Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada; Department of Urology, University of Bern, Bern, Switzerland.
GenomeDx Biosciences, Inc., Vancouver, British Columbia, Canada.
Eur Urol. 2017 Oct;72(4):544-554. doi: 10.1016/j.eururo.2017.03.030. Epub 2017 Apr 5.
An early report on the molecular subtyping of muscle-invasive bladder cancer (MIBC) by gene expression suggested that response to neoadjuvant chemotherapy (NAC) varies by subtype.
To investigate the ability of molecular subtypes to predict pathological downstaging and survival after NAC.
DESIGN, SETTING, AND PARTICIPANTS: Whole transcriptome profiling was performed on pre-NAC transurethral resection specimens from 343 patients with MIBC. Samples were classified according to four published molecular subtyping methods. We developed a single-sample genomic subtyping classifier (GSC) to predict consensus subtypes (claudin-low, basal, luminal-infiltrated and luminal) with highest clinical impact in the context of NAC. Overall survival (OS) according to subtype was analyzed and compared with OS in 476 non-NAC cases (published datasets).
Gene expression analysis was used to assign subtypes.
Receiver-operating characteristics were used to determine the accuracy of GSC. The effect of GSC on survival was estimated by Cox proportional hazard regression models.
The models generated subtype calls in expected ratios with high concordance across subtyping methods. GSC was able to predict four consensus molecular subtypes with high accuracy (73%), and clinical significance of the predicted consensus subtypes could be validated in independent NAC and non-NAC datasets. Luminal tumors had the best OS with and without NAC. Claudin-low tumors were associated with poor OS irrespective of treatment regimen. Basal tumors showed the most improvement in OS with NAC compared with surgery alone. The main limitations of our study are its retrospective design and comparison across datasets.
Molecular subtyping may have an impact on patient benefit to NAC. If validated in additional studies, our results suggest that patients with basal tumors should be prioritized for NAC. We discovered the first single-sample classifier to subtype MIBC, which may be suitable for integration into routine clinical practice.
Different molecular subtypes can be identified in muscle-invasive bladder cancer. Although cisplatin-based neoadjuvant chemotherapy improves patient outcomes, we identified that the benefit is highest in patients with basal tumors. Our newly discovered classifier can identify these molecular subtypes in a single patient and could be integrated into routine clinical practice after further validation.
早期的一项关于肌层浸润性膀胱癌（MIBC）分子亚型的报告表明，新辅助化疗（NAC）的反应因亚型而异。
研究分子亚型对 NAC 后病理降期和生存的预测能力。
设计、设置和参与者：对 343 例 MIBC 患者的 NAC 前经尿道膀胱肿瘤切除术标本进行全转录组谱分析。根据四种已发表的分子分型方法对样本进行分类。我们开发了一种单样本基因组分型分类器（GSC），以预测在 NAC 背景下最具临床影响的共识亚型（ Claudin-low 、基底、浸润性 luminal 和 luminal ）。分析了根据亚型的总生存期（OS），并与 476 例非 NAC 病例（已发表的数据集）的 OS 进行了比较。
基因表达分析用于分配亚型。
接收器工作特性被用来确定 GSC 的准确性。通过 Cox 比例风险回归模型估计 GSC 对生存的影响。
该模型以高一致性生成了预期比例的亚型，并且跨分型方法的 GSC 具有很高的准确性（73%），预测的共识亚型的临床意义可以在独立的 NAC 和非 NAC 数据集得到验证。有和没有 NAC 的 luminal 肿瘤的 OS 最好。Claudin-low 肿瘤无论治疗方案如何，OS 均较差。与单独手术相比，NAC 后基底肿瘤的 OS 改善最为显著。本研究的主要局限性在于其回顾性设计和数据集间比较。
分子分型可能对 NAC 患者的获益产生影响。如果在进一步的研究中得到验证，我们的结果表明，基底肿瘤患者应优先考虑 NAC。我们发现了第一个用于 MIBC 亚型分类的单样本分类器，它可能适合整合到常规临床实践中。
肌层浸润性膀胱癌可以识别不同的分子亚型。尽管基于顺铂的新辅助化疗可以改善患者的预后，但我们发现基底肿瘤患者的获益最大。我们新发现的分类器可以在单个患者中识别这些分子亚型，并在进一步验证后可以整合到常规临床实践中。
