective molecular assessment of the tissue of origin for cancers with uncertain diagnosis and improves diagnostic accuracy for MPeM compared to standard pathology. Methods: We retrospectively evaluated 23 patients (pts) with cancer of unknown primary (CUP) or uncertain diagnoses, with peritoneal/retroperitoneal carcinomatosis and reported as malignant mesothelioma using a 92-gene assay (CancerTYPE ID), a validated classifier for predicting tumor types, between January 2013 to December 2016. Pathology was verified by central review. Clinicopathologic data including immunohistochemistry (IHC) was collected using archived pathology specimens and reports. Results: Pts had a median age of 64 years (range: 39 – 93) at diagnosis, 57% were females and 74% had biopsy from omentum/peritoneum. Original histopathology was reported as poorly differentiated in 81% and as adenocarcinoma, carcinoma and malignant neoplasm in 10 (43%), 7 (30%) and 6 (27%) of cases, respectively. The number of IHC stains performed ranged between 0 and 28 (median: 10). Key IHC stains are shown in the table. Conclusions: In this cohort of CUP or uncertain diagnoses with a molecular cancer classification of malignant mesothelioma, we found huge variability and critical gaps in pathological work-up. Integration of molecular cancer classification using the 92-gene assay helped resolve this diagnostic uncertainty, further supporting its clinical utility to complement standard pathology. The impact of these findings goes beyond just MPeM and may benefit numerous pts with orphan cancers, who account for nearly 20% of all cancers diagnosed globally. [Table: see text]
The combination of CD8 and TIM3 expression to predict survival outcomes in hepatocellular carcinoma.
Authors: Mitsuo Shimada, Yuma Wada, Takayuki Noma, Yu Saito, Yuji Morine
Journal: Journal of Clinical Oncology (2024)

543 Background: CD8+ T cells have anti-tumor immunity in a variety of cancers including hepatocellular carcinoma (HCC). Tumor-infiltrating CD8+ T cells express immune checkpoint proteins and focus on a therapeutic targeting. T cell immunoglobulin and mucin domain protein 3 (TIM3) has been reported to be associated with suppression of anti-tumor immunity, poor prognosis, and tumor progression in HCC, resulting in up-regulation on exhausted CD8+ T cells. As the exhausted T cells showed a decrease of effector cytokine production and cytolytic activity, leading to the tumor progression, TIM3 is one of the most important exhaustion markers. In the present study, we investigated the role of CD8 and TIM3 as a prognostic biomarker in HCC. Methods: We analyzed 474 HCC patients with clinical and transcriptomic data from The Cancer Genome Atlas (TCGA: n=359) and GSE 76427 (n=115) to examine associations between CD8, TIM3, and programmed death receptor-1/programmed cell death ligand 1 (PD-1/PD-L1) expression and survival outcomes. Each gene was divided into low- and high-expression groups using the tertiles of gene expression. Results: The patients with high CD8 and low TIM3 expression were associated with better overall survival (OS) (P=0.021 and P=0.025, respectively) in TCGA, while PD-1/PD-L1 were not associated with OS (P=0.306 and P=0.318, respectively). Moreover, the patients with high CD8 and low TIM3 expression were validated in GSE dataset (P=0.014 and P=0.009, respectively). The patients with high CD8 and low TIM3 expression were associated with improved OS compared with the overall HCC patient (P=0.008). Among the patients with high CD8 expression, low TIM3 expression (non-exhausted CD8+ T cells) was associated with better OS (P=0.009), but PD-1/PD-L1 were not associated with OS (P=0.491 and P=0.772, respectively). Finally, multivariate analysis showed that the patients withnon-exhausted CD8+ T cells were significantly superior for the survival outcomes (Hazard ratio=2.80, 95% CI=1.27–6.19, P=0.01). Conclusions: High CD8 and low TIM3 expression is associated with better OS in HCC than PD-1/PD-L1, suggesting that CD8 and TIM3 are useful biomarkers for predicting HCC prognosis. Restoring exhausted T cells via the suppression of TIM3 is a promising strategy for cancer treatment, which become a breakthrough in the cancer immunotherapy.
Phase 2 study of cabozantinib (Cabo) and pembrolizumab (Pembro) in metastatic gastric/gastroesophageal adenocarcinoma (mGEA) resistant or refractory to immune checkpoint inhibitors (ICI).
