Radiomics combined with transcriptomics to predict response to immunotherapy from patients treated with PD-1/PD-L1 inhibitors for advanced NSCLC

IntroductionIn this study, we aim to build radiomics and multiomics models based on transcriptomics and radiomics to predict the response from patients treated with the PD-L1 inhibitor.Materials and methodsOne hundred and ninety-five patients treated with PD-1/PD-L1 inhibitors were included. For all patients, 342 radiomic features were extracted from pretreatment computed tomography scans. The training set was built with 110 patients treated at the Léon Bérard Cancer Center. An independent validation cohort was built with the 85 patients treated in Dijon. The two sets were dichotomized into two classes, patients with disease control and those considered non-responders, in order to predict the disease control at 3 months. Various models were trained with different feature selection methods, and different classifiers were evaluated to build the models. In a second exploratory step, we used transcriptomics to enrich the database and develop a multiomic signature of response to immunotherapy in a 54-patient subgroup. Finally, we considered the HOT/COLD status. We first trained a radiomic model to predict the HOT/COLD status and then prototyped a hybrid model integrating radiomics and the HOT/COLD status to predict the response to immunotherapy.ResultsRadiomic signature for 3 months’ progression-free survival (PFS) classification: The most predictive model had an area under the receiver operating characteristic curve (AUROC) of 0.94 on the training set and 0.65 on the external validation set. This model was obtained with the t-test selection method and with a support vector machine (SVM) classifier. Multiomic signature for PFS classification: The most predictive model had an AUROC of 0.95 on the training set and 0.99 on the validation set. Radiomic model to predict the HOT/COLD status: the most predictive model had an AUROC of 0.93 on the training set and 0.86 on the validation set. HOT/COLD radiomic hybrid model for PFS classification: the most predictive model had an AUROC of 0.93 on the training set and 0.90 on the validation set.ConclusionIn conclusion, radiomics could be used to predict the response to immunotherapy in non-small-cell lung cancer patients. The use of transcriptomics or the HOT/COLD status, together with radiomics, may improve the working of the prediction models

Aflatoxin-Induced TP53 R249S Mutation in HepatoCellular Carcinoma in Thailand: Association with Tumors Developing in the Absence of Liver Cirrhosis

Primary Liver Cancer (PLC) is the leading cause of death by cancer among males in Thailand and the 3rd among females. Most cases are hepatocellular carcinoma (HCC) but cholangiocarcinomas represent between 4 and 80% of liver cancers depending upon geographic area. Most HCC are associated with chronic infection by Hepatitis B Virus while a G→T mutation at codon 249 of the TP53 gene, R249S, specific for exposure to aflatoxin, is detected in tumors for up to 30% of cases. We have used Short Oligonucleotide Mass Analysis (SOMA) to quantify free circulating R249S-mutated DNA in plasma using blood specimens collected in a hospital case:control study. Plasma R249S-mutated DNA was detectable at low concentrations (≥67 copies/mL) in 53 to 64% of patients with primary liver cancer or chronic liver disease and in 19% of controls. 44% of patients with HCC and no evidence of cirrhosis had plasma concentrations of R249S-mutated DNA ≥150 copies/mL, compared to 21% in patients with both HCC and cirrhosis, 22% in patients with cholangiocarcinoma, 12% in patients with non-cancer chronic liver disease and 3% of subjects in the reference group. Thus, plasma concentrations of R249S-mutated DNA ≥150 copies/mL tended to be more common in patients with HCC developing without pre-existing cirrhosis (p = 0.027). Overall, these results support the preferential occurrence of R249S-mutated DNA in HCC developing in the absence of cirrhosis in a context of HBV chronic infection

Editorial: The Role of the EMT Program in Regulating the Immune Response in Carcinoma

