tbuckley/cabot-search huggingface dataset:
A highly sensitive, low input, and automated assay for molecular residual disease detection (MRD) using whole-genome sequencing (WGS).
Authors: Li Liu, Jeff Tsai, Khai Luong, Sven Bilke, Michael Davila, Yuan Ding, Manh Vu Do, Jacob Gibson, Artem Movsesyan, Kyria Roessler, Fan Song, Heather Talia, Pete Taylor, Jacquelyn Truong, Weixin Wu, Yunjiao Zhu, James Han, Traci L. Pawlowski
Journal: Journal of Clinical Oncology (2024)

3060 Background: Molecular residual disease (MRD) detection using cell-free DNA (cfDNA) for solid tumors requires a highly sensitive and specific assay that can overcome the limitation of low abundance circulating-tumor DNA (ctDNA) in a standard blood draw with fast sample-to-answer turn-around time (TAT). Here we describe the development and analytical performance of Illumina’s TruSight Oncology MRD WGS assay (TSO MRD, for research use only), for detecting MRD using tumor-informed whole-genome sequencing (WGS) of cfDNA extracted from plasma samples across multiple cancer types. Methods: The TSO MRD assay was built using Illumina’s best-in-class WGS library preparation, informatics and sequencing technologies. The assay is composed of two major steps, fingerprinting and ctDNA detection. At the fingerprinting step, the DNA from tumor tissue and matched normal samples is analyzed through WGS to generate a sample specific somatic variant list. At the ctDNA detection step, the cfDNA extracted from plasma is analyzed through shallow WGS and the presence of ctDNA is detected using the tumor specific fingerprint as an input in the MRD analysis pipeline. The plasma extraction and WGS library preparation workflows are fully automated for high-throughput sample processing with minimum hands-on time and touch points. Results: Testing of commercial MRD reference materials and ctDNA-positive samples serially diluted into normal cfDNA background demonstrated a limit of detection of down to 0.001% VAF or 10 parts per million (PPM) in multiple cancer types. Testing of a panel of normal plasma samples from healthy individuals assessed against 20 sets of fingerprints from multiple cancer types demonstrated an analytical specificity of 99.7%. Testing of ctDNA samples with multiple operators, instruments and library prep start days demonstrated high reproducibility in MRD detection. The ctDNA testing works at an optimal input amount of 5 ng and a minimum input amount down to 2 ng, which yields a high sample success rate from one standard 10 ml of blood draw. The TAT of the fingerprinting and the ctDNA detection steps is 5-7 days, respectively. Conclusions: The TSO MRD assay demonstrated high analytical sensitivity and specificity in detecting the presence of ctDNA from low input plasma samples with automated workflow and fast TAT. This assay enables a single streamlined solid tumor MRD platform for multiple cancer types.
The microtubule-destabilizing agent AUS_001 as a candidate for glioblastoma therapy.
Authors: Marina Koutsioumpa, Aaron L. Carlson, Tessa DesRochers, Peter Y.W. Chan, April L. Risinger, Robert Adams, Cedric Bardy, Daniel Thomas, Herman Lelie
Journal: Journal of Clinical Oncology (2024)

3114 Background: The development of novel drugs targeting glioblastoma (GBM) is crucial due to the aggressive nature of this brain cancer, which often resists current treatments. Microtubules are a well-established target for cancer treatment, however there is a need to identify microtubule targeting agents (MTAs) with decreased toxicity and the ability to also retain efficacy in drug-resistant tumors. The novel MTA, AUS_001 has been shown to impede the growth of 15 established glioma cell lines with a half-maximal inhibitory concentration in the range of 0.04-0.246uM. The goal of the current study was to explore its potential in GBM treatment. Methods: Co-cultures of primary Human brain endothelial cells, pericytes and astrocytes layered in an insert were applied for the assessment of Blood Brain Barrier (BBB) permeability. AUS_001 efficacy against GBM was studied in vitro and in an ex vivo platform of advanced 3D cell culture systems. Differences in drug response were investigated between a Temozolomide (TMZ)-resistant human GBM cell line and parental cells. The ability of AUS_001 to overcome taxane-associated drug resistance was explored in P-glycoprotein (P-gp) and βIII-tubulin over-expression models of drug resistance. A microelectrode array system was used to assess the electrical activity and functionality of human Pluripotent Stem Cell (hPSC)-derived midbrain and cortical neurons, upon dose escalation drug treatments followed by a full media change to allow the recovery period. Results: By employing a 3D Human BBB Model, we demonstrated that AUS_001 is a good BBB permeability substrate. AUS_001 prevents the growth of Parental Primary Patient-Derived GBM and Patient-Derived Glioma Lines enriched in Cancer Stem cells under 2D culturing conditions with high potency. To this end, we evaluated the effect of AUS_001 in 3D spheroids originating from primary GBM patient-derived tumors that include all cells present in each patient’s primary tumor. AUS_001 efficiently prevented the growth of these tumors, including cases where the standard of care, TMZ was not effective. Notably, 2D GBM cultures with acquired TMZ resistance retained sensitivity to the cytotoxic effects of AUS_001. We also found that AUS_001 is less prone to mechanisms of resistance to currently approved MTAs, including increased expression of the βIII-isotype of tubulin or the P-gp drug efflux pump. An in vitro neurotoxicity model revealed that functional damage caused by AUS_001 was reversible, while paclitaxel-treated neurons suffered sustained neurotoxicity. Conclusions: Collectively, we show that AUS_001 has the potential to circumvent significant limitations of clinically approved MTAs, including brain penetration, drug resistance and peripheral neuropathy, making it a promising approach for the treatment of GBM.
