MS-CPFI: A model-agnostic Counterfactual Perturbation Feature Importance algorithm for interpreting black-box Multi-State models.

Multi-state processes (Webster, 2019) are commonly used to model the complex clinical evolution of diseases where patients progress through different states. In recent years, machine learning and deep learning algorithms have been proposed to improve the accuracy of these models' predictions (Wang et al., 2019).

Gemcitabine plus platinum-based chemotherapy in combination with bevacizumab for kidney metastatic collecting duct and medullary carcinomas: Results of a prospective phase II trial (BEVABEL-GETUG/AFU24).

Background: Renal medullary carcinoma (RMC) and collecting duct carcinoma (CDC) are rare entities with a poor outcome. First-line metastatic treatment is based on gemcitabine + platinum chemotherapy (GC) regimen but retrospective data suggest enhanced anti-tumour activity with the addition of bevacizumab. Therefore, we performed a prospective assessment of the safety and efficacy of GC + bevacizumab in metastatic RMC/CDC.

IDNetwork: A deep illness-death network based on multi-state event history process for disease prognostication.

Multi-state models can capture the different patterns of disease evolution. In particular, the illness-death model is used to follow disease progression from a healthy state to an intermediate state of the disease and to a death-related final state. We aim to use those models in order to adapt treatment decisions according to the evolution of the disease.

NF1 mutations identify molecular and clinical subtypes of lung adenocarcinomas.

The tumor suppressor gene neurofibromin 1 (NF1) is a major regulator of the RAS-MAPK pathway. NF1 mutations occur in lung cancer but were not extensively explored. We hypothesized that NF1-mutated tumors could define a specific population with a distinct clinical and molecular profile.

[IHC, FISH, CISH, NGS in non-small cell lung cancer: What changes in the biomarker era?].

Lung cancer is the leading cause of cancer deaths in France, with about 30,000 deaths per year. The overwhelming majority (90 %) are tobacco-related. The prognosis is dark but great therapeutic advances have been made with the development of targeted therapies first and then immunotherapy afterwards.

Validity of Targeted Next-Generation Sequencing in Routine Care for Identifying Clinically Relevant Molecular Profiles in Non-Small-Cell Lung Cancer: Results of a 2-Year Experience on 1343 Samples.

Theranostic assays are based on single-gene testing, but the ability of next-generation sequencing (NGS) to interrogate numerous genetic alterations will progressively replace single-gene assays. Although NGS was evaluated to screen for theranostic mutations, its usefulness in clinical practice on large series of samples remains to be demonstrated. NGS performance was assessed following guidelines.

, and Mutations Predict Tumor Immune Profile and the Response to Anti-PD-1 in Lung Adenocarcinoma.

By unlocking antitumor immunity, antibodies targeting programmed cell death 1 (PD-1) exhibit impressive clinical results in non-small cell lung cancer, underlining the strong interactions between tumor and immune cells. However, factors that can robustly predict long-lasting responses are still needed. We performed in-depth immune profiling of lung adenocarcinoma using an integrative analysis based on immunohistochemistry, flow-cytometry, and transcriptomic data.

Epithelial-to-Mesenchymal Transition and MicroRNAs in Lung Cancer.

Despite major advances, non-small cell lung cancer (NSCLC) remains the major cause of cancer-related death in developed countries. Metastasis and drug resistance are the main factors contributing to relapse and death. Epithelial-to-mesenchymal transition (EMT) is a complex molecular and cellular process involved in tissue remodelling that was extensively studied as an actor of tumour progression, metastasis and drug resistance in many cancer types and in lung cancers.

Molecular classification of pulmonary sarcomatoid carcinomas suggests new therapeutic opportunities.

Background: Pulmonary sarcomatoid carcinoma (SC) is a rare disease with poor prognosis and with strong inter- and intratumor heterogeneity. However, molecular classification is currently focused on activating MET mutations. We sought to better characterize the molecular diversity of SC using mutational signatures that reflect different mutational processes, such as tobacco-associated adducts (signature 4), BRCA1/BRCA2 deficiency (signature 3), or APOBEC enzyme deamination (signatures 2 and 13).

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IMMUNE CHECKPOINT INHIBITORS IN ADVANCED NON-SMALL CELL LUNG CANCER: T-cell-directed strategies represent currently a major advance in the treatment of advanced non-small-cell lung cancer, regarding their efficacy and tolerance. Nivolumab and pembrolizumab, two monoclonal antibodies targeting programmed cell death protein 1 (PD-1) have shown their efficacy in phase III studies. Several other drugs are developed and the benefit of association is being evaluated.

Base-Position Error Rate Analysis of Next-Generation Sequencing Applied to Circulating Tumor DNA in Non-Small Cell Lung Cancer: A Prospective Study.

Background: Circulating tumor DNA (ctDNA) is an approved noninvasive biomarker to test for the presence of EGFR mutations at diagnosis or recurrence of lung cancer. However, studies evaluating ctDNA as a noninvasive "real-time" biomarker to provide prognostic and predictive information in treatment monitoring have given inconsistent results, mainly due to methodological differences. We have recently validated a next-generation sequencing (NGS) approach to detect ctDNA.

Plasma Circulating Tumor DNA in Pancreatic Cancer Patients Is a Prognostic Marker.

Purpose: Despite recent therapeutic advances, prognosis of patients with pancreatic adenocarcinoma remains poor. Analyses from tumor tissues present limitations; identification of informative marker from blood might be a promising alternative. The aim of this study was to assess the feasibility and the prognostic value of circulating tumor DNA (ctDNA) in pancreatic adenocarcinoma.

Analysis of Base-Position Error Rate of Next-Generation Sequencing to Detect Tumor Mutations in Circulating DNA.

