tbuckley/cabot-search huggingface dataset:
Nature and distribution of methyl thioadenosine phosphorylase (<i>MTAP</i>) genomic loss in human tumors.
Authors: Andrea Necchi, Antonio Cigliola, Valentina Tateo, Chiara Mercinelli, Jeffrey S. Ross, Dean Pavlick
Journal: Journal of Clinical Oncology (2024)

3067 Background: MTAP genomic loss, often but not exclusively a bi-allelic homozygous deletion, has recently emerged as important biomarker guiding a novel synthetic lethality mechanism for drugs in the class of PRMT5 and MAT2A inhibitors. In the current study, we assessed the nature and distribution of MTAP complete and partial loss in a variety of tumor samples. Methods: A total of 291,391 tissue samples underwent comprehensive genomic profiling (CGP) using a hybrid-capture method to evaluate all classes of genomic alterations (GA), and determine the microsatellite instability (MSI) status, tumor mutational burden (TMB), homologous recombination deficiency (HRD) score and genomic ancestry. The distribution of both complete and partial loss of MTAP was also determined. Results: MTAP GA were found in 8.6% of total with 9.3% genomic loss and 0.1% each short variant mutations and rearrangements. Important (not rare) tumor types with the most frequent MTAP loss included: 42.6% of glioblastoma (GBM), 13.4% of non-small cell lung cancer (NSCLC), 22.3% of pancreatic ductal and 24.9% of bladder urothelial carcinomas. The most frequently co-altered GA included CDKN2A (99.7%), CDKN2B (95.1%), TP53 (55.4%), KRAS (30.1%), TERT(20.5%) and PIK3CA (12%). In tumor types with frequent known targetable driver GA including short variant mutations in EGFR, ERBB2, BRAF, FGFR2-3and MET and fusions involving ALK, RET, ROS1 and NTRK1-3, MTAP loss was not associated with decreased frequencies of GA in these genes. The frequencies of MSI-high status was 0.3% and of TMB≥10 mut/Mb was 17%. In total, 63.7% of the MTAP loss cases involved deletion of all 8 MTAP exons (complete loss) with partial loss accounting for 36.3% of cases. All partial loss cases involved loss of multiple exons (35.8%) except for loss of only exon 8 (0.5%). There was no impact of MTAP loss status on genomic ancestry, cosmic trinucleotide signature and HRD score. The multiple exon loss frequencies included exons 2-8 loss in 24.7%, exons 5-8 loss in 4.1%, exons 6-8 loss in 3.3%, exons 3-8 loss in 1.6%, exons 7-8 in 1.1%, exon 4-8, 1-5, 2-7,2-5, 1-4, 2-6, 3-7 and 5-7 all at less than 1% frequencies. Conclusions: MTAPloss is a frequent GA of emerging clinical importance as the trials using PRMT5 and MTA-2 inhibitors progress. MTAPloss is frequent in common cancers of the brain, lung, pancreas and bladder and not associated with diminishment of other targetable driver mutations. Although one-third of MTAP loss is a partial loss, the partial loss cases involve near total (exons 2-8) loss and may well also be indicative of PRMT5/MAT2A inhibitor benefit. This study strengthens the opportunity to consider a tumor-agnostic approach to targeted therapies. [Table: see text]
ctDNA as a biomarker in phase II study of tepotinib in advanced solid cancers with <i>MET</i> exon 14 skipping mutation or amplification (KCSG AL19-17).