RNA-based fusion testing in gastrointestinal (GI) carcinomas: A single-institution experience.
Authors: Bennett Adam Caughey, Charlotte Wang, A. John Iafrate, Ryan Bruce Corcoran
Journal: Journal of Clinical Oncology (2024)

3061 Background: Molecular profiling with next-generation sequencing is critical to provide appropriate clinical care in most GI cancers. However, outside of biliary tract cancers (BTCs), the utility of routine comprehensive fusion testing in GI carcinomas is not well established. We evaluated fusion testing of GI carcinomas in routine clinical care at Massachusetts General Hospital Cancer Center (MGHCC). Methods: Patients with confirmed GI carcinomas who underwent RNA-based tissue fusion testing at MGHCC between Jan 2016 and April 2023 were included. Samples with tumor cellularity &lt;20% or not meeting quality controls were excluded. Fusions of known clinical relevance were evaluated for molecular and histopathologic associations. Results: 2300 GI cancers with at least 1 fusion assay were included (see Table). As expected, BTCs had the highest incidence of fusions (13.7%), 80% of which were FGFR2. Fusions were detected in 3.9-7.7% of colorectal (CRC), pancreatic ductal (PDAC), esophagogastric (EGC), and small bowel (SBC) carcinomas. Fusions of BRAF, FGFR1-3, NTRK1/3, RSPO2/3, and NRG1 were rare (excepting FGFR2 in BTCs) but observed in 3 or more cancer types. Consistent with prior studies, the 3 NTRK1 fusions observed in CRC were associated with MLH1 loss and 15 of 21 (71%) PDAC tumors with fusions were KRAS wild-type (WT). RSPO2/3fusions were the second most frequent after FGFR1-3. RSPO3fusions were predominantly seen in CRC and SBC and were associated with poorly differentiated histology (43%), microsatellite stability (100%), APC WT (92.6%), and KRAS (44.4%), BRAF V600E (40%), and BRCA1/2 mutations (29.6%). Of 5 RSPO2fusions, 4 were in EGC and 100% had poorly differentiated histology and TP53 mutations. No fusions were detected in 47 GI neuroendocrine tumors. Conclusions: Although individually rare, in aggregate RNA-based testing identifies clinically relevant fusions in a small but significant fraction of BTC, CRC, PDAC, EGC, and SBC. Molecular selection may identify subpopulations in which fusion testing is higher yield. CRC and SBC harboring RSPO3 fusions have a distinct molecular and pathologic phenotype, including a potentially novel association with BRCA1/2 mutations. Several detected fusions had novel partners that were nonetheless predicted actionable, highlighting the utility of partner-agnostic fusion testing in this population. [Table: see text]
First-in-human phase 1/2a study of the first-in-class, next-generation CDK4-selective inhibitor PF-07220060 + endocrine therapy (ET): Updated safety data in patients with HR+/HER2− mBC.
