Department of Medical Oncology, British Columbia Cancer Agency , Vancouver , British Columbia , Canada.
Department of Urologic Sciences, University of British Columbia , Vancouver , British Columbia , Canada.
J Urol. 2019 Jul;202(1):49-56. doi: 10.1097/JU.0000000000000136. Epub 2019 Jun 7.
Immune checkpoint inhibitors have had a major impact on the management of advanced urothelial cancer. Despite the impact only a minority of patients derive benefit. In this context predictive biomarkers which can assist in patient selection are needed. In this systematic review we surveyed the current biomarkers which have been investigated in clinical studies and their potential for patient selection.
We searched MEDLINE® and EMBASE®, and manually reviewed major meeting abstracts to find studies in humans of immune checkpoint inhibitors given for urothelial cancer that included biomarkers and clinical outcomes. Studies had to provide the correlation between biomarkers and outcomes to be included in analysis. Results published only in abstract form were included since several important biomarker studies have yet to be published.
We retrieved 1,236 studies, of which 921 were unique and screened, including 144 which met criteria for full review and 25 were included in the analysis. The manual search yielded 1 additional entry not included in our systematic review for a total of 26 entries. The checkpoint inhibitors used in these studies included atezolizumab, avelumab, durvalumab, ipilimumab, nivolumab and pembrolizumab. The biomarkers tested included PD-L1 immunohistochemistry, molecular subtyping and immune gene expression analysis by RNA sequencing, targeted gene panels for mutations in DNA damage repair genes and estimation of the tumor mutational burden, genomic alterations and the total mutational burden by exome sequencing, analysis of tumor immune infiltrate by immunohistochemistry and T-cell receptor sequencing, and analysis of circulating immune cells and cytokines.
No single biomarker has been able to accurately predict the response to immune checkpoint inhibitors. Most studies included only a treatment arm and without a comparator arm it is not possible to ascertain whether biomarkers are predictive or merely prognostic. While PD-L1 immunohistochemistry has been largely unsuccessful, other biomarkers reflecting the immunogenicity of the underlying tumor, the characteristics of the immune infiltrate and the properties of the patient immune system have shown promising data. However, all are in need of validation.
免疫检查点抑制剂已对晚期尿路上皮癌的治疗产生了重大影响。尽管如此，仅有少数患者从中受益。在这种情况下，需要能够辅助患者选择的预测性生物标志物。在本系统评价中，我们调查了目前在临床研究中已进行研究的生物标志物及其在患者选择中的潜在作用。
我们检索了 MEDLINE® 和 EMBASE®，并手动查阅了主要会议摘要，以找到针对接受免疫检查点抑制剂治疗的尿路上皮癌患者的包含生物标志物和临床结局的研究。纳入分析的研究必须提供生物标志物与结局之间的相关性。由于一些重要的生物标志物研究尚未发表，因此我们纳入了仅以摘要形式发表的结果。
我们检索到 1236 项研究，其中 921 项为唯一且经过筛选的研究，包括 144 项符合全文审查标准的研究和 25 项纳入分析的研究。手动检索还获得了我们系统评价中未包含的另外 1 项研究，共计 26 项研究。这些研究中使用的免疫检查点抑制剂包括阿替利珠单抗、阿维鲁单抗、度伐利尤单抗、伊匹单抗、纳武利尤单抗和派姆单抗。检测的生物标志物包括 PD-L1 免疫组化、基于 RNA 测序的分子亚型和免疫基因表达分析、针对 DNA 损伤修复基因突变的靶向基因面板和肿瘤突变负荷估计、外显子组测序的基因组改变和总突变负荷、免疫组化和 T 细胞受体测序分析肿瘤免疫浸润、以及循环免疫细胞和细胞因子分析。
没有单一的生物标志物能够准确预测对免疫检查点抑制剂的反应。大多数研究仅包含治疗组，且没有对照组，因此无法确定生物标志物是预测性的还是仅仅是预后性的。尽管 PD-L1 免疫组化的结果大多不尽如人意，但其他反映肿瘤免疫原性、免疫浸润特征和患者免疫系统特性的生物标志物显示出了有前景的数据。然而，所有这些都需要验证。
