Machine learning identifies activation of RUNX/AP-1 as drivers of mesenchymal and fibrotic regulatory programs in gastric cancer.

Gastric cancer (GC) is the fifth most common cancer worldwide and is a heterogeneous disease. Among GC subtypes, the mesenchymal phenotype (Mes-like) is more invasive than the epithelial phenotype (Epi-like). Although gene expression of the epithelial-to-mesenchymal transition (EMT) has been studied, the regulatory landscape shaping this process is not fully understood.

Transcriptome Deconvolution Reveals Absence of Cancer Cell Expression Signature in Immune Checkpoint Blockade Response.

Unlabelled: Immune checkpoint therapy (ICB) has conferred significant and durable clinical benefit to some patients with cancer. However, most patients do not respond to ICB, and reliable biomarkers of ICB response are needed to improve patient stratification. Here, we performed a transcriptome-wide meta-analysis across 1,486 tumors from ICB-treated patients and tumors with expected ICB outcomes based on microsatellite status.

Oncogene-Driven Non-Small Cell Lung Cancers in Patients with a History of Smoking Lack Smoking-Induced Mutations.

Unlabelled: Non-small cell lung cancers (NSCLC) in nonsmokers are mostly driven by mutations in the oncogenes EGFR, ERBB2, and MET and fusions involving ALK and RET. In addition to occurring in nonsmokers, alterations in these "nonsmoking-related oncogenes" (NSRO) also occur in smokers. To better understand the clonal architecture and genomic landscape of NSRO-driven tumors in smokers compared with typical-smoking NSCLCs, we investigated genomic and transcriptomic alterations in 173 tumor sectors from 48 NSCLC patients.

Precision Endpoints for Contemporary Precision Oncology Trials.

Traditional endpoints such as progression-free survival and overall survival do not fully capture the pharmacologic and pharmacodynamic effects of a therapeutic intervention. Incorporating mechanism-driven biomarkers and validated surrogate proximal endpoints can provide orthogonal readouts of anti-tumor activity and delineate the relative contribution of treatment components on an individual level, highlighting the limitation of solely relying on aggregated readouts from clinical trials to facilitate go/no-go decisions for precision therapies.

Detection of circulating tumor DNA with ultradeep sequencing of plasma cell-free DNA for monitoring minimal residual disease and early detection of recurrence in early-stage lung cancer.

Background: In early-stage non-small cell lung cancer (NSCLC), recurrence is frequently observed. Circulating tumor DNA (ctDNA) has emerged as a noninvasive tool to risk stratify patients for recurrence after curative intent therapy. This study aimed to risk stratify patients with early-stage NSCLC via a personalized, tumor-informed multiplex polymerase chain reaction (mPCR) next-generation sequencing assay.

Brief Report: Droplet Digital Polymerase Chain Reaction Versus Plasma Next-Generation Sequencing in Detecting Clearance of Plasma EGFR Mutations and Carcinoembryonic Antigen Levels as a Surrogate Measure.

Introduction: To compare the performance of droplet digital polymerase chain reaction (ddPCR) and plasma next-generation sequencing (NGS) in detecting clearance of plasma EGFR (pEGFR) mutations.

Methods: Patients with treatment-naive advanced EGFR-mutated lung cancer treated with first-line tyrosine kinase inhibitors (TKIs) were included. pEGFR were measured at baseline and first response assessment using ddPCR and NGS.

PUREE: accurate pan-cancer tumor purity estimation from gene expression data.

Tumors are complex masses composed of malignant and non-malignant cells. Variation in tumor purity (proportion of cancer cells in a sample) can both confound integrative analysis and enable studies of tumor heterogeneity. Here we developed PUREE, which uses a weakly supervised learning approach to infer tumor purity from a tumor gene expression profile.

Comprehensive molecular phenotyping of -deficient gastric cancer reveals pervasive epigenomic reprogramming and therapeutic opportunities.

Objective: Gastric cancer (GC) is a leading cause of cancer mortality, with being the second most frequently mutated driver gene in GC. We sought to decipher -specific GC regulatory networks and examine therapeutic vulnerabilities arising from loss.

Design: Genomic profiling of GC patients including a Singapore cohort (>200 patients) was performed to derive mutational signatures of inactivation across molecular subtypes.

PD-L1 score as a prognostic biomarker in asian early-stage epidermal growth factor receptor-mutated lung cancer.

Aim: To determine the prognostic value of programmed death-ligand 1 (PD-L1) score in early-stage epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC), contrasted against EGFR-wildtype NSCLC.

