Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
Eur Urol. 2020 Jun;77(6):701-710. doi: 10.1016/j.eururo.2020.02.028. Epub 2020 Mar 9.
The PURE-01 study (NCT02736266) evaluated the use of pembrolizumab before radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC).
To evaluate the ability of molecular signatures to predict the pathological complete response (CR: ypT0N0) and progression-free survival (PFS) after pembrolizumab and RC.
DESIGN, SETTING, AND PARTICIPANTS: We analyzed the expression data from patients with T2-4aN0M0 MIBC enrolled in the PURE-01 study (N=84) and from patients of a retrospective multicenter cohort treated with cisplatin-based neoadjuvant chemotherapy (NAC; N=140).
Neoadjuvant pembrolizumab or NAC and RC.
Immune signatures and molecular subtyping (The Cancer Genome Atlas, consensus model, and genomic subtyping classifier [GSC]) were evaluated in relation to CR and PFS. Multivariable logistic regression analyses for CR were used, adjusting for gender and clinical T stage.
The Immune190 signature was significant for CR on multivariable logistic regression analyses (p= 0.02) in PURE-01, but not in the NAC cohort (p= 0.7). Hallmark signatures for interferon gamma (IFNγ; p= 0.004) and IFNα response (p= 0.006) were also associated with CR for PURE-01, but not for NAC (IFNγ: p= 0.9 and IFNα: p= 0.8). In PURE-01, 93% of patients with the highest Immune190 scores (>1st quartile) had 2-yr PFS versus 79% of those with lower scores; no difference was observed in NAC patients, as well as for the other hallmarks in both groups. The neuroendocrine-like subtype had the worst 2-yr PFS in all three subtyping models (33%) and the GSC claudin-low subtype had the best, with no recurrences in 2 yr. Basal subtypes (across classifications) with higher Immune190 scores showed 100% 2-yr PFS after pembrolizumab therapy (p = 0.04, compared with basal-Immune190 low). Statistical analyses are limited by the small number of events and short follow-up.
Higher RNA-based immune signature scores were significantly associated with CR and numerically improved PFS outcomes after pembrolizumab, but not after NAC. These data emphasize that RNA profiling is a potential tool for personalizing neoadjuvant therapy selection.
We used gene expression profiling to evaluate the association between immune gene expression and response to neoadjuvant immunotherapy, compared with standard chemotherapy, in patients with muscle-invasive bladder cancer (MIBC). We found a significant association between immune gene expression and response to pembrolizumab, but not chemotherapy. We conclude that gene expression profiling has the potential to guide personalized neoadjuvant therapy in MIBC.
PURE-01 研究（NCT02736266）评估了在肌层浸润性膀胱癌（MIBC）患者接受根治性膀胱切除术（RC）前使用派姆单抗的效果。
评估分子特征预测派姆单抗联合 RC 后病理完全缓解（CR：ypT0N0）和无进展生存期（PFS）的能力。
设计、地点和参与者：我们分析了来自 PURE-01 研究（N=84）中 T2-4aN0M0 MIBC 患者和接受顺铂为基础新辅助化疗（NAC；N=140）的回顾性多中心队列中患者的表达数据。
新辅助派姆单抗或 NAC 联合 RC。
在与 CR 和 PFS 相关的情况下评估免疫特征和分子亚型（癌症基因组图谱、共识模型和基因组亚型分类器[GSC]）。CR 的多变量逻辑回归分析用于调整性别和临床 T 分期。
在 PURE-01 中，Immune190 特征在多变量逻辑回归分析中与 CR 显著相关（p=0.02），但在 NAC 队列中不显著（p=0.7）。干扰素γ（IFNγ；p=0.004）和 IFNα 反应（p=0.006）的标志性特征也与 PURE-01 的 CR 相关，但与 NAC 无关（IFNγ：p=0.9 和 IFNα：p=0.8）。在 PURE-01 中，93%的 Immune190 评分最高（>第 1 四分位）的患者在 2 年时有 PFS，而评分较低的患者为 79%；在 NAC 患者中未观察到差异，在两组的其他标志物中也未观察到差异。神经内分泌样亚型在所有三种亚型模型中均有最差的 2 年 PFS（33%），GSC 紧密连接低亚型最好，2 年内无复发。在派姆单抗治疗后，具有更高 Immune190 评分的基底亚型（跨分类）显示出 100%的 2 年 PFS（p=0.04，与基底-Immune190 低相比）。统计分析受到事件数量少和随访时间短的限制。
较高的基于 RNA 的免疫特征评分与 CR 显著相关，并且在派姆单抗后数值上改善了 PFS 结局，但在 NAC 后没有。这些数据强调了 RNA 分析是个性化新辅助治疗选择的潜在工具。
我们使用基因表达谱来评估免疫基因表达与肌层浸润性膀胱癌（MIBC）患者对新辅助免疫治疗的反应与标准化疗的相关性。我们发现免疫基因表达与派姆单抗的反应之间存在显著关联，但与化疗无关。我们得出结论，基因表达谱有可能指导 MIBC 的个体化新辅助治疗。
