Molecular Biomarkers as Classifiers to Individualize Therapy of Esophagus Cancer

描述（由申请人提供）：尽管癌症治疗取得了进展，但局部（II期或III期）食管癌患者术前放化疗预后不佳（5年生存率<20%）。治疗会带来可怕的后果。目前，没有任何临床或治疗参数可以帮助个体化治疗（选择某些治疗或避免其他治疗）。众所周知，对放化疗的反应（通过检查切除标本来判断）各不相同。病理完全缓解（pathCR），定义为没有残留癌，或缺乏反应（=50%残留癌或exCRTR）决定患者的预后。大约25%的患者达到pathCR，另外25%的患者表现为exCRTR。pathCR患者比<pathCR患者生存时间长，而exCRTR患者生存时间短于<exCRTR患者。如果能够在患者接受治疗前识别出区分这些不同结果的生物标志物，我们就可以开始个体化治疗（pathCR患者避免手术，exCRTR患者避免放化疗）。我们假设某些生物标志物特征可能与pathCR或exCRTR高度相关。因此，R21的具体目的是：(1)确定NF-kB、gli1和SHH在术前放化疗食管癌患者中的分布及其临床相关性（pathCR和exCRTR）；（2A）评估特定类别药物对临床结果的影响；（2b）建立选定耐药生物标志物表达的定量要求，建立独立的临床相关性，然后研究它们是否提高了新出现的NF-kB、Gli1和SHH特征的特异性。(3)在我们的CLIA认证实验室建立SHH、Gli1、NF-kB和选定药物相关生物标志物的免疫组化标准化定量分析。在达到预定的里程碑后，我们将开始R33，具体目标如下：(1)前瞻性地验证来自回顾性队列（60个初步队列+ 175个回顾性队列= 235）的212个样本中已建立的NF-kB、SHH、gli1和耐药生物标志物对pathCR和exCRTR的特征。（2A）建立447例患者（来自初步、回顾性和前瞻性队列）的各种临床结果（pathCR、部分缓解[1%至50%残留癌]和exCRTR）的预测模型，以获得最有希望的生物标志物特征。（2B）将临床参数和药物类别添加到特异性目的2A中建立的nomogram图中。因此，本研究旨在利用生物标志物特征为食管癌的个体化治疗铺平道路。公共卫生相关性：本研究（R21/R33）的目的是研究接受术前放化疗的食管癌患者未经治疗的癌组织，以发现某些分子生物标志物分类是否有助于个体化治疗。该研究分两个阶段提出：回顾性（R21）和前瞻性（R33）。只有在R21中有希望的发现才会在R33阶段得到验证。在R21期，NFkB、Shh和gli1的免疫组织化学（IHC）以及相关的药物相关生物标志物将用于建立生物标志物特征的分布和临床相关性（pathCR和exCRTR）。免疫组化方法将标准化，并从研究实验室转移到经认证的免疫组化临床实验室。

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.