A Comprehensive Genomic Analysis of Nucleophosmin (NPM1) in Acute Myeloid Leukemia.

This study investigates genomic alterations (GA) between NPM1-mutated (NPM1mut) and wild-type (NPM1wt) acute myeloid leukemia (AML), aiming to better understand the AML genomic profile. NPM1mut AML represents a distinct clinical AML subtype with high relapse rates despite initial responsiveness to chemotherapy. A total of 4206 AML cases from 2019 to 2024 were analyzed using the FoundationOne Heme assay, incorporating comprehensive DNA and RNA sequencing.

Real-World Validity of Tissue-Agnostic Circulating Tumor DNA Response Monitoring in Lung Cancers Treated With Chemotherapy, Immunotherapy, or Targeted Agents.

Introduction: Circulating tumor DNA (ctDNA) monitoring is emerging as a minimally invasive complement to tumor imaging. We evaluated the validity of tissue-agnostic ctDNA quantification across four treatment modalities in NSCLC and SCLC.

Methods: Data from consenting patients were collected from electronic health records as part of the Prospective Clinico-Genomic study (NCT04180176).

Fragmentomic-based algorithm to computationally predict tumor-somatic, germline, and clonal hematopoiesis variant origin in liquid biopsy.

Purpose: Genomic profiling of tumors by liquid biopsy (LBx) is a pragmatic alternative to profiling tissue. Despite recent methodologic advances, clonal hematopoiesis (CH) variants arising from hematopoietic stem cells may confound LBx results. Distinguishing the origin of variants detected by LBx will greatly enhance treatment decision-making for patients with cancer.

Switch-like gene expression modulates disease risk.

While switch-like gene expression ("on" in some individuals and "off" in others) has been linked to biological variation and disease susceptibility, a systematic analysis across tissues is lacking. Here, we analyze genomes, transcriptomes, and methylomes from 943 individuals across 27 tissues, identifying 473 switch-like genes. The identified genes are enriched for associations with cancers and immune, metabolic, and skin diseases.

Elevated ctDNA Tumor Fraction Is Associated with Improved Mutation Detection but Worse Overall Survival in Advanced Non-Small Cell Lung Cancer: A Lung-MAP Study.

Purpose: ctDNA is a powerful diagnostic companion to tissue profiling. Tumor fraction (TF) is a global assessment of an individual's ctDNA burden. We evaluated the impact of plasma TF on mutation detection and clinical outcomes in patients with previously treated, advanced non-small cell lung cancer on the Lung Master Protocol (Lung-MAP).

Circulating tumor DNA monitoring and blood tumor mutational burden in patients with metastatic solid tumors treated with atezolizumab.

Immune checkpoint inhibitors are important for treatment across tumor types but are not universally effective in controlling disease. Early understanding of tumor response, or lack thereof, can inform treatment decisions. This study evaluates changes in circulating tumor DNA (ctDNA) and blood tumor mutational burden (bTMB) for associations with response to programmed cell death 1 ligand 1 (PD-L1) blockade.

Genomic landscape and homologous recombination repair deficiency signature in stage I-III and de novo stage IV primary breast cancers.

Purpose: We compared genomic alterations and a homologous recombination deficiency (HRD) signature (HRDsig) in primary tumors from stage I-III to those in de novo stage IV breast cancers and from stage I-III cancers with early (<2 years after diagnosis) versus late (>2 years) recurrence.

Methods: De-identified genomic and clinical data of primary breast cancers (stage I-III N = 910, stage IV N = 783) from the United States, the nationwide clinico-genomic database of Flatiron Health and Foundation Medicine were analyzed. Genomic results included the mutation status of 324 cancer-related genes and HRDsig, a DNA scar-based measure of HRD.

Clinical Use of Liquid-Based Comprehensive Genomic Profiling in Gastrointestinal Stromal Tumors.

Treatment for gastrointestinal stromal tumor (GIST) focuses on tyrosine kinase inhibitors, the selection of which depends on specific mutations. We sought to determine the clinical use of liquid biopsy in advanced GIST. Liquid (n = 181) (FoundationOne Liquid CDx) and tissue (n = 2198) (FoundationOne and FoundationOne CDx) comprehensive genomic profiling of GIST were evaluated.

Switch-like Gene Expression Modulates Disease Susceptibility.

