Identification and Validation of Protein Biomarkers of Response to Neoadjuvant Platinum Chemotherapy in Muscle Invasive Urothelial Carcinoma.
Identification and Validation of Protein Biomarkers of Response to Neoadjuvant Platinum Chemotherapy in Muscle Invasive Urothelial Carcinoma.
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DOI：
10.1371/journal.pone.0131245
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Netto G
中科院分区：
文献类型：
--
作者：
Baras AS;Gandhi N;Munari E;Faraj S;Shultz L;Marchionni L;Schoenberg M;Hahn N;Hoque MO;Berman D;Bivalacqua TJ;Netto G
仅膀胱切除术治疗的肌肉侵袭性尿路上皮性膀胱癌（MIBC）患者的5年癌症特异性生存率（CSS）约为50%。铂基新辅助化疗（NAC）加膀胱切除术导致MIBC患者5年CSS边际增加5-10%。有趣的是，对NAC （<ypT2）有应答者的5年CSS为90%，与MIBC对NAC有抗性的患者的30-40%的CSS形成鲜明对比。虽然NAC在MIBC中的应用越来越多，但由于担心膀胱切除术的延迟、潜在的副作用以及无法预测疗效，NAC仍未被广泛应用。最近提出的化学反应性的分子特征，在这种情况下可能被证明是有用的，将具有相当大的实用性，但尚未转化为临床实践。我们结合人类蛋白图谱（Human Protein Atlas， HPA）的抗体数据库，重新分析了来自nac治疗的MIBC队列的mRNA表达数据，以确定免疫组织化学（IHC）可检测的候选蛋白质生物标志物。这些候选生物标志物随后在来自NAC初始MIBC活检标本的独立队列的组织微阵列中进行测试，其中患者接受新辅助吉西他滨顺铂NAC治疗并随后进行膀胱切除术。在我们的队列中也检查了先前与NAC反应相关的临床参数。我们对发现队列（n = 33）和HPA中可用的mRNA基因表达数据进行了分析，得出8个候选蛋白质生物标志物。在我们独立的NAC治疗的MIBC队列中，GDPD3和SPRED1的组合形成了一个与NAC反应状态显著相关的多变量分类树（Goodman-Kruskal γ = 0.85 p<0.0001）。该模型独立于年龄和临床肿瘤分期等临床因素，而这些因素先前与我们组的NAC反应有关。结合活检标本中IHC检测到的这两种蛋白质生物标志物以及相关的临床参数，形成了一个预测模型，能够将我们的队列（n = 37）中NAC耐药的可能性显著分为两部分：低26% n = 19和高89% n = 18， Fisher的精确p = 0.0002)。我们证明了将NAC反应的基因表达特征从发现队列翻译为易于适用于我们独立队列中MIBC活检标本的免疫组织化学标记的可行性。本研究的结果正在其他验证队列中进行表征。此外，我们预计在MIBC中出现的体细胞突变也将对NAC反应预测很重要。本研究的发现与目前对MIBC变异组织学亚型的理解之间的关系，以及与NAC反应相关的MIBC分子亚型的进化，仍有待充分表征。
The 5-year cancer specific survival (CSS) for patients with muscle invasive urothelial carcinoma of the bladder (MIBC) treated with cystectomy alone is approximately 50%. Platinum based neoadjuvant chemotherapy (NAC) plus cystectomy results in a marginal 5-10% increase in 5-year CSS in MIBC. Interestingly, responders to NAC (<ypT2) have a 5-year CSS of 90% which is in stark contrast to the 30-40% CSS for those whose MIBC is resistance to NAC. While the implementation of NAC for MIBC is increasing, it is still not widely utilized due to concerns related to delay of cystectomy, potential side-effects, and inability to predict effectiveness. Recently suggested molecular signatures of chemoresponsiveness, which could prove useful in this setting, would be of considerable utility but are yet to be translated into clinical practice. mRNA expression data from a prior report on a NAC-treated MIBC cohort were re-analyzed in conjunction with the antibody database of the Human Protein Atlas (HPA) to identify candidate protein based biomarkers detectable by immunohistochemistry (IHC). These candidate biomarkers were subsequently tested in tissue microarrays derived from an independent cohort of NAC naive MIBC biopsy specimens from whom the patients were treated with neoadjuvant gemcitabine cisplatin NAC and subsequent cystectomy. The clinical parameters that have been previously associated with NAC response were also examined in our cohort. Our analyses of the available mRNA gene expression data in a discovery cohort (n = 33) and the HPA resulted in 8 candidate protein biomarkers. The combination of GDPD3 and SPRED1 resulted in a multivariate classification tree that was significantly associated with NAC response status (Goodman-Kruskal γ = 0.85 p<0.0001) in our independent NAC treated MIBC cohort. This model was independent of the clinical factors of age and clinical tumor stage, which have been previously associated with NAC response by our group. The combination of both these protein biomarkers detected by IHC in biopsy specimens along with the relevant clinical parameters resulted in a prediction model able to significantly stratify the likelihood of NAC resistance in our cohort (n = 37) into two well separated halves: low-26% n = 19 and high-89% n = 18, Fisher’s exact p = 0.0002). We illustrate the feasibility of translating a gene expression signature of NAC response from a discovery cohort into immunohistochemical markers readily applicable to MIBC biopsy specimens in our independent cohort. The results from this study are being characterized in additional validation cohorts. Additionally, we anticipate that emerging somatic mutations in MIBC will also be important for NAC response prediction. The relationship of the findings in this study to the current understanding of variant histologic subtypes of MIBC along with the evolving molecular subtypes of MIBC as it relates to NAC response remains to be fully characterized.