International audienceNo abstract availabl

New insights into the role of EMT in tumor immune escape

International audienceNovel immunotherapy approaches have provided durable remission in a significant number of cancer patients with cancers previously considered rapidly lethal. Nonetheless, the high degree of nonresponders, and in some cases the emergence of resistance in patients who do initially respond, represents a significant challenge in the field of cancer immunotherapy. These issues prompt much more extensive studies to better understand how cancer cells escape immune surveillance and resist immune attacks. Here, we review the current knowledge of how cellular heterogeneity and plasticity could be involved in shaping the tumor microenvironment (TME) and in controlling antitumor immunity. Indeed, recent findings have led to increased interest in the mechanisms by which cancer cells undergoing epithelial-mesenchymal transition (EMT), or oscillating within the EMT spectrum, might contribute to immune escape through multiple routes. This includes shaping of the TME and decreased susceptibility to immune effector cells. Although much remains to be learned on the mechanisms at play, cancer cell clones with mesenchymal features emerging from the TME seem to be primed to face immune attacks by specialized killer cells of the immune system, the natural killer cells, and the cytotoxic T lymphocytes. Recent studies investigating patient tumors have suggested EMT as a candidate predictive marker to be explored for immunotherapy outcome. Promising data also exist on the potential utility of targeting these cancer cell populations to at least partly overcome such resistance. Research is now underway which may lead to considerable progress in optimization of treatments

Implementing ctDNA Analysis in the Clinic: Challenges and Opportunities in Non-Small Cell Lung Cancer

Tumor genomic profiling has a dramatic impact on the selection of targeted treatment and for the identification of resistance mechanisms at the time of progression. Solid tissue biopsies are sometimes challenging, and liquid biopsies are used as a non-invasive alternative when tissue is limiting. The clinical relevance of tumor genotyping through analysis of ctDNA is now widely recognized at all steps of the clinical evaluation process in metastatic non-small cell lung cancer (NSCLC) patients. ctDNA analysis through liquid biopsy has recently gained increasing attention as well in the management of early and locally advanced, not oncogene-addicted, NSCLC. Its potential applications in early disease detection and the response evaluation to radical treatments are promising. The aim of this review is to summarize the landscape of liquid biopsies in clinical practice and also to provide an overview of the potential perspectives of development focusing on early detection and screening, the assessment of minimal residual disease, and its potential role in predicting response to immunotherapy. In addition to available studies demonstrating the clinical relevance of liquid biopsies, there is a need for standardization and well-designed clinical trials to demonstrate its clinical utility

High Circulating Sonic Hedgehog Protein Is Associated With Poor Outcome in EGFR-Mutated Advanced NSCLC Treated With Tyrosine Kinase Inhibitors

International audienceIntroduction: Growing preclinical evidence has suggested that the Sonic hedgehog (Shh) pathway is involved in resistance to tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). However, little is known concerning the prognostic value of this pathway in this context. Materials and Methods: We investigated the relationship between plasma levels of Shh and EGFRm NSCLC patients’ outcome with EGFR TKIs. We included 74 consecutive patients from two institutions with EGFRm advanced NSCLC treated by EGFR TKI as first-line therapy. Plasma samples were collected longitudinally for each patient and were analyzed for the expression of Shh using an ELISA assay. The activation of the Shh–Gli1 pathway was assessed through immunohistochemistry (IHC) of Gli1 and RT-qPCR analysis of the transcripts of Gli1 target genes in 14 available tumor biopsies collected at diagnosis (baseline). Results: Among the 74 patients, only 61 had baseline (diagnosis) plasma samples, while only 49 patients had plasma samples at the first evaluation. Shh protein was detectable in all samples at diagnosis (n = 61, mean = 1,041.2 ± 252.5 pg/ml). Among the 14 available tumor biopsies, nuclear expression of Gli1 was observed in 57.1% (8/14) of patients’ biopsies. Shh was significantly (p 1, and patients presenting more than 2 metastatic sites and L858R mutation. Higher levels of Shh correlated with poor objective response to TKI, shorter progression-free survival (PFS), and T790M-independent mechanism of resistance. In addition, the rise of plasma Shh levels along the treatment was associated with the emergence of drug resistance in patients presenting an initial good therapy response. Conclusion: These data support that higher levels of plasma Shh at diagnosis and increased levels of Shh along the course of the disease are related to the emergence of TKI resistance and poor outcome for EGFR-TKI therapy, suggesting that Shh levels could stand both as a prognostic and as a resistance biomarker for the management of EGFR-mutated NSCLC patients treated with EGFR-TKI. Copyrigh