Authors: Antonio Giordano, Manish Sharma, Anja Williams, Peter Schmid, Diana Fabiola Flores Diaz, Manuel Magallanes, Binghe Xu, Min Yan, Sacha Jon Howell, Erika P. Hamilton, Cynthia Basu, Jennifer Park, Heather Neumann, Maria Delioukina, Timothy A. Yap
Journal: Journal of Clinical Oncology (2024)

3108 Background: PF-07220060 is a novel, highly selective CDK4 inhibitor with significant CDK6 sparing. Preliminary data have been reported for the monotherapy dose-escalation cohort (Part 1A) and ET combination dose-finding cohorts (Parts 1B-C) in the first-in-human study of PF-07220060 in patients (pts) with advanced solid tumors (1). Herein, we report updated safety data for PF-07220060 + ET in pts with HR+/HER2− advanced/metastatic breast cancer (mBC), including extended follow-up data for pts in dose-finding cohorts (Parts 1B-C) and first disclosure of data for pts in dose-expansion cohorts (Parts 2B-C). Methods: In Parts 1B and 1C of this Phase 1/2a study (NCT04557449),PF-07220060 + ET (letrozole [LET] or fulvestrant [FUL], respectively) was administered to pts with HR+/HER2− mBC as ≥2L therapy after prior CDK4/6 inhibitors (CDK4/6i). In dose-expansion cohort 2B, pts with HR+/HER2− mBC received 1L PF-07220060 + LET; in Part 2C, pts with progression after prior ET received PF-07220060 + FUL. Pts in Parts 2B-C were CDK4/6i-naïve. Primary objective was to evaluate safety and tolerability of PF-07220060 + ET. Results: At data cutoff (Nov 1, 2023), 33 pts received PF-07220060 (300 or 400 mg BID) + ET in Parts 1B-C; 34 pts in Part 2B and 36 pts in Part 2C received PF-07220060 (300 mg BID) with LET or FUL, respectively. Table summarizes patient characteristics in each cohort. In the pooled 1B-C cohort, the most common TEAEs were neutropenia (54.5% [18.2% G3]), diarrhea (42.4% [0% G3]), and nausea (42.4% [3.0% G3]). In Parts 2B-C, the most common TEAEs were neutropenia (61.8%/36.1% [23.5%/11.1% G3]), leukopenia (38.2%/33.3% [0%/13.9% G3]), and anemia (23.5%/27.8% [0%/2.8% G3]). No &gt;G3 TEAEs were reported in Parts 1B-C or 2B-C. In Parts 1B-C, 2B, and 2C, TEAEs leading to discontinuation were reported in 3.0%, 5.9%, and 8.3% of pts, respectively; dose reductions due to AEs were reported in 12.1%, 5.9%, and 8.3% of pts, respectively. Median (range) relative dose intensity (RDI) of PF-07220060 was 98.3% (52.5–100) in Parts 1B-C, 99.8% (37.2–100) in Part 2B, and 99.7% (68.6–100) in Part 2C. Conclusions: PF-07220060 + ET was well tolerated in pts with HR+/HER2− mBC across post-CDK4/6i and CDK4/6i-naïve cohorts. Incidence of G3 neutropenia and other TEAEs was low, enabling high RDI and potential for continuous target coverage. 1. Yap, et al. J Clin Oncol. 2023;41(16_suppl):3009. Clinical trial information: NCT04557449 . [Table: see text]
Correlation of ctDNA and radiographic imaging features derived from <sup>18</sup>F-FDG PET/CT for patients with metastatic melanoma treated with immunotherapy.
Authors: Mikaela R. Dell'Oro, Ojaswita Lokre, Elin S. Gray, Roslyn J. Francis, Timothy G. Perk, Martin A. Ebert, Michael Millward
Journal: Journal of Clinical Oncology (2024)

3057 Background: 18 F-FDG PET/CT scans are used to assess tumor response for patients undergoing immunotherapy for metastatic melanoma (MM). Evaluating the relationship between features derived from quantitative medical image analysis and markers in blood samples such as circulating tumor DNA (ctDNA) may present an opportunity to discover imaging and blood biomarkers that can influence future patient care. This study evaluates the correlation of ctDNA and radiographic imaging features derived from FDG PET/CT. Methods: Whole-body FDG PET/CT scans from MM patients between 2014-2020 were retrospectively collected under IRB-approved protocol. Patients received pembrolizumab (n=20), ipilimumab (n=4), nivolumab (n=7), or a combination of ipilimumab and nivolumab (n=19). TRAQinform IQ software (AIQ Solutions) identified and quantified regions of interest suspicious of cancer (lesion-ROI), enabling extraction of imaging features including SUV max , SUV mean , and SUV total in baseline ( BL ) and follow-up ( FU ) images and change. Plasma ctDNA concentration (copies/ml) and frequency abundance (FA) were evaluated for the first sample ( 1 ) after immunotherapy had started (between baseline and first on-treatment scan), and the next available sample ( 2 ). Patients were further grouped by ctDNA mutation for analysis. Correlation between imaging features and ctDNA features was assessed using Spearman coefficient (ρ). Results: The patient cohort included 32 males and 19 females with average age of 62 years (range 23-83). For all 51 patients, moderate correlation was observed in SUV max,BL with ctDNA copies/ml 1 (ρ = 0.48, p&lt;&lt; 0.001) and ctDNA FA 1 (ρ = 0.49, p &lt;&lt; 0.001) and in SUV total,BL with ctDNA FA 1 (ρ= 0.41, p &lt; 0.001). In BRAF mutation patients (N=32), moderate correlations existed between SUV max,BL with ctDNA copies/ml 1 (ρ = 0.49, p = 0.0041 and ctDNA FA 1 (ρ = 0.05, p = 0.0035), and SUV total,BL with ctDNA copies/ml 2 (ρ = 0.42, p = 0.017), ctDNA FA 1 (ρ = 0.40, p = 0.023), and ctDNA FA 2 (ρ = 0.43, p = 0.012). All the other combinations displayed weak correlations (ρ &lt; 0.39, p &gt; 0.05). Conclusions: This study shows that in patients with MM receiving immunotherapy, quantitative features from blood biomarkers such as ctDNA correlate with FDG PET/CT imaging features. Combining blood biomarkers with imaging features that are spatially localizable may strengthen prognostication in this patient group. Further analysis is being performed with more types of ctDNA mutations.