Authors: Farshid Dayyani, Joseph Chao, Fa-Chyi Lee, Thomas H. Taylor, Kristen Neumann, May T Cho
Journal: Journal of Clinical Oncology (2024)

315 Background: Most mGEA patients (pt) progress on therapy including ICI, with about 5% progression-free at 6 mo (PFS-6) with single agent ICI in later lines of therapy. Alternative therapeutic approaches are needed. Cabo is a multi-tyrosine kinase inhibitor thought to enhance the immunomodulatory effects of ICI. This study reports on safety and efficacy of the combination of Cabo+Pembro in mGEA resistant or refractory to ICI. Methods: Investigator-initiated, single‐arm, single institution, phase 2 study in pts with mGEA after ≥1L of fluoropyrimidine and platinum-containing regimens. Pts with a PD-L1 CPS score ≥10% had also progressed on ICI. Cabo dose was 40mg p.o. daily on days 1 through 21 of a 21‐day cycle, with Pembro 200 mg i.v. on day 1. The primary endpoint was PFS-6, with H0=5%, Ha≥20%, requiring n=27 evaluable pts and n≥4 pts with PFS-6 to reject H0 in favor of Ha. Results: 27 pts were enrolled. Median age 58 years (24-87), female (n=14), ECOG 0/1= 13/14, GC/GEJ= 16/11, Non-Hispanic White/Hispanic/Asian= 12/8/7. The primary endpoint was met with n=6 pts having PFS&gt;6mo. After a median follow-up of 31.4mo (range 3.3-42.5), PFS-6 is 22.2% (95% CI 9.0-39.0). The median PFS and OS are 2.3mo (95% CI 1.7-4.1) and 5.5mo (3.1-14.0), respectively. The most common mutations were TP53 (78.3%) and CDH1/PIK3CA/CTNNB1 (17.4% each). In exploratory analyses, 5/7 (71.4%) pts in the top quartile for PFS had alterations in the cMET-PI3K-AKT pathway. The most common any grade (G) treatment related adverse events (TRAE) were diarrhea (25.9%), fatigue (18.5%), hypertension and muscle cramps (14.8% each). G3-4 TRAE were seen in n=3 pts (Hypertension, Thromboembolic event, esophageal perforation; each n=1). No G5 were observed. Conclusions: The addition of Cabo to Pembro shows clinical benefit in ICI resistant or refractory mGEA with an observed PFS-6 of 22.2%. The regimen appears tolerable with no new safety signals. An exploratory association of alterations in the cMET-PI3K-AKT pathway with prolonged PFS needs to be confirmed in a larger cohort. Clinical trial information: NCT04164979 .
External validation of the ARCAD nomogram in a real-world cohort of patients with stage IV colorectal cancer (CRC).
Authors: James Yu, Jiannong Li, Michael Schell, Pablo Gonzalez Ginestet, John Raymond Zalcberg, John Simes, Ian Marschner, Richard D. Kim, Katrin Marie Sjoquist
Journal: Journal of Clinical Oncology (2024)

38 Background: The ARCAD CRC nomogram is designed to predict 1-yr survival in stage 4 CRC to assist with prognostication (Sjoquist, JNCI, 2018). However, this nomogram was developed using patients (pts) enrolled in clinical trials. We sought to externally validate these data in a real-world cohort. Methods: We used the Flatiron database from nationwide records collected from 2013-2020 to create a retrospective Flatiron real-world cohort (FRWC) of pts with histologically confirmed stage 4 CRC. Pts with baseline blood tests prior to treatment (Tx) who had received at least 1 line of Tx were included. Missing data (&lt;8.5%) were imputed using R package MissForest. A multivariable Cox proportional hazards model for overall survival (OS) was applied to fit the reduced model derived from the published ARCAD nomogram as variables from the full model such as number and sites of metastasis were unavailable in Flatiron. The C-index was used to validate the fitted models. The area under a time-dependent ROC (AUROC) analysis was applied to indicate the model prediction performance. Results: A total of 9710 pts, 5740 of whom were deceased were analyzed. The FRWC was older (64 vs 61) and had a poorer ECOG-PS (2+ 14.7% vs 4.2%) compared to the ARCAD. A reduced ARCAD nomogram was derived from the full model (Table). The reduced nomogram calibration was as good as the full model (C-index 0.67 vs 0.68). The 1-yr OS prediction in FRWC using the reduced ARCAD nomogram was good with an AUROC of 0.74. The predictive and observed 1-yr OS using the reduced ARCAD nomogram in the FRWC was 0.640 (95% CI 0.637, 0.644) and 0.727 (95% CI 0.718,0.736). Conclusions: The ARCAD nomogram was validated in the very large FRWC. The observed underestimation of survival by the ARCAD nomogram in the FRWC is likely due to recent advances in Tx options for CRC including targeted- or immunotherapy as the FRWC is more recent compared to pts enrolled in the ARCAD cohort (1997-2012). Our findings indicate that the ARCAD nomogram is a promising decision-making tool for clinicians to predict 1-yr OS in real-world populations. [Table: see text]
Molecular differences with therapeutic implications in early-onset compared to average-onset cholangiocarcinoma.