Association between TP53 R249S mutation and polymorphisms in TP53 intron 1 in hepatocellular carcinoma

Ortiz-Cuaran, Sandra Cox, David Villar, Stephanie Friesen, Marlin D Durand, Geoffroy Chabrier, Amelie Khuhaprema, Thiravud Sangrajrang, Suleeporn Ognjanovic, Simona Groopman, John D Hainaut, Pierre Le Calvez-Kelm, Florence eng Research Support, Non-U.S. Gov't 2013/07/10 06:00 Genes Chromosomes Cancer. 2013 Oct;52(10):912-9. doi: 10.1002/gcc.22086. Epub 2013 Jul 8.International audienceOver 100 single nucleotide polymorphisms (SNP) are validated in the TP53 tumor suppressor gene. They define haplotypes, which may differ in their activities. Therefore, mutation in cancer may occur at different rates depending upon haplotypes. However, these associations may be masked by differences in mutations types and causes of mutagenesis. We have analyzed the associations between 19 SNPs spanning the TP53 locus and a single specific aflatoxin-induced TP53 mutation (R249S) in 85 in hepatocellular carcinoma cases and 132 controls from Thailand. An association with R249S mutation (P = 0.007) was observed for a combination of two SNPs (rs17882227 and rs8064946) in a linkage disequilibrium block extending from upstream of exon 1 to the first half of intron 1. This domain contains two coding sequences overlapping with TP53 (WRAP53 and Hp53int1) suggesting that sequences in TP53 intron 1 encode transcripts that may modulate R249S mutation rate in HCC

A 13-gene expression-based radioresistance score highlights the heterogeneity in the response to radiation therapy across HPV-negative HNSCC molecular subtypes

Abstract Background Radiotherapy for head and neck squamous cell carcinomas (HNSCC) is associated with a substantial morbidity and inconsistent efficacy. Human papillomavirus (HPV)-positive status is recognized as a marker of increased radiosensitivity. Our goal was to identify molecular markers associated with benefit to radiotherapy in patients with HPV-negative disease. Methods Gene expression profiles from public repositories were downloaded for data mining. Training sets included 421 HPV-negative HNSCC tumors from The Cancer Genome Atlas (TCGA) and 32 HNSCC cell lines with available radiosensitivity data (GSE79368). A radioresistance (RadR) score was computed using the single sample Gene Set Enrichment Analysis tool. The validation sets included two panels of cell lines (NCI-60 and GSE21644) and HPV-negative HNSCC tumor datasets, including 44 (GSE6631), 82 (GSE39366), and 179 (GSE65858) patients, respectively. We finally performed an integrated analysis of the RadR score with known recurrent genomic alterations in HNSCC, patterns of protein expression, biological hallmarks, and patterns of drug sensitivity using TCGA and the E-MTAB-3610 dataset (659 pancancer cell lines, 140 drugs). Results We identified 13 genes differentially expressed between tumor and normal head and neck mucosa that were associated with radioresistance in vitro and in patients. The 13-gene expression-based RadR score was associated with recurrence in patients treated with surgery and adjuvant radiotherapy but not with surgery alone. It was significantly different among different molecular subtypes of HPV-negative HNSCC and was significantly lower in the “atypical” molecular subtype. An integrated analysis of RadR score with genomic alterations, protein expression, biological hallmarks and patterns of drug sensitivity showed a significant association with CCND1 amplification, fibronectin expression, seven hallmarks (including epithelial-to-mesenchymal transition and unfolded protein response), and increased sensitivity to elesclomol, an HSP90 inhibitor. Conclusions Our study highlights the clinical relevance of the molecular classification of HNSCC and the RadR score to refine radiation strategies in HPV-negative disease