Efficacy and safety of FCN-159, a MEK1/2 inhibitor in pediatric participants with neurofibromatosis type 1: Results from a phase 2 trial.
Authors: JinHu Wang, Wenbin Li, Kang Zeng, Xiaoxi Lin, Yanling Li, Zhonghai Guan, Zhuang Kang, Changxing Li, Xiaojie Hu, Yaohui Ma, Zhuli Wu, Xingli Wang, Pu Han, Hongmei Lin, Wen Zhong
Journal: Journal of Clinical Oncology (2024)

3096 Background: Neurofibromatosis type 1(NF1) is an autosomal dominant tumor predisposition syndrome characterized by NF1 gene variants, resulting in over-activation of the RAS pathway. Plexiform neurofibroma (PN) is benign tumors that arise from nerve tissue and are a hallmark feature of NF1. They typically grow along nerves and cause disfigurement, pain, and other complications depending on their location and size. FCN-159, a highly potent and selective inhibitor of MEK1/2 by targeting inhibition of the RAS pathway, holds promise as a therapeutic agent for treating NF1-related PN. Methods: A multi-center, open-label phase 1/2 clinical trial was conducted to assess the safety and efficacy in pediatric patients(pts) with NF1-related PN. Here, we reported the safety and efficacy outcomes observed during phase 2 in pediatric pts, who received FCN-159 at the 5 mg/m 2 dose once daily on a continuous basis in a 28-day cycle. Preliminary findings from the phase 1/2 trial were previously disclosed at ASCO 2023. Results: As of November 24, 2023,46 pts enrolled. The median age is 8.0 years (range 2-17). The most frequent PN related complications were disfigurement (69.6%) and pain (63.0%). Median volume of target neurofibroma were 37.7 cm³ (range 2.2-1144.1). Efficacy outcomes are reported for 43 pts (modified intent-to-treat population). With the median follow-up of 15.1 months (range 14.1-16.4), the investigator and Blinded Independent Review Committee (BIRC) assessed ORR were 48.8% and 30.2%, respectively. The mDoR and median mPFS were not reached. Preliminary efficacy data are presented in the table. Among the 16 pediatric subjects with tumor pain at baseline (overall tumor pain NRS≥1) and at least one post-baseline assessment, pain scores decreased by at least 2 points in 81.3% (13/16) pts, and pain scores reduced to 0 points (indicating no pain sensation) in 81.3% (13/16) pts, signifying clinically meaningful improvement. 43 pts (93.5%) experienced TRAEs with grade ≥3 TRAEs occurred in 8 pts (17.4%), including dermatitis acneiform (4.3%), folliculitis (4.3%), pneumonia (2.2%), upper respiratory tract infection (2.2%), ejection fraction decreased (2.2%), and blood creatine phosphokinase increased (2.2%). 2 pts (4.3%) reported treatment-related serious adverse events (one case of dermatitis acneiform and pneumonia each). No TRAEs resulting in dose reduction, discontinuation or death. Conclusions: FCN-159 demonstrated good tolerability and exhibited notable anti-tumor activity in pediatric pts with NF1-related PN. Clinical trial information: NCT04954001 . [Table: see text]
Discovery of long non-coding RNA biomarkers for prognosis in pediatric acute lymphoblastic leukemia.