Authors: Yaewon Yang, Eun Joo Kang, Soohyeon Lee, Yu Jung Kim, Sun Min Lim, Myung-Ju Ahn, Youngjoo Lee, Tae Min Kim, Ilhwan Kim, Hee Kyung Ahn, Soonil Lee, So Yeon Oh, Bae Woo Kyun, Hyewon Ryu, Kyong Hwa Park, Ki Hyeong Lee
Journal: Journal of Clinical Oncology (2024)

3050 Background: Tepotinib consistently demonstrated antitumor activity in patients with MET exon 14 skipping mutation ( METex14) and promising activity in various cancers with MET amplification, according to previous reports. We assessed plasma ctDNA as a potential biomarker in MET-dysregulated advanced cancer patients with tepotinib treatment. Methods: KM-08 (KCSG AL19-17, NCT04647838) was a phase 2, multicenter study with tepotinib treatment for patients with advanced or metastatic solid cancers harboring either METex14 or MET amplification detected in tissue-based next-generation sequencing (NGS). For exploratory analyses, we analyzed the genetic profile using liquid-based NGS testing with AlphaLiquid-100 panel (IMBdx Inc. Seoul, KR) at baseline (T0), after six weeks during treatment (T1), and at the time of disease progression (T2). Results: Baseline ctDNA NGS data was available in 28 (80%) out of 35 patients enrolled in the trial. Among them, METex14 or MET amplification was detected in 18 patients, with a sensitivity of 64.3%. The most commonly co-mutated gene was TP53, followed b y PIK3CA, ATM, MYCN, and KRAS. The objective response rate (ORR) in plasma MET positive (PM+) patients was higher (81.2%) than the ORR in plasma MET negative (PM−) patients’ group (30.0%). In contrast, PM− group had a longer progression-free survival (PFS) and overall survival (OS) than PM+ group. PFS was 11.0 months (95% CI 8.1, 13.9) vs 6.0 months (95% CI 3.6, 8.3) and OS was NR vs 14.0 months (95% CI 4.7, 23.3), respectively. The molecular responder (MR, MET alteration variant allele frequency [VAF] T1/T0 &lt;50%) was 80.0% (12/15 patients), and the molecular non-responder (MNR, METVAF T1/T0≥50%) was 20.0% (3/15 patients). ORR was higher in the MR group (91.7%) than in the MNR group (33.3%). PFS and OS were longer in the MR group than in the MNR group, 6.0 months (95% CI 0.0, 14.5) vs 3.0 months (95% CI 1.4, 4.6) with P= 0.114 and NR vs 4.0 months (95% CI 2.4, 5.6) with P= 0.067, respectively. Out of the 20 patients with samples available at T2, one had an on-target mutation on MET (D1228N, and Y1230H) while two had off-target emerging oncogenic alterations in KRAS, BRAF, and ERBB2 genes. Conclusions: In the liquid biomarker analysis in the MET-dysregulated cancer patients who were treated with tepotinib, the presence of ctDNA METalteration at baseline was associated with a higher response rate but shorter PFS and OS. The molecular response was well correlated with the radiological response and associated with better outcomes. (Funded by Merck KGaA, Darmstadt, Germany, ClinicalTrials.gov number, NCT04647838.) Clinical trial information: NCT04647838 .
Paired matched normal sequencing to accurately identify somatic clonal hematopoiesis mutations (CHm) in solid tumor tissue and plasma specimens.
Authors: Karina Eterovic, Felipe Batalini, Susan Troxel, Brent Urban, Mechelle Harcar, Jacob Shreeve, Diane Ilsley, Ananddeep Patel, Matthew Watters, Kirthi Kutumbaka, Pratheesh Sathyan, Jennifer S. LoCoco, Marni Brisson Tierno, Tyler J Moss
Journal: Journal of Clinical Oncology (2024)

3051 Background: Clonal hematopoiesis (CH), characterized by the presence of somatic mutations in blood cells, can be found in cancer-related genes when sequencing tumor tissue or plasma samples. Inability to distinguish somatic, tumor-derived mutations from CHm can lead to inaccurate treatment decisions. In this prospective study, we confirmed potential CHm in solid tumors by sequencing and analysis of paired matched normal (PMN) specimens. Methods: We prospectively enrolled 56 patients diagnosed with advanced cancer, including lung (16), colorectal (13), breast (10), gastric (7), ovarian (2), pancreatic (2), liver (2), cervix (1), uterine (1), fallopian tube (1), and perihilar bile duct (1). Targeted next-generation sequencing using a 523 gene panel was performed on paired formalin-fixed paraffin-embedded (FFPE) and circulating tumor DNA (ctDNA) samples. Additionally, whole exome sequencing was performed on PMN buffy coat samples. Analysis of all three specimens was performed to classify somatic mutations as tumor-derived or CHm. Results: We identified 21 potential CHm within the FFPE and ctDNA samples of 13 patients (23.2% of the cohort) with lung (7), breast (2), liver (2), colorectal (1), and gastric (1) cancers. CHm were further confirmed when present in buffy coat samples. The VAF of CHm in FFPE and ctDNA samples exhibited a wide range, spanning from 0.85% to 38.4%, with 7 of those identified at &lt;2% VAF. For these same aberrations, VAF in buffy coat samples ranged from 1.6% to 48%, with seven mutations exhibiting VAF levels &lt;5%. Four of these CHm were classified as oncogenic or likely oncogenic. Four CHm, including an oncogenic TP53 mutation, were identified in the oldest patient (75 years old, lung cancer), while an oncogenic DNMT3A mutation was detected in the youngest patient (42 years old, breast cancer). Both had a 30-year history of smoking. Conclusions: Our findings identified somatic CHm in a substantial subset (23.2%) of solid tumors, with four identified as oncogenic or likely oncogenic mutations. The broad spectrum of VAFs for CHm suggests that using VAF as a cut-off to exclude likely CHm may be unreliable. The low VAF CHm found in matched normal specimens indicates low-pass sequencing may not detect critical CHm, even in paired analysis. The diverse age range of patients with CHm (42 to 75 years old) suggests that CHm are not restricted to older populations, and that additional factors, such as smoking history, may play a role. These findings underscore the importance of incorporating routine PMN buffy coat sequencing into clinical practice, to identify somatic CHm that can impact personalized cancer treatment strategies.
Enhancing cancer detection through AI-driven high content analysis of circulating tumor cells.
Authors: Sachin Apurwa, Muqeet Shaikh, Sagar Devhad, Shoeb Patel, Rohit Chougule, Pradyumna Shejwalkar, Archana Adhav, Apurva Dalvi, Dadasaheb Akolkar, Darshana Patil, Rajan Datar, Ashok K Vaid
Journal: Journal of Clinical Oncology (2024)

3054 Background: The advancements in automated High Content Analysis (HCA) for Circulating Tumor Cells (CTCs) detection necessitate the integration of high-throughput screening (HTS) and Artificial Intelligence (AI) to improve cancer diagnosis efficiency and accuracy. Traditional approaches to cancer detection have faced limitations in speed, cost, and analysis depth, driving the need for innovative solutions in assay development and execution. Methods: We obtained peripheral blood from 150 asymptomatic individuals and 63 newly diagnosed cases of solid organ cancers including Lung, Breast, Head and Neck, Colorectal, Pancreas, Esophagus, Gynecologic cancers. We used differential apoptosis based negative enrichment technique and HCS fluorescent imaging for identification of CTCs and CTC like immune cells from the relevant blood samples. We devised AutoML algorithms which were trained on a cohort of 4,135 cropped region of interest (ROI) images of true CTCs and CTC-mimicking immune cells. These images were annotated with the coordinates of the top-left and bottom-right corners of rectangles to specify ROIs. This method employs a combination of automated sample processing, integration with the Laboratory Information Management System (LIMS) integration, digital filtration, and decision matrix algorithms for sample classification and smooth data flow. The image quality criteria were established prior to dataset analysis. The algorithms underwent training, testing, and validation based on expert recommendations, with dataset splitting of 80% for training, 10% for testing, and 10% for validation phases. Results: The automated deep learning model achieved remarkable performance metrics, presenting an accuracy of 96.66% (95% CI, 96.07%-97.19%), a specificity of 95.34% (95% CI, 94.37%-96.18%), and a sensitivity of 98.14% (95% CI, 97.44%-98.69%) in detecting true CTCs. Additional analysis included the area under the curve and confusion matrix evaluations, indicating the model's robustness in distinguishing between true positive and true negative specimens. This efficiency and precision in data handling, processing, and analysis demonstrate significant advancements in HCA screening, offering enhanced assay development, execution flexibility, and the facilitation of detailed cell-by-cell analysis for cancer detection from a large set of Peripheral Blood Mononuclear Cells (PBMCs) from samples obtained for screening or diagnosis. Conclusions: This study successfully evaluated a deep learning model for the detection of circulating tumor cells (CTCs) in peripheral blood mononuclear cells (PBMCs) using image data from HTS platform. The model achieved superior performance, demonstrating its potential for cancer detection from blood samples.
