Translation of Predictive Cancer Biomarkers into Clinical Practice

描述(由申请人提供)：诊断基因表达谱在十年前首次被识别，以识别儿童白血病的亚群。从那时起，数以千计的研究(2909项发表在《公共医学杂志》上)被认为是癌症诊断和治疗的有用工具。在现实中，很少有人将NCI资助的临床方案纳入患者的前瞻性癌症诊断和治疗分层。儿童肿瘤学小组长期以来一直在进行儿童癌症治疗的试验，覆盖了北美几乎所有16岁以下的儿童人口。作为这些研究的一部分，在近250家参与机构中的一家接受COG方案治疗的每一名患者都要接受中央诊断审查。对于儿童横纹肌肉瘤，这是年轻人最常见的肉瘤形式，这一审查被用来建立资格和治疗分层。目前，对于那些被认为患有低、中、高风险横纹肌肉瘤的患者，单独的治疗方案是开放的。不幸的是，用于识别这些层的标准是繁琐和不精确的，包括组织病理学回顾，临床标准，如年龄，分期，解剖位置，以及手术后疾病的程度。近年来，仅在肺泡亚组中发现的一种独特的嵌合基因(PAX-FKHR/FOXO)已被用于识别这一固有的预后不良组。不幸的是，组织病理学和遗传学发现往往不一致(约30%的组织病理学定义的肺泡型RMS缺乏易位)。此外，显然还有更多的遗传因素涉及到准确和可重复的诊断和预后，这超出了目前的标准。在这项提案中，我们寻求创建临床上有用的诊断和预后生物标记物配置文件，这些配置文件可以应用于常规处理(福尔马林固定、石蜡包埋)的肿瘤组织，从而整合到每个将根据COG STS RMS方案入院的患者的检查中。这些生物标志物简介是在过去五年中作为NCI资助的努力(主任的挑战和规范)的一部分而创建的，并于最近发布。它们是通过对数百名患者冰冻肿瘤组织的全基因组基因表达谱得出的，但尚未在FFPE样本上得到验证。此外，原始技术不容易以及时、成本效益高的方式应用于临床，必须确定和验证替代技术平台。在这里，我们建议在第一年内，在CLIA认证的实验室内对COG STS RMS方案进行广泛的交叉验证，使用各种技术治疗患者，并选择最符合这些标准的方案。在第二年，我们建议在作为单独资助的SPECS倡议的一部分进行全基因组图谱分析的当前方案患者上，前瞻性地测试新分析的敏感性和特异性。经过验证的配置文件随后将被纳入未来的COG STS RMS方案，使用COG广泛用于其他诊断研究的中央参考实验室模型进行风险分层治疗。 公共卫生相关性：癌症的基因识别特征，如基因表达水平，当与诊断和预后等重要临床参数相关时，可以有益地用于创建预测性生物标记物配置文件，可以在治疗前预测个别患者的诊断和预后。这些信息反过来可以用来对患者进行分层，以获得最佳治疗。在这里，我们建议将在NCI SPECS计划的支持下创建的健壮且可重现的诊断和预后简档转换为适用于所有肿瘤标本的临床工具，无论是冰冻的还是固定的，并前瞻性地将它们应用于儿童肿瘤组软组织肉瘤委员会正在开发的治疗儿童横纹肌肉瘤的新的临床试验。

DESCRIPTION (provided by applicant): Diagnostic gene expression profiles were first identified ten years ago to identify subsets of childhood leukemia. Since then, untold thousands of studies (2909 listed in PubMed using 'cancer diagnosis microarrays') have been published purporting to be useful tools for cancer diagnosis and treatment. In reality, few have been incorporated for prospective cancer diagnosis and treatment stratification of patients on NCI funded clinical protocols. The Children's Oncology Group has long conducted trials of childhood cancer treatment that include virtually the entire childhood population of North America for patients under the age of 16. As part of those studies, each patient to be admitted for treatment on a COG protocol in one of the nearly 250 participating institutions undergoes central diagnostic review. In the case of childhood rhabdomyosarcoma, the most common form of sarcoma in the young, this review is used to establish eligibility as well as treatment stratification. Currently, separate protocols are open for those deemed to have low, intermediate, or high risk rhabdomyosarcoma. Unfortunately, the criteria used to identify these strata are cumbersome and imprecise, involving histopathology review, clinical criteria like age, stage, anatomic site, and extent of post-surgical disease. In recent years, identification of a unique chimeric gene (PAX-FKHR/FOXO) found only in the alveolar subgroup has been used to identify this intrinsically poor prognosis group. Unfortunately, the histopathology and genetic findings are often discordant (~30% of histopathologically defined alveolar RMS lacks a translocation). Further, there are clearly additional genetic factors that are involved in accurate and reproducible diagnosis and prognosis that go beyond the current criteria. In this proposal, we seek to create clinically useful diagnostic and prognostic biomarker profiles that can be applied to routinely processed (formalin fixed, paraffin embedded) tumor tissue and thus incorporated into the workup of every patient to be admitted on a COG STS RMS protocol. These biomarker profiles have been created over the past five years as part of an NCI funded effort (Director's Challenge and SPECS) and are recently published. They were derived by whole genome gene expression profiling of hundreds of patients' frozen tumor tissue, but they have not been validated on FFPE specimens. Further, the original technology is not readily applied in a timely, cost- effective manner for clinical use, and an alternate technology platform must be identified and validated. Here we propose in the first year to perform extensive cross validation within a CLIA certified laboratory on COG STS RMS protocol treated patients using a variety of technologies and choose the one that best meets these criteria. In the second year we propose to prospectively test the sensitivity and specificity of the new assay on current protocol patients that have been whole-genome profiled as part of the separately funded SPECS initiative. The validated profiles will then be incorporated into future COG STS RMS protocols for risk-stratified therapy using a central reference lab model widely used by COG for other diagnostic studies. PUBLIC HEALTH RELEVANCE: Genomically identified features of cancer like gene expression levels, when correlated with important clinical parameters like diagnosis and prognosis, can be beneficially employed to create predictive biomarker profiles that can predict prior to therapy the diagnosis and prognosis of an individual patient. This information in turn can be used to stratify patients for optimal therapy. Here we propose to translate robust and reproducible diagnostic and prognostic profiles created with the support of the NCI SPECS program into clinical tools applicable to all tumor specimens, frozen or fixed, and to apply them prospectively to new clinical trials for the treatment of childhood rhabdomyosarcoma being developed by the Soft Tissue Sarcoma committee of Children's Oncology Group.