Background: Detecting single-nucleotide variations and insertions/deletions in circulating tumor DNA is challenging because of their low allele frequency. The clinical use of circulating tumor DNA to characterize tumor genetic alterations requires new methods based on next-generation sequencing.

Methods: We developed a method based on quantification of error rate of each base position [position error rate (PER)].

Multiplex Detection of Rare Mutations by Picoliter Droplet Based Digital PCR: Sensitivity and Specificity Considerations.

In cancer research, the accuracy of the technology used for biomarkers detection is remarkably important. In this context, digital PCR represents a highly sensitive and reproducible method that could serve as an appropriate tool for tumor mutational status analysis. In particular, droplet-based digital PCR approaches have been developed for detection of tumor-specific mutated alleles within plasmatic circulating DNA.

Intratumoral Immune Cell Densities Are Associated with Lung Adenocarcinoma Gene Alterations.

Rationale: Tumor-infiltrating immune cells affect lung cancer outcome. However, the factors that influence the composition and function of the tumor immune environment remain poorly defined and need investigation, particularly in the era of immunotherapy.

Objectives: To determine whether the tumoral immune environment is related to lung adenocarcinoma mutations.

[Lung cancer molecular testing, what role for Next Generation Sequencing and circulating tumor DNA].

Molecular screening has become a standard of care for patients with advanced cancers and impacts on how to treat a patient. Advances in genomic technologies with the development of high throughput sequencing methods will certainly improve the possibilities to access a more accurate molecular diagnosis and to go beyond the identification of validated targets as a large number of genes can be screened for actionable changes. Moreover, accurate high throughput testing may help tumor classification in terms of prognosis and drug sensitivity.

[What future for circulating tumor DNA? Current data and prospects in colorectal, non-small cell lung and pancreatic cancers].

Ten years after the discovery of the predictive value of KRAS status for anti-EGFR antibodies, other genes involved in oncogenesis and therapeutic responses were identified and are now systematically sought. Molecular diagnosis often requires invasive procedures, sometimes iatrogenic, and is limited by feasibility problems, quantity and quality of samples. Identifying these mutations from blood biomarkers would reduce costs and diagnostic delay.

Different prognostic impact of STK11 mutations in non-squamous non-small-cell lung cancer.

STK11 is commonly mutated in lung cancer. In light of recent experimental data showing that specific STK11 mutants could acquire oncogenic activities due to the synthesis of a short STK11 isoform, we investigated whether this new classification of STK11 mutants could help refine its role as a prognostic marker. We conducted a retrospective high-throughput genotyping study in 567 resected non-squamous non-small-cell lung cancer (NSCLC) patients.

Bleomycin-Induced Pneumonitis in the Treatment of Ovarian Sex Cord-Stromal Tumors: A Systematic Review and Meta-analysis.

Objective: Adult ovarian sex cord-stromal tumors (SCSTs) are a rare histological subtype of ovarian cancer associated with a favorable prognosis. Bleomycin-containing regimens are standards of care, although pneumonitis may cause potentially fatal dose-limiting toxicity. We aimed to evaluate the safety of bleomycin in SCST treatment.

[Obesity and lung cancer: incidence and repercussions on epidemiology, pathology and treatments].

Introduction: Obesity and lung cancer are major public health problems. The purpose of this work is to review the data concerning this association.

Method: We report clinical and epidemiological data on obesity and discuss the impact on the incidence of lung cancer, as well as the safety and efficiency of anti-tumor treatments.

Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort.

Purpose: Approximately 1% of lung adenocarcinomas are driven by oncogenic ROS1 rearrangement. Crizotinib is a potent inhibitor of both ROS1 and ALK kinase domains.

Patients And Methods: In the absence of a prospective clinical trial in Europe, we conducted a retrospective study in centers that tested for ROS1 rearrangement.

[Therapeutic impact of molecular diagnosis in metastatic non-small cell lung cancer: targeted therapies in 2013].

Recent advances in the molecular characterization of metastatic unresectable lung cancers have markedly improved the management of patients. Today, molecular tests should be performed routinely in all patients with non-squamous non-small cell lung cancer, and in case of squamous cell carcinoma occurring in a non-smoker. In the presence of EGFR mutation or ALK rearrangement, specific inhibitors have shown superior efficacy to chemotherapy in first-line treatment for anti-EGFR (erlotinib and gefitinib) and in second-line treatment for anti-ALK (crizotinib).

Triple combination of bevacizumab, gemcitabine and platinum salt in metastatic collecting duct carcinoma.

Background: Collecting duct carcinoma (CDC) is a rare and aggressive subtype of kidney cancer that responds to platinum-based chemotherapy. Recent phase II trials have established enhanced antitumor activity on combining bevacizumab with chemotherapy in patients with metastatic urothelial carcinoma, a tumor that shares many features with CDC. Our aim was to investigate whether combining bevacizumab with platinum-based chemotherapy might not also show promise in metastatic CDC (mCDC) patients.

Loss of heterozygosity at 13q13 and 14q32 predicts BRCA2 inactivation in luminal breast carcinomas.

BRCA2 is the major high-penetrance predisposition gene for luminal (estrogen receptor [ER] positive) breast cancers. However, many BRCA2 mutant carriers lack family history of breast/ovarian cancers and do not benefit from genetic testing. Specific genomic features associated with BRCA2 inactivation in tumors could help identify patients for whom a genetic test for BRCA2 may be proposed.

New insights into the management of renal cell cancer.

Kidney cancer is composed of several bio-histological entities. The most frequent type, clear-cell carcinoma, is not homogenous regarding gene mutations or transcriptomic profiles, but the biologic classifications are not yet mature. Therefore, biologically driven strategies of treatment have not yet been developed in the clinical setting.