Predictive signature of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer integrating mRNA expression, taxonomic subtypes, and clinicopathological features.
Predictive signature of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer integrating mRNA expression, taxonomic subtypes, and clinicopathological features.
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整合mRNA表达、分类亚型及临床病理特征的肌肉浸润性膀胱癌对新辅助化疗反应的预测标志物 。
DOI：
10.3389/fonc.2023.1155244
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发表时间：
2023
影响因子：
4.7
通讯作者：
中科院分区：
文献类型：
--
作者：
新辅助化疗（NAC）后行膀胱切除术是肌层浸润性膀胱癌（MIBC）的标准治疗方案。病理反应与更长的生存期相关，但目前可用的临床病理变量均无法识别可能产生反应的患者，这凸显了对预测性生物标志物的需求。我们试图通过整合临床评分、分类亚型和基因表达，确定一种预测NAC反应的特征标志物。
1994年至2014年，从西班牙两家医院的MIBC患者（T2 - 4N0/+M0期）中收集了治疗前的肿瘤样本。根据分期、肾积水情况和组织学特征确定临床评分。通过免疫组织化学确定分类亚型（BASQ、管腔型和混合型）。利用NanoString nCounter平台对84例患者中一组涉及DNA损伤修复和免疫反应的41个定制基因进行了分析。通过套索（LASSO）惩罚逻辑回归确定与病理反应相关的基因。2000年之前，NAC方案为顺铂/甲氨蝶呤/长春碱，此后大多数患者接受顺铂/吉西他滨治疗。采用受试者工作特征曲线下面积（AUC）评估整合特征标志物预测病理反应的能力。采用 Kaplan - Meier法分析总生存期（OS）和疾病特异性生存期（DSS）。
LASSO筛选出8个基因纳入特征标志物（RAD51、干扰素γ（IFNγ）、CHEK1、CXCL9、c - MET、角蛋白14（KRT14）、HERC2、叉头框蛋白A1（FOXA1））。仅将3个基因（RAD51、IFNɣ、CHEK1）纳入模型时，观察到最高的预测准确性。包含这3个基因的临床 - 分类 - 基因表达整合特征标志物的预测能力（AUC = 0.71）高于仅临床评分加分类亚型（AUC = 0.58）或仅临床评分（AUC = 0.56）。该整合特征标志物还与OS（p = 0.02）和DSS（p = 0.02）显著相关。
我们已经确定了一种用于预测MIBC患者对NAC反应的特征标志物，该标志物将3个基因的表达与临床病理特征及分类亚型相结合。目前正在进行前瞻性研究以验证这些结果。
Neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care in muscle-invasive bladder cancer (MIBC). Pathological response has been associated with longer survival, but no currently available clinicopathological variables can identify patients likely to respond, highlighting the need for predictive biomarkers. We sought to identify a predictive signature of response to NAC integrating clinical score, taxonomic subtype, and gene expression. From 1994 to 2014, pre-treatment tumor samples were collected from MIBC patients (stage T2-4N0/+M0) at two Spanish hospitals. A clinical score was determined based on stage, hydronephrosis and histology. Taxonomic subtypes (BASQ, luminal, and mixed) were identified by immunohistochemistry. A custom set of 41 genes involved in DNA damage repair and immune response was analyzed in 84 patients with the NanoString nCounter platform. Genes related to pathological response were identified by LASSO penalized logistic regression. NAC consisted of cisplatin/methotrexate/vinblastine until 2000, after which most patients received cisplatin/gemcitabine. The capacity of the integrated signature to predict pathological response was assessed with AUC. Overall survival (OS) and disease-specific survival (DSS) were analyzed with the Kaplan-Meier method. LASSO selected eight genes to be included in the signature (RAD51, IFNγ, CHEK1, CXCL9, c-MET, KRT14, HERC2, FOXA1). The highest predictive accuracy was observed with the inclusion in the model of only three genes (RAD51, IFNɣ, CHEK1). The integrated clinical-taxonomic-gene expression signature including these three genes had a higher predictive ability (AUC=0.71) than only clinical score plus taxonomic subtype (AUC=0.58) or clinical score alone (AUC=0.56). This integrated signature was also significantly associated with OS (p=0.02) and DSS (p=0.02). We have identified a predictive signature for response to NAC in MIBC patients that integrates the expression of three genes with clinicopathological characteristics and taxonomic subtypes. Prospective studies to validate these results are ongoing.
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1.9
作者：
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通讯作者：
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