Methods: Consecutive patients with Stage IA-IIIA NSCLC diagnosed 1st January 2010-31st December 2019 at National Cancer Centre Singapore with evaluable EGFR and PD-L1 status were included. Co-primary end-points were 2-year disease-free survival (DFS) and 5-year overall survival (OS) by Kaplan-Meier method.

A Randomized Phase 2 Trial of Nivolumab Versus Nivolumab-Ipilimumab Combination in EGFR-Mutant NSCLC.

Introduction: Although immune checkpoint inhibitors (ICIs) have dramatically improved outcomes for nononcogene-addicted NSCLC, monotherapy with programmed cell death protein-1 (PD1) inhibition has been associated with low efficacy in the EGFR-mutant setting. Given the potential for synergism with combination checkpoint blockade, we designed a trial to test the activity of combination nivolumab (N)-ipilimumab (NI) in EGFR-mutant NSCLC.

Methods: This is a randomized phase 2 study (NCT03091491) of N versus NI combination in EGFR tyrosine kinase inhibitor (TKI)-resistant NSCLC, with crossover permitted on disease progression.

Clinical and Genomic Features of Exon 20 Insertion Mutations and Characterization of Expression by Immunohistochemistry in East Asian Non-Small-Cell Lung Cancer.

Purpose: -altered non-small-cell lung cancer (NSCLC) represents a diverse subgroup, including mutations, amplifications, and overexpression. However, exon 20 insertion mutations are emerging as a distinct molecular subtype with expanding therapeutic options. We describe the molecular epidemiology and genomic features of -altered NSCLC in an Asian tertiary cancer center.

Accurate somatic variant detection using weakly supervised deep learning.

Identification of somatic mutations in tumor samples is commonly based on statistical methods in combination with heuristic filters. Here we develop VarNet, an end-to-end deep learning approach for identification of somatic variants from aligned tumor and matched normal DNA reads. VarNet is trained using image representations of 4.

Regulatory enhancer profiling of mesenchymal-type gastric cancer reveals subtype-specific epigenomic landscapes and targetable vulnerabilities.

Objective: Gastric cancer (GC) comprises multiple molecular subtypes. Recent studies have highlighted mesenchymal-subtype GC (Mes-GC) as a clinically aggressive subtype with few treatment options. Combining multiple studies, we derived and applied a consensus Mes-GC classifier to define the Mes-GC enhancer landscape revealing disease vulnerabilities.

Accurate Ensemble Prediction of Somatic Mutations with SMuRF2.

Accurate identification of somatic mutations is crucial for discovery and identification of driver mutations in cancer tumors. Here, we describe the updated Somatic Mutation calling method using a Random Forest (SMuRF2), an ensemble method that combines the predictions and auxiliary features from individual mutation callers using supervised machine learning. SMuRF2 provides an efficient workflow to predict both somatic point mutations (SNVs) and small insertions/deletions (indels) in cancer genomes and exomes.

Deficiency of the splicing factor RBM10 limits EGFR inhibitor response in EGFR-mutant lung cancer.

Molecularly targeted cancer therapy has improved outcomes for patients with cancer with targetable oncoproteins, such as mutant EGFR in lung cancer. Yet, the long-term survival of these patients remains limited, because treatment responses are typically incomplete. One potential explanation for the lack of complete and durable responses is that oncogene-driven cancers with activating mutations of EGFR often harbor additional co-occurring genetic alterations.

A pan-cancer metabolic atlas of the tumor microenvironment.

Tumors are heterogeneous cellular environments with entwined metabolic dependencies. Here, we use a tumor transcriptome deconvolution approach to profile the metabolic states of cancer and non-cancer (stromal) cells in bulk tumors of 20 solid tumor types. We identify metabolic genes and processes recurrently altered in cancer cells across tumor types, highlighting pan-cancer upregulation of deoxythymidine triphosphate (dTTP) production.

A phase 1b study of OXIRI in pancreatic adenocarcinoma patients and its immunomodulatory effects.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal and debilitating disease with limited therapeutic options. The aim of this clinical study was to evaluate the safety, efficacy and pharmacokinetics of a novel regimen comprised of metronomic oxaliplatin (O), chronomodulated capecitabine (X) and UGT1A1 genotype-guided dosing of irinotecan (IRI) [OXIRI] as well as its immunomodulatory effects. Thirty-six patients were enrolled into either dose-escalation or expansion cohorts.