Authors: Tien-Chan Hsieh, Zixiu Li, Peng Zhou, Chan Zhou
Journal: Journal of Clinical Oncology (2024)

3055 Background: Acute lymphoblastic leukemia (ALL) ranks among the most prevalent pediatric cancers. Molecular testing, including cytogenetics, has been widely used for prognosticating pediatric ALL. However, cytogenetic testing in pediatric ALL is incapable of detecting submicroscopic genetic changes and suffers from variable sensitivity, which may lead to heterogeneous outcomes within cytogenetic subgroups. In addition to conventional prognostic biomarkers, long non-coding RNAs (lncRNAs) are expressed in both a disease- and tissue-specific manner, emerging as promising biomarkers. However, well-established lncRNA prognostic biomarkers for pediatric ALL have yet to be identified. Therefore, in this study, we discovered three singular lncRNA prognostic biomarkers and a prognostic panel composed of multi-lncRNAs for pediatric ALL using our newly developed BAMBI method. Methods: This study utilized RNA-seq data from 561 distinct individuals, comprising 647 blood or bone marrow biospecimens obtained from pediatric patients with ALL from the dbGaP TARGET dataset. Among these individuals with RNA-seq and survival data, 25.8% deceased during follow-up. The average age at enrollment was 8.1 years. Of this cohort, 36.0% were female, and 61.5% were Caucasian white. Initially, our lncRNA identification tool, Flnc (Li Z., et al., Noncoding RNA. 2022), was employed to identify and quantify both novel and known lncRNAs expressed in pediatric ALL. Subsequently, our machine-learning based method, BAMBI, was utilized to discover lncRNAs as new prognostic biomarkers in pediatric ALL. Results: Three lncRNAs (ZBTB47 and NKTR antisense RNA, AC097359.2’s new isoform, and a novel lncRNA near STXBP5) were identified as individual putative biomarkers for prognosis. Each of these three lncRNA biomarkers exhibited predictive power for survival, with accuracy ranging from 68.2% to 72.8% and AUROC scores ranging from 67.7% to 75%. Furthermore, we established three lncRNA biomarker panels composed of these three lncRNAs along with a few additional lncRNAs, which showed improved prediction power with accuracy ranging from 78.3% to 79.6%, and AUROC scores ranging from 82.1% to 85.2%. Conclusions: We discovered both singular lncRNA and panels of multi-lncRNAs as prognostic biomarkers of pediatric ALL patients. These putative lncRNA biomarkers could be further validated through independent cohorts or prospective clinical study designs.
Preclinical characterization of HBW-012-E, a novel, potent, selective, safe, and orally active KRAS G12D inhibitor with superior pharmacokinetic (PK) properties and anti-tumor efficacy.
Authors: Ning Lee, Yingfu Li, Guanfeng Liu, Jiang Li, Junfeng Ren
Journal: Journal of Clinical Oncology (2024)

3115 Background: HBW-012-E is a newly identified KRAS G12D small molecule inhibitor with improved oral bioavailability than MRTX1133, the more advanced clinical candidate with poor bioavailability. Methods: Small molecules were designed through our medicinal chemistry efforts, aiming to discover KRAS G12D inhibitors that are of good oral bioavailability. The compounds were screened via pERK and cell viability (CTG) assays in multiple cell types. The optimized compounds were further evaluated based on their PK properties and toxicity. The anti-tumor efficacy of the leads was confirmed in a mouse GP2D (with KRAS G12D) colon cancer model. Results: As shown in the table, HBW-012-E has better potency and PK characteristics than MRTX1133. In the GP2D model, comparing head-to-head with the same vehicle and protocol (50 mg/kg, BID, PO), HBW-012-E can not only inhibit tumor growth completely but also further regress tumor size by ~40%, whereas MRTX1133 can hardly inhibit tumor growth. HBW-012-E demonstrated anti-tumor efficacy in a dose-dependent manner; at a dose as low as 10 mg/kg, it achieved ~80 % tumor inhibition rate (TGI). Preliminary toxicity tests showed that HBW-012-E is safe: weak inhibition of CYP450 enzymes, negative mini-Ames test, excellent kinase selectivity, and no obvious abnormalities in the 14-day rat or mouse toxicity test. Conclusions: A new KRAS G12D inhibitor, HBW-012-E, was identified. Its preclinical profile, including potency, efficacy, and PK properties, are all superior to MRTX1133, and its safety meets the criteria of clinical development. It can potentially be used to treat intractable tumors mediated by KRAS G12D mutations, such as pancreatic cancer that still lacks effective treatments. [Table: see text]