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或III期）食管癌患者在接受术前放化疗治疗时预后不良（5年生存率<20%）。治疗伴随着可怕的后果。目前，没有任何临床或治疗参数可以帮助个性化治疗（选择某些治疗或避免其他治疗）。众所周知，对放化疗的反应（通过检查切除的标本来判断）各不相同。病理学完全缓解（pathCR）定义为不存在残留癌症或缺乏缓解（≥ 50%残留癌症或exCRTR），决定了患者结局。大约25%的患者达到pathCR，另外25%的患者表现出exCRTR。pathCR患者的生存期比<pathCR患者长得多，exCRTR患者的生存期比<exCRTR患者短得多。如果能够在患者接受治疗前确定区分这些不同结局的生物标志物，我们就可以开始个体化治疗（避免pathCR患者的手术，避免exCRTR患者的放化疗）。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的具体目标是（1）确定分布和临床相关性（pathCR和exCRTR）在接受术前放化疗的食管癌患者中NF-κ B、Gli-1和SHH的表达;（2A）评估所使用的特定类别的药物对临床结果的影响和（2 B）建立所选耐药生物标志物表达的定量要求，建立独立的临床相关性，然后研究它们是否改善了新出现的NF-kB、Gli-1和SHH特征的特异性（3）在我们的CLIA认证实验室中建立SHH、Gli 1、NF-kB和选定的药物相关生物标志物的IHC标准化定量测定。在达到预先规定的里程碑后，我们将着手进行R33，具体目标如下：（1）Proximity验证来自回顾性队列（60个初步样本+175个回顾性样本= 235个）的pathCR和exCRTR的已确立NF-κ B、SHH、Gli-1和耐药生物标志物特征，这些样本来自将接受术前放化疗的前瞻性患者。(2A)在447例患者（来自初步、回顾性和前瞻性队列）中建立各种临床结局（pathCR、部分缓解[1%至50%残留癌症]和exCRTR）的预测模型，以获得最有希望的生物标志物特征。(2B)在具体目标2A中建立的列线图中添加临床参数和药物类别。因此，该提案旨在为使用生物标志物签名的食管癌个体化治疗铺平道路。 公共卫生相关性：本研究（R21/R33）的目的是研究来自接受术前放化疗的食管癌患者的未经治疗的癌组织，以发现某些分子生物标志物分类是否有助于个性化治疗。该项目分两个阶段提出：回顾性（R21）和前瞻性（R33）。只有在R21中有希望的发现将在R33阶段得到验证。在R21阶段，将使用NFkB、Shh和Gli-1以及相关药物相关生物标志物的免疫组织化学（IHC）来确定生物标志物特征的分布和临床相关性（pathCR和exCRTR）。将对IHC方法进行标准化，并将其从研究实验室转移至经认证的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.