Precision cancer medicine platform trials: Concepts and design of AcSé-ESMART.

Precision cancer medicine brought the promise of improving outcomes for patients with cancer. High-throughput molecular profiling of tumors at treatment failure aims to direct a patient to a treatment matched to the tumor profile. In this way, improved outcome has been achieved in a small number of patients whose tumors exhibit unique targetable oncogenic drivers.

PD-1 Blockade in Solid Tumors with Defects in Polymerase Epsilon.

Unlabelled: Missense mutations in the polymerase epsilon (POLE) gene have been reported to generate proofreading defects resulting in an ultramutated genome and to sensitize tumors to checkpoint blockade immunotherapy. However, many POLE-mutated tumors do not respond to such treatment. To better understand the link between POLE mutation variants and response to immunotherapy, we prospectively assessed the efficacy of nivolumab in a multicenter clinical trial in patients bearing advanced mismatch repair-proficient POLE-mutated solid tumors.

Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients with -Mutant Metastatic Non-Small Cell Lung Cancer.

Purpose: The limited knowledge on the molecular profile of patients with -mutant non-small cell lung cancer (NSCLC) who progress under BRAF-targeted therapies (BRAF-TT) has hampered the development of subsequent therapeutic strategies for these patients. Here, we evaluated the clinical utility of circulating tumor DNA (ctDNA)-targeted sequencing to identify canonical mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with -mutant NSCLC.

Experimental Design: This was a prospective study of 78 patients with advanced -mutant NSCLC, enrolled in 27 centers across France.

From single-arm studies to externally controlled studies. Methodological considerations and guidelines.

Single-arm studies are sometimes used as pivotal studies but they have methodological limitations which prevent them from obtaining the high level of reliability as for a randomised controlled study which remains the gold standard in the evaluation of new treatments. The objective of this roundtable was to discuss the limitations of these single-arm studies, to analyse available and acceptable solutions in order to propose guidelines for their conduct and assessment. Single-arm studies themselves are intrinsically inappropriate for demonstrating the benefit of a new treatment because it is impossible to infer the benefit from a value obtained under treatment without knowing what it would have been in the absence of the new treatment.

Persistent response to vemurafenib in metastatic ameloblastoma with BRAF mutation: a case report.

Background: Ameloblastomas are uncommon locally aggressive tumors of odontogenic epithelium that rarely metastasize. Currently, there is no standard of care for the metastatic forms. Several studies have shown that ameloblastomas frequently have a BRAF mutation.

Fertility preservation and cancer: How many persons are concerned?

Objective: A significant proportion of cancer survivors experience chronic health sequelae, one of them being fertility impairment. However, even if many reports, guidelines and positions papers focus on fertility preservation and its needs, access to fertility preservation is not currently offered to all the patients concerned, and the targeted population is not well counted.

Study Design: A cross sectional study was conducted using the French cancer cohort, a cohort covering the whole French population and including around 7 million of cancer patients.

Equal access to innovative therapies and precision cancer care.

Patients with cancers of differing histologies that express certain biomarkers are likely to benefit from treatment with targeted therapies. However, targets can be present in malignancies other than those indicated by a drug's label, and as a result, affected patients will have no access to those potentially useful drugs. To tackle this issue, the French National Cancer Institute developed the AcSé Programme in 2013.

Translational research: precision medicine, personalized medicine, targeted therapies: marketing or science?

Personalized medicine is based on: 1) improved clinical or non-clinical methods (including biomarkers) for a more discriminating and precise diagnosis of diseases; 2) targeted therapies of the choice or the best drug for each patient among those available; 3) dose adjustment methods to optimize the benefit-risk ratio of the drugs chosen; 4) biomarkers of efficacy, toxicity, treatment discontinuation, relapse, etc. Unfortunately, it is still too often a theoretical concept because of the lack of convenient diagnostic methods or treatments, particularly of drugs corresponding to each subtype of pathology, hence to each patient. Stratified medicine is a component of personalized medicine employing biomarkers and companion diagnostics to target the patients likely to present the best benefit-risk balance for a given active compound.

Methodology for small clinical trials.

Small clinical trials are trials in which the number of patients does not enable the objective of the study to be appropriately met with the usual methodological rules. This situation is common in the case of rare diseases, in paediatrics, in certain cancer pathologies or when the number of patients exposed to the treatment needs to be limited. The principal methodological problems are initially identified, and the classical methods (controlled, randomised, double-blind trial using parallel groups, crossover trial, factorial design, trial performed with several measures repeated over time, add-on design, randomised withdrawal design or early-escape design) and more uncommon methods (sequential approaches, meta-analyses, the 'N of 1' method and other methods that facilitate decision making or modelling) are then discussed.

Methodology for the evaluation of drugs in pregnant women.

Although drugs are prescribed during pregnancy with some reluctance, they fulfill a real need in some circumstances. Adequate drug evaluation is thus essential, either based on efficacy and safety or mainly safety, using available data from non-pregnant women. Evaluation methodology is not fundamentally different during pregnancy.