Personalized circulating tumor DNA for minimal residual disease and dynamic assessment in patients undergoing neoadjuvant chemotherapy for breast cancer: Preliminary analysis from MSK-LINC.
Authors: Hong-Kyu Kim, Julia Ah-Reum An, Christopher Gareth Smith, Jisun KIM, Luc Cabel, Enrico Moiso, Emanuela Ferraro, Anton Safonov, Konner Nelson, Kathleen Szuhany, Joshua Z. Drago, Larry Norton, Amy Xu, Howard I. Scher, Sarat Chandarlapaty, Atif J. Khan, Bob T. Li, Mark E. Robson, George Plitas, Pedram Razavi
Journal: Journal of Clinical Oncology (2024)

3049 Background: Identification of minimal residual disease (MRD) with circulating tumor DNA (ctDNA) in pts with early-stage breast cancer holds promise to identify risk of relapse. MSK-LINC is prospective ctDNA plasma analysis of breast cancer pts. This pilot study evaluated the utility of serial ctDNA assessment as a biomarker for monitoring MRD and recurrence prediction in clinical stage II-III breast cancer pts undergoing neoadjuvant chemotherapy (NAC). Methods: 30 pts who underwent NAC across all subtypes were identified from MSK-LINC. The ctDNA analysis was performed at baseline, on-NAC, post-NAC/pre-surgery, within 8 weeks post-surgery, and during follow-up. Personalized ctDNA RaDaR assays were designed using whole exome sequencing data of paired primary tumor and germline samples from each pt. ctDNA levels were quantified as an estimated variant allele fraction (eVAF). Results: ctDNA panels were successfully designed for 29/30 pts (16 Stage II, 13 Stage III), including 6 HR+/HER2-, 12 HER2+, and 11 TNBC, with a median follow up of 4.2 years. The bespoke ctDNA assays targeted a median of 48 variants (21-51), with a median of 43 variants (11-48) passing quality control. A total of 175 plasma samples were analyzed, including 24 baseline and 24 post-surgery. A 100% ctDNA detection rate was observed at baseline in the 24 pts for whom a baseline sample was available (median eVAF 0.33%, range 0.0083% - 8.91%). Pathologic complete response (pCR) was achieved in 11 pts who remained disease free; and of the 18 pts without a pCR, 5 recurred. All patients with a pCR were ctDNA negative post treatment. In 3/5 patients who recurred, MRD detection was achieved, including one patient with persistent ctDNA positivity throughout all timepoints. For the other two pts, ctDNA was first detected in follow-up plasma collected at 4.4 and 9.8 months prior to clinical recurrence. Conclusions: This study demonstrates the potential of ctDNA as a dynamic biomarker for monitoring disease burden in pts with high-risk early-stage breast cancer, highlighting its remarkable sensitivity at baseline and its capability for MRD detection preceding clinical recurrence. These findings suggest the need for further research to fully understand the relationship between ctDNA dynamics during and after NACT with prediction of breast cancer outcomes. ctDNA detection rates in plasma samples across collection timepoints. [Table: see text]
The exact predictive value of HBcrAg and HBV RNA in serological status and disease activity in CHB
Authors: Xin Luo, Jixian Yu
Journal: Hepatology (2024)

Department of Hepatology, Affiliated Xixi Hospital in Hangzhou, Zhejiang University of Traditional Chinese Medicine, Hangzhou, China Running title: The exact predictive value of HBcrAg and HBV RNA. Correspondence Jixian Yu, Department of Hepatology, Affiliated Xixi Hospital in Hangzhou Zhejiang University of Traditional Chinese Medicine Hengbu Street 2 Road, Hangzhou, Zhejiang, 310023, China. Email: [email protected]
Bintrafusp alfa and chemotherapy as first-line treatment in biliary tract cancer: A randomized phase 2/3 trial
Authors: Do-Youn Oh, Masafumi Ikeda, Choong-kun Lee, Carlos Rojas, Chih-Hung Hsu, Jin Won Kim, Lin Shen, Junji Furuse, Joon Oh Park, Mitesh Borad, Filippo de Braud, John Bridgewater, Sunyoung S. Lee, Markus Moehler, Francois Audhuy, Motonobu Osada, Masashi Sato, Changhoon Yoo
Journal: Hepatology (2024)