A fundamental challenge in biomedicine is understanding the mechanisms predisposing individuals to disease. While previous research has suggested that switch-like gene expression is crucial in driving biological variation and disease susceptibility, a systematic analysis across multiple tissues is still lacking. By analyzing transcriptomes from 943 individuals across 27 tissues, we identified 1,013 switch-like genes.

Switch-like Gene Expression Modulates Disease Susceptibility.

A fundamental challenge in biomedicine is understanding the mechanisms predisposing individuals to disease. While previous research has suggested that switch-like gene expression is crucial in driving biological variation and disease susceptibility, a systematic analysis across multiple tissues is still lacking. By analyzing transcriptomes from 943 individuals across 27 tissues, we identified 1,013 switch-like genes.

Measurement of ctDNA Tumor Fraction Identifies Informative Negative Liquid Biopsy Results and Informs Value of Tissue Confirmation.

Purpose: Liquid biopsy (LBx) for tumor profiling is increasingly used, but concerns remain regarding negative results. A lack of results may truly reflect tumor genomics, or it may be a false negative that would be clarified by tissue testing. A method of distinguishing between these scenarios could help clarify when follow-on tissue testing is valuable.

Liquid Biopsy of Lung Cancer Before Pathological Diagnosis Is Associated With Shorter Time to Treatment.

Purpose: Studies have investigated the early use of liquid biopsy (LBx) during the diagnostic workup of patients presenting with clinical evidence of advanced lung cancer, but real-world adoption and impact has not been characterized. The aim of this study was to determine whether the use of LBx before diagnosis (Dx; LBx-Dx) enables timely comprehensive genomic profiling (CGP) and shortens time until treatment initiation for advanced non-small-cell lung cancer (aNSCLC).

Materials And Methods: This study used the Flatiron Health-Foundation Medicine electronic health record-derived deidentified clinicogenomic database of patients with aNSCLC from approximately 280 US cancer clinics.

Homologous Recombination Deficiency Landscape of Breast Cancers and Real-World Effectiveness of Poly ADP-Ribose Polymerase Inhibitors in Patients With Somatic /, Germline , or Homologous Recombination Deficiency Signature.

Purpose: Poly ADP-ribose polymerase inhibitors (PARPi) are approved for patients with human epidermal growth factor receptor 2-negative metastatic breast cancer (mBC) and germline pathogenic/likely pathogenic variant (hereafter mutation) in the / genes (g); however, clinical benefit has also been demonstrated in mBC with somatic / mutations (s) or germline mutations (g). This study aims to describe the genomic landscape of homologous recombination repair (HRR) gene alterations in mBC and assess PARPi treatment outcomes for patients with g compared with other HRR genes and by status of a novel homologous recombination deficiency signature (HRDsig).

Methods: A real-world (RW) clinico-genomic database (CGDB) of comprehensive genomic profiling (CGP) linked to deidentified, electronic health record-derived clinical data was used.

Real-World Genomic Profile of EGFR Second-Site Mutations and Other Osimertinib Resistance Mechanisms and Clinical Landscape of NSCLC Post-Osimertinib.

Introduction: The emergence of osimertinib as standard of care for EGFR-mutant NSCLC has renewed the need to understand and overcome drug resistance. We sought to understand the genomics and real-world treatment landscape of NSCLC with EGFR C797S and other on- and off-target resistance mechanisms.

Methods: Comprehensive genomic profiling (CGP) results from tissue or blood samples from 93,065 patients with NSCLC were queried for osimertinib EGFR second-site resistance mutations (ssEGFRms; C797, L718, G724, G796, L792).

Pan-Cancer Analysis of Copy-Number Features Identifies Recurrent Signatures and a Homologous Recombination Deficiency Biomarker to Predict Poly (ADP-Ribose) Polymerase Inhibitor Response.

Purpose: Copy-number (CN) features reveal the molecular state of cancers and may have predictive and prognostic value in the treatment of cancer. We sought to apply published CN analysis methods to a large pan-cancer data set and characterize ubiquitous CN signatures across tumor types, including potential utility for treatment selection.

Methods: We analyzed the landscape of CN features in 260,333 pan-cancer samples.

Circulating Tumor DNA Monitoring on Chemo-immunotherapy for Risk Stratification in Advanced Non-Small Cell Lung Cancer.

Purpose: Chemoimmunotherapy (chemoIO) is a prevalent first-line treatment for advanced driver-negative non-small cell lung cancer (NSCLC), with maintenance therapy given after induction. However, there is significant clinical variability in the duration, dosing, and timing of maintenance therapy after induction chemoIO. We used circulating tumor DNA (ctDNA) monitoring to inform outcomes in patients with advanced NSCLC receiving chemoIO.

