Molecular Biomarkers as Classifiers to Individualize Therapy of Esophagus Cancer

描述(申请人提供)：尽管癌症治疗取得了进步，但接受术前放化疗的局部(II或III期)食道癌患者的预后很差(&lt；20%的5年存活率)。治疗与可怕的后果相关。目前，任何临床或治疗参数都不能帮助个体化治疗(选择某些治疗方法或避免其他治疗方法)。众所周知，对放化疗的反应(通过检查切除的标本来判断)是不同的。病理完全反应(Path CR)，定义为无残留癌或无反应(=50%残留癌或exCRTR)决定了患者的预后。大约25%的患者实现了路径CR，另有25%的患者表现为exCRTR。路径CR患者的生存期比路径CR患者长得多，而exCRTR患者的生存期比&lt；exCRTR患者短得多。如果能在患者接受治疗前找出区分这些不同结果的生物标记物，我们就可以开始个体化治疗(在路径CR患者中避免手术，在exCRTR患者中避免放化疗)。我们推测，某些生物标记物的信号可能与通路CR或exCRTR高度相关。因此，R21的具体目标是：(1)建立食道癌患者术前放化疗中NF-kB、Gli-1和SHH的分布和临床相关性(路径CR和exCRTR)；(2)评估特定类别药物对临床结果的影响；(2)为选定的耐药生物标记物的表达建立定量要求，建立独立的临床相关性，然后研究它们是否提高了新兴的NF-kB、Gli-1和SHH信号的特异性(S)(3)在我们CLIA认证的实验室建立SHH、Gli1、NF-kB和选定的药物相关生物标记物的IHC标准化定量检测方法。在达到预先指定的里程碑后，我们将开始R33，具体目标如下：(1)前瞻性地验证已建立的NF-kB、SHH、Gli-1和耐药生物标记物的标志物(S)在212例将接受术前放化疗的预期患者的队列中(60例初步+175例回顾=235例)中的路径CR和exCRTR值。(2)对447例患者(来自初步、回顾和前瞻性队列)的不同临床结果(路径CR、部分缓解[1%~50%残留癌]和exCRTR)建立预测模型，以得出最有前景的生物标记物特征(S)。(2B)将临床参数和药物类别添加到在具体目标2A中确定的标准图中。因此，这项建议试图为使用生物标记物签名的食道癌个体化治疗铺平道路。公共卫生相关性：这项研究(R21/R33)的目标是研究接受术前放化疗的食道癌患者的未经治疗的癌症组织，以发现某些分子生物标记物分类器是否有助于个体化治疗。这将分两个阶段提出：回顾(R21)和预期(R33)。只有R21中有希望的发现将在R33阶段得到验证。在R21阶段，将使用NFkB、Shh和Gli-1的免疫组织化学(IHC)以及相关的药物相关生物标记物来建立生物标记物的分布和临床相关性(路径CR和exCRTR)。IHC方法将被标准化，并从研究实验室转移到经认证的IHC临床实验室。

DESCRIPTION (provided by applicant): Despite the advances in therapy of cancer, patients with localized (stage II or III) esophageal carcinoma when treated with preoperative chemoradiation have a dismal prognosis (<20% 5-year survival rate). Treatment is associated with dire consequences. Currently, none of the clinical or therapeutic parameters can help to individualize therapy (select certain treatments or avoid others). It is known that response to chemoradiation (as judged by examining the resected specimen) varies. Pathologic complete response (pathCR), defined as the absence of residual cancer, or lack of response (=50% residual cancer or exCRTR) dictates patient outcome. Approximately 25% of patients achieve a pathCR and another 25% exhibit exCRTR. Patients with pathCR survive much longer than those with <pathCR and patients with exCRTR live much shorter than those with <exCRTR. If one could identify biomarkers that would distinguish these different outcomes before patients received treatment, we could begin to individualize therapy (avoid surgery in pathCR patients and avoid chemoradiation in exCRTR patients). We hypothesize that certain biomarker signatures may highly correlate with pathCR or exCRTR. Thus, the specific aims for R21 are (1) Establish the distribution and clinical relevance (pathCR and exCRTR) of NF-kB, Gli-1, and SHH in esophageal cancer patients undergoing preoperative chemoradiation; (2A) Assess the effect of specific classes of drugs used on clinical outcome and (2 B) Establish quantitative requirements for the expression of selected drug-resistance biomarkers, establish independent clinical relevance and then study if they improve the specificity of the emerging NF-kB, Gli-1, and SHH signature(s) (3) Establish IHC standardized quantitative assays of SHH, Gli1, NF-kB and selected drug- related biomarkers in our CLIA certified laboratory. Upon reaching the prespecified milestones, we will embark on R33 with the following specific aims (1) Prospectively validate the established NF-kB, SHH, Gli-1, and drug- resistance biomarkers' signature(s) for pathCR and exCRTR from the retrospective cohort (60 preliminary + 175 retrospective = 235) in 212 samples from prospective patients who will have preoperative chemoradiation. (2A) Establish a predictive model for various clinical outcomes (pathCR, partial response [1% to 50% residual cancer], and exCRTR) in 447 patients (derived from the preliminary, retrospective, and prospective cohorts) to derive the most promising biomarker signature(s). (2B) Add clinical parameters and classes of drug to the nomogram established in specific aim 2A. Thus, this proposal seeks to pave the path to individualized therapy for esophageal cancer using biomarker signatures. PUBLIC HEALTH RELEVANCE: The goal of this study (R21/R33) is to study untreated cancer tissue from esophageal cancer patients receiving preoperative chemoradiation to discover if certain molecular biomarker classifiers can help individualize therapy. This is being proposed in two phases: retrospective (R21) and prospective (R33). Only promising findings in the R21 will be validated in the R33 phase. In the R21 phase, the immunohistochemistry (IHC) of NFkB, Shh and Gli-1 as well as relevant drug-related biomarkers will be used to establish a distribution and clinical relevance (pathCR and exCRTR) of biomarker signatures. The IHC methods will be standardized and transferred from the research laboratory to a certified IHC clinical laboratory.