Background and Aims: We compared the safety and efficacy of bintrafusp alfa (BA) in combination with gemcitabine+cisplatin (GemCis), to those of GemCis alone, in patients with biliary tract cancer. Approach and Results: This randomized, double-blind, placebo-controlled, adaptive design phase 2/3 trial (NCT04066491) included adults who are treatment-naive with locally advanced/metastatic biliary tract cancer. Patients (N = 297) were randomized to receive an IV infusion of BA (2400 mg once/3 wk) plus GemCis (gemcitabine 1000 mg/m 2 +cisplatin 25 mg/m 2 on days 1 and 8/3 wk; 8 cycles) (BA group, n = 148) or placebo+GemCis (placebo group, n = 149). The primary end point was overall survival (OS). For adaptation analysis (phase 2-phase 3; data cutoff: May 20, 2021), efficacy was assessed in the first 150 patients who were antibiotic-naive when 80 progression-free survival events had occurred and ≥ 19 weeks of follow-up had been completed (BA, n = 73; placebo, n = 77). Median OS (95% CI) for the BA (11.5 mo [9.3–not estimable]) and placebo (11.5 mo [10.0–not estimable]) groups was comparable (hazard ration 1.23 [95% CI 0.66–2.28]; p = 0.7394); OS data maturity was 27.2% (41 events/151 patients). The most common grade ≥3 treatment-related adverse event was anemia (BA, 26.0%; placebo, 22.8%). Bleeding adverse events were reported more frequently in the BA group (28.8%) versus the placebo group (7.4%). Deaths within 60 days of the first dose were reported in 7.5% and 1.3% of patients in the BA and placebo groups, respectively. Conclusions: BA+GemCis did not provide a clinically meaningful benefit compared with GemCis alone as first-line treatment for biliary tract cancer, and the study was discontinued early (terminated: August 20, 2021).
FDA Approval Summary: Repotrectinib for locally advanced or metastatic ROS1-positive non-small cell lung cancer
Authors: Michael I. Barbato, Diana Bradford, Yi Ren, Stephanie L. Aungst, Claudia P. Miller, Lili Pan, Jeanne F. Zirkelbach, Yangbing Li, Youwei Bi, Jianghong Fan, Manuela Grimstein, Sarah E. Dorff, Anup K. Amatya, Pallavi S. Mishra-Kalyani, Barbara Scepura, Peter Schotland, Opeyemi Udoka, Idara Ojofeitimi, John K. Leighton, Nam A. Rahman, Richard Pazdur, Harpreet Singh, Paul G. Kluetz, Nicole Drezner
Journal: Clinical Cancer Research (2024)

Abstract On November 15, 2023, the U.S. Food and Drug Administration (FDA) granted traditional approval to repotrectinib (Augtyro, Bristol Myers Squibb Corporation) for the treatment of adult patients with locally advanced or metastatic receptor tyrosine kinase encoded by the ROS1 gene (ROS1)-positive non–small cell lung cancer (NSCLC). The approval was based on TRIDENT-1, a single-arm trial with multiple cohorts of patients with ROS1 fusion-positive (hereafter “ROS1-positive”) NSCLC (NCT03093116), who were either treatment naïve or had received prior ROS1 tyrosine kinase inhibitor (TKI) and/or platinum-based chemotherapy. The primary efficacy outcome measure is objective response rate (ORR) assessed by blinded independent central review (BICR) using response evaluation criteria in solid tumors version 1.1. ORR was assessed in 71 patients who were ROS1 TKI naïve and 56 patients who had received a prior ROS1 TKI. Among the 71 patients who were ROS1 TKI naïve, the ORR was 79% (95% CI, 68–88), median duration of response was 34.1 months (95% CI, 26–NE). In patients who had received a prior ROS1 TKI and no prior chemotherapy, the ORR was 38% (95% CI, 25–52). The median duration of response was 14.8 months (95% CI, 7.6–NE); BICR-assessed responses were observed in CNS metastases in patients in both cohorts and in patients who developed resistance mutations following prior TKI therapy. The most common (&amp;gt;20%) adverse reactions were dizziness, dysgeusia, peripheral neuropathy, constipation, dyspnea, ataxia, fatigue, cognitive disorders, and muscular weakness. A unique feature of this ROS1 TKI approval is the inclusion of robust evidence of efficacy in patients with ROS1-positive NSCLC who had progressed on prior ROS1 TKIs.