Authors: Thejus Jayakrishnan, Yasmine Baca, Joanne Xiu, Mehrie Patel, Benjamin Adam Weinberg, Emil Lou, Jashodeep Datta, Moh'd M. Khushman, Pat Gulhati, Sanjay Goel, Tiago Biachi de Castria, Vaia Florou, Kanika G. Nair, Suneel Deepak Kamath, Alok A. Khorana
Journal: Journal of Clinical Oncology (2024)

536 Background: Early-onset cholangiocarcinoma (eoCCA) is among early-onset cancers with the fastest rising rates, yet little is known about its biology. We sought to compare the molecular characteristics of eoCCA with average-onset CCA (aoCCA) with an age cut-off of 50 years, utilizing a real-world multi-omics dataset. Methods: The study comprised patients whose tumors underwent molecular analysis at Caris Life Sciences (Phoenix, AZ) using whole exome and whole transcriptome analyses. Patients were categorized by age as eoCCA defined as &lt;50 years and aoCCA &gt;50 years. Gene expression profiles were analyzed for transcriptional signatures predictive of immunotherapy response including the T-cell inflamed score (TIS) and interferon-gamma (IFG) score. P values (adjusted for multiple testing) were considered significant at False Discovery Rate (FDR) P&lt;0.05 for molecular comparisons and FDR P&lt;0.25 for Gene Set Enrichment Analysis (GSEA). Insurance claims data was used for survival comparison using Kaplan-Meier estimates. Results: The study included 5587 patients - 453 patients with eoCCA and 5134 with aoCCA (Table). Of targetable mutations ( FGFR2, IDH1, IDH2, ERBB2, BRCA, BRAF), FGFR2 fusion was significantly more prevalent in eoCCA (15.7% vs 5.9% in aoCCA, FDR P&lt;0.001). Rates trended higher in eoCCAfor MSI-H tumors (4.1% vs 2.4%), and high tumor mutational burden (6.1% vs 5.1%) but not significantly different (FDR P=1). The IFG score (Fold Change FC: 1.1, FDR P=0.01) and TIS (FC:17.3, FDR P=0.03) were significantly higher in aoCCA vs eoCCA. On GSEA, angiogenesis was enriched in eoCCA (normalized enrichment score NES=1.51, FDR P=0.16) while IFG (NES= -1.58, FDR P =0.06) and inflammatory response (NES= -1.46, FDR P=0.18) were enriched in aoCCA. Median OS was longer in eoCCA (16.5 vs 13.3 months, Hazard Ratio (HR) 0.86, 95%CI 0.78-0.95, P=0.004). Among patients treated with immunotherapy, median OS was longer in patients with eoCCA (19.2 months, n=19) vs aoCCA (7.6 months, n=150) - HR 0.52, 95%CI 0.28-0.94, p=0.03. No survival difference was identified in patients on chemotherapy (HR 0.91, 95%CI 0.76-1.08, P=0.28). Conclusions: In the largest age-stratified analysis of molecular characteristics of CCA, we identified crucial differences, including higher prevalence of FGFR2 fusions and significant differences in immunotherapy-related markers, angiogenesis enrichment, and inflammatory response. Patients with eoCCA experienced better outcomes with immunotherapy even though immune-oncology-relevant markers favored aoCCA. Our findings, especially higher FGFR2 fusion prevalence in eoCCA, underscore the need for NGS testing and the potential for age-tailored therapeutic strategies. [Table: see text]
Atezolizumab and bevacizumab in combination with TACE for patients with BCLC B HCC.