Molecular residual disease detection in resected, muscle-invasive urothelial cancer with a tissue-based comprehensive genomic profiling-informed personalized monitoring assay.

Introduction: Circulating tumor DNA (ctDNA) detection postoperatively may identify patients with urothelial cancer at a high risk of relapse. Pragmatic tools building off clinical tumor next-generation sequencing (NGS) platforms could have the potential to increase assay accessibility.

Methods: We evaluated the widely available Foundation Medicine comprehensive genomic profiling (CGP) platform as a source of variants for tracking of ctDNA when analyzing residual samples from IMvigor010 (ClinicalTrials.

Validity and utility of blood tumor mutational burden (bTMB) is dependent on circulating tumor DNA (ctDNA) shed: SCRUM-Japan MONSTAR-SCREEN.

Background: The tumor mutational burden (TMB) is a genomic biomarker associated with the benefits from immune checkpoint inhibitors (ICIs) cancer therapy. An elevated blood TMB (bTMB) in circulating tumor DNA (ctDNA) represents a compelling non-invasive diagnostic approach; however, the validity and utility of this emerging biomarker across cancer types have not been examined.

Patient And Methods: The blood and tissue TMB was measured in a large pan-tumor clinical cohort and the MONSTAR-SCREEN observational study (UMIN000036749) using the FoundationOne Liquid CDx and FoundationOne CDx assays.

A Novel HRD Signature Is Predictive of FOLFIRINOX Benefit in Metastatic Pancreatic Cancer.

Background: Pancreatic cancer (PC) represents an aggressive disease with median overall survival (OS) of less than 1 year in the front-line setting. FOLFIRINOX and gemcitabine and paclitaxel (GP) are standard of care options for these patients; however, optimal selection of therapy is challenging.

Methods: Comprehensive genomic profiling was performed on 8358 PC patients.

Gene communities in co-expression networks across different tissues.

With the recent availability of tissue-specific gene expression data, e.g., provided by the GTEx Consortium, there is interest in comparing gene co-expression patterns across tissues.

Comprehensive genomic profiling and treatment patterns across ancestries in advanced prostate cancer: a large-scale retrospective analysis.

Background: Men of African ancestry experience the greatest burden of prostate cancer globally, but they are under-represented in genomic and precision medicine studies. Therefore, we sought to characterise the genomic landscape, comprehensive genomic profiling (CGP) utilisation patterns, and treatment patterns across ancestries in a large, diverse, advanced prostate cancer cohort, to determine the impact of genomics on ancestral disparities.

Methods: In this large-scale retrospective analysis, the CGP-based genomic landscape was evaluated in biopsy sections from 11 741 patients with prostate cancer, with ancestry inferred using a single nucleotide polymorphism-based approach.

Immunocal® limits gliosis in mouse models of repetitive mild-moderate traumatic brain injury.

Successive traumatic brain injuries (TBIs) exacerbate neuroinflammation and oxidative stress. No therapeutics exist for populations at high risk of repetitive mild TBIs (rmTBIs). We explored the preventative therapeutic effects of Immunocal®, a cysteine-rich whey protein supplement and glutathione (GSH) precursor, following rmTBI and repetitive mild-moderate TBI (rmmTBI).

Comprehensive pan-cancer genomic landscape of KRAS altered cancers and real-world outcomes in solid tumors.

Recent clinical development of KRAS inhibitors has heightened interest in the genomic landscape of KRAS-altered cancers. We performed a pan-cancer analysis of KRAS-altered samples from 426,706 adult patients with solid or hematologic malignancies using comprehensive genomic profiling; additional analyses included 62,369 liquid biopsy and 7241 pediatric samples. 23% of adult pan-cancer samples had KRAS alterations; 88% were mutations, most commonly G12D/G12V/G12C/G13D/G12R, and prevalence was similar in liquid biopsies.

Early circulating tumor DNA dynamics as a pan-tumor biomarker for long-term clinical outcome in patients treated with durvalumab and tremelimumab.

There is an urgent need to identify biomarkers of early response that can accurately predict the benefit of immune checkpoint inhibitors (ICI). Patients receiving durvalumab/tremelimumab had tumor samples sequenced before treatment (baseline) to identify variants for the design of a personalized circulating tumor (ctDNA) assay. ctDNA was assessed at baseline and at 4 and/or 8 weeks into treatment.