Examining response to immunotherapy in clear-cell renal cell carcinoma using baseline serum metabolic signatures.
Authors: Leila Pirhaji, Matthew Morris, Jonah Eaton, Min Zhang
Journal: Journal of Clinical Oncology (2024)

2604 Background: Clear cell renal cell carcinoma (ccRCC) accounts for 80% of kidney cancer cases. While immune checkpoint blockade (ICB) is a front-line treatment, most patients do not have durable clinical benefit, and current biomarkers fail to predict response. Previous studies reported metabolic alterations in response to ICB based on profiling of 202 targeted metabolites. To identify metabolic signatures predicting response to ICB at baseline, we have developed mzLearn, a data-driven algorithm that overcomes obstacles in liquid chromatography/mass spectrometry (LC/MS) measurements of untargeted metabolomics at scale. Methods: We used baseline and post-treatment raw LC/MS data (n=1,650) from ccRCC patients in Phase I (n=91) and Phase III (n=741) trials (Workbench IDs ST001236 and ST001237), where anti-PD-1 treatment yielded a significant increase in overall survival compared to mTOR inhibitor. mzLearn detected 4,018 signals present in &gt;60% of all samples. The identified signals have 90% accuracy in detecting targeted metabolites with 10% false positives while effectively overcoming signal drifts and batch effects. We then performed unsupervised K-means clustering of baseline metabolomic features and supervised linear and Cox proportional hazard models to find minimal subsets of those features associated with clinical benefit after adjusting for clinical variables, e.g., age and prognostic scores. We then developed logistic regression models to predict clinical benefit (CB), i.e., tumor shrinkage with ≥6 months progression-free survival (PFS). Finally, we used PIUMet (1), a network-based tool for untargeted metabolomic analysis, to identify linked mechanisms. Results: We identified three main metabolomic subtypes with distinct PFS in response to treatments. We identified a cluster of anti-PD-1 responders (n=279) with significantly higher PFS (p=2e-5, HR=0.56) and a non-responder cluster (n=261) who showed no significant effect from anti-PD-1 relative to mTOR inhibition (p=0.874, HR=1.02). Importantly, one subtype (n=201) tended to have higher PFS after mTOR inhibition (p=0.11, HR=1.27). Next, using supervised methods, we identified 97 baseline metabolite features associated with clinical benefit in the ICB arm. A smaller subset of top-scoring features predicts CB with a cross-validated AUC of 78% and the AUC=71% when tested in the independent Phase I cohort. PIUMet analysis of these features predicted their association with sphingolipid metabolism and arginine/proline metabolism. Conclusions: We showed baseline metabolic stratification of ccRCC patients can predict treatment response and discovered novel blood-based metabolic signatures of predicting response to ICB at baseline. These results establish a solid foundation for predictive biomarker discovery and potentially therapeutic recommendations after further validation. 1. Pirhaji et al. Nat. Met. 2016.
Inflammasomes and Acute Kidney Injury
Authors: Daniel A. Muruve
Journal: Journal of the American Society of Nephrology (2024)

Department of Medicine, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada Correspondence: Dr. Daniel A. Muruve, email: [email protected] See related article, "Long Non-coding RNA Neat1, NOD-Like Receptor Family Protein 3 Inflammasome, and Acute Kidney Injury," on pages XXX–XXX.