Albin Nicolas, Mc Leer Anne, Sakhri Linda
Groupe hospitalier mutualiste de Grenoble, institut de cancérologie Daniel-Hollard, 8, rue Docteur-Calmette, 38028 Grenoble cedex 1, France.
Université Grenoble-Alpes, CHU de Grenoble, département d'anatomie et de cytologie pathologiques, unité fonctionnelle de pathologie moléculaire, pôle biologie, 38043 Grenoble cedex 9, France.
Bull Cancer. 2018 Apr;105(4):375-396. doi: 10.1016/j.bulcan.2018.01.009. Epub 2018 Mar 1.
In recent years, high-throughput sequencing techniques have been developed for cancerology and many clinical trials are currently structured around biomarkers that can guide specific treatment choices. This approach is characteristic of precision medicine, which is actually a concept initiated several decades ago with, for example, retinoic acid in promyelocytic leukemia. This paper will review the different types of molecular alterations and « -omics » biological analyses, bioinformatics tools, coupled drug/biomarkers already validated, the ethical issues of whole genomic sequencing of an individual as part of an inclusion in a clinical trial and finally the first results of precision medicine trials. The AcSé crizotinib program, supported by the Inca (french Cancer National Institute), is emblematic of a success of this personalized medicine illustrated by 4 points: the discovery of a cohort of patients with lung cancer with a ROS1 rearrangement characteristic of a sensitivity to crizotinib, a rapid availability of this innovation through the implementation of a temporary recommendation for use (ANSM), the obtention of a conditional marketing authorization by the pharmaceutical industry and finally, financial assumption of responsibility by French social security (HAS), despite preliminary and non-comparative data. In the case of cancers refractory to standard chemotherapy, and regarding our system of access to drugs illustrated by the PROFILER clinical trial, this approach allows the access to a therapeutic drug targeting specific biomarkers only in 7% of patients included. This does not bode well for efficient treatment and even less for survival. Allowing patients to be included in trials that identify molecular targets by molecular screening, and not being able to propose the drug of interest is a traumatic event for those patients who live in the hope of an immediate future. In refractory disease we must rethink precision medicine in a more humanistic vision for our patients and not only in a dimension of medico-industrial promotion. The implementation of a new multi-drug/multi-molecular target program could address this issue.
近年来，高通量测序技术已应用于肿瘤学领域，目前许多临床试验都是围绕可指导特定治疗选择的生物标志物展开的。这种方法是精准医学的特点，而精准医学实际上是几十年前就已提出的一个概念，例如在早幼粒细胞白血病中使用维甲酸。本文将回顾不同类型的分子改变和“组学”生物学分析、生物信息学工具、已验证的联合药物/生物标志物、将个体全基因组测序作为临床试验纳入标准的伦理问题，以及精准医学试验的初步结果。由法国国家癌症研究所（Inca）支持的AcSé克唑替尼项目是这种个性化医疗成功的典型代表，体现在以下四点：发现了一组具有ROS1重排、对克唑替尼敏感的肺癌患者队列；通过实施临时使用建议（ANSM）迅速实现了这一创新药物的可及性；制药行业获得了有条件的上市许可；最后，尽管数据是初步的且非对比性的，但法国社会保障部门（HAS）承担了经济责任。对于对标准化疗难治的癌症，就我们以PROFILER临床试验为例的药物获取系统而言，这种方法仅能使7%纳入试验的患者获得针对特定生物标志物的治疗药物。这对有效治疗而言并非好兆头，对生存的影响更甚。让患者纳入通过分子筛查确定分子靶点的试验，但却无法提供他们所期望的药物，这对于那些寄希望于不久后能获得治疗的患者来说是一次痛苦的经历。在难治性疾病中，我们必须以更具人文关怀的视角为患者重新思考精准医学，而不仅仅局限于医药产业推广的层面。实施一项新的多药/多分子靶点项目或许可以解决这一问题。