Authors: Stacey Stein, Wei Cheng, Christina Wiess, Jeffrey Pollak, JuanCarlos Perez Lozada, Julius Chapiro, David C. Madoff
Journal: Journal of Clinical Oncology (2024)

TPS584 Background: The combination of atezolizumab and bevacizumab (AB) is an effective regimen for patients with advanced HCC 1 . Moving effective systemic therapy to earlier stages of HCC is a priority in improving outcomes. Assessing the safety of the combination of AB and TACE is essential to evaluating this regimen. Methods: This is an open-label, single arm pilot study. The primary objective of this study is to examine the safety and tolerability of AB with TACE. The secondary objectives are response rate, time to progression, overall survival, time to TACE progression (TTTP), and time to untaceable progression. Approximately 24 patients will be enrolled. AB will be given every 3 weeks (A: 1200 mg; 15 mg/kg) weeks and TACE will be planned for each patient to be completed in up to 4 treatments. B will be held for cycles that are within 4 weeks before or after each TACE. Imaging will be every 8 weeks for the first year, then every 12 weeks for the second year. Based on data from the GO30140 and the IMbrave 150 studies, we assume the rate of grade 3 or higher AEs is approximately 55% for AB and will likely be higher with the addition of TACE. Safety will be continuously monitored using the Bayesian Predictive Probability (PP) approach 2 . The PP that the rate of grade 3 or higher AEs is related to the combination is greater than 70% by the end of the trial based on toxicity data in the current stage will be continuously updated. Inclusion criteria includes patients over 18 years old with an ECOG PS of 0 or 1, no cirrhosis or Child-Pugh A cirrhosis, diagnosis of HCC by imaging or biopsy, and EGD within 6 months with no evidence of gastroesophageal varices with bleeding or high risk of bleeding unless treated. Patients are excluded if they are candidates for curative intent therapy, have had hepatic encephalopathy in the last 12 months, have occlusion of the hepatic artery or main portal vein, or have history of significant autoimmune disease. 1. Finn, Richard S., et al. New England Journal of Medicine 382.20 (2020): 1894-1905. 2 Lee J and Liu D. Clinical Trials. 2008; 5(2): 93-106. Clinical trial information: NCT05776875 .
Developing a comprehensive cell-free DNA (cfDNA) epigenetic signature (ep-Sig) with diagnostic and prognostic value in hepatocellular carcinoma (HCC).
Authors: Ashish Manne, Soumya Jogi, Sravan Jeepalyam, Ashwini K. Esnakula
Journal: Journal of Clinical Oncology (2024)

553 Background: HCC is one of the deadliest tumors with poor outcomes often diagnosed in late stages. Current surveillance strategies (alfa-fetoprotein (AFP) plus ultrasound (USG)) for high-risk population (HRP) have poor sensitivity (SN) and reasonable specificity (SP) of 61% and 92%, respectively. Triple phase computed tomography (CT) imaging has good sensitivity and specificity (≈ 90% for both) but the evidence does not support its use for routine surveillance. All these modalities do not have prognostic (survival) value. We attempted to develop a non-invasive, cfDNA-based tests to improve the diagnostic value of the current standard of care modalities (AFP and USG) and help in predicting the outcomes at diagnosis. We hypothesized that RNA and gene expression in HCC tissues is a surrogate for epigenome (DNA-methylation changes). Methods: We curated a 21-gene cfDNA ep-Sig from the literature with a proven prognostic value. Evidence suggests epigenetic changes in every gene of this panel affect HCC outcomes influencing clinicopathological characteristics (large tumor size, vascular invasion, advanced staging) or early post-operative recurrence, and survival. We compared RNA and gene expression of the genes in the ep-Sig between normal (NT) and HCC tissues using a web-based tool, TNMplot.com that uses the data from the Gene Expression Omnibus of the National Center for Biotechnology Information (NCBI-GEO) or Cancer Genome Atlas (TCGA), Therapeutically Applicable Research to Generate Effective Treatments (TARGET), and The Genotype-Tissue Expression (GTEx) repositories was used create this tool. It uses Mann-Whitney or Kruskal-Wallis tests to compute statistical significance. Results: RNA expression of all the genes from the ep-Sig was significantly higher in HCC than NT (1.133, p=5.84e-15). Gene expression was 19/21 genes was higher in HCC tissues (1.15, p=1.3e-08). The other 2 genes were not detected in the tested samples. Conclusions: Our ep-Sig which has a proven prognostic value and reliable prevalence in HCC patients. This study is the first step in developing clinically useful blood-based test that can revamp the current diagnostic and screening practices when used alongside AFP and USG.