Immuno-Oncology Biomarkers for Gastric and Gastroesophageal Junction Adenocarcinoma: Why PD-L1 Testing May Not Be Enough

Oncologist. 2018 Oct;23(10):1171-1177. doi: 10.1634/theoncologist.2018-0034. Epub 2018 Apr 27.

Abstract

Purpose: The treatment of patients with advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinomas has been transformed by the U.S. Food and Drug Administration approval of pembrolizumab. Tumor and adjacent tissue must stain positively for the programmed cell death ligand 1 (PD-L1) protein by companion diagnostic testing. However, some patients with PD-L1-negative tumors also benefit from pembrolizumab. High microsatellite instability (MSI) and tumor mutational load (TML) are positive predictive biomarkers for immune checkpoint inhibition (ICI) in other tumors. We sought to identify more patients who could benefit from ICI using alternative PD-L1 thresholds, MSI, and TML.

Methods: Tumor specimens underwent next-generation sequencing (NGS) and PD-L1 testing using immunohistochemistry. NGS was used to determine TML and MSI.

Results: We profiled 581 G/GEJ adenocarcinoma specimens. PD-L1 staining was scored for intensity (0, none; 1+, weak; 2+, moderate; 3+, strong). Using 2+ staining at a 5% threshold, 9.3% of tumors were PD-L1 positive, and using 1+ staining at 1%, 16.2% were PD-L1 positive. 6.9% of tumors had high MSI. High TML (≥17 mutations per megabase) was seen in 6.9%, and medium TML (≥7) was seen in 56.5% of tumors. Thirty (5.2%) PD-L1-negative tumors at the 1+, 1% threshold had high TML or high MSI. Primary tumors had higher rates of high TML (8.8% vs. 3.9%; p = .0377) and high MSI (8.5% vs. 3.9%; p = .0471) than metastases.

Conclusion: PD-L1 testing alone fails to detect patients who may benefit from ICI. Lower PD-L1 thresholds and TML testing should be considered in future clinical trials.

Implications for practice: Pembrolizumab is approved by the U.S. Food and Drug Administration for patients with refractory gastric and gastroesophageal cancers if the tumor and adjacent tissue stain positively for the programmed cell death ligand 1 (PD-L1) protein by companion diagnostic testing. Tumor mutational load, microsatellite instability (MSI), and alternative PD-L1 testing thresholds may serve as predictive biomarkers for response to immune checkpoint inhibition, and standard PD-L1 testing will not identify all patients who may benefit from this therapy.

摘要

目的。美国食品药品监督管理局已经批准派姆单抗用于治疗晚期胃癌和胃食管交界部(G/GEJ)腺癌患者,这给此类癌症的治疗带来了转变。在伴随诊断试验中,肿瘤及其周围组织的染色结果必须为程序性死亡配体1(PD‐L1) 蛋白阳性。然而,某些PD‐L1阴性肿瘤患者也可从派姆单抗中获益。高微卫星不稳定性(MSI)和肿瘤基因突变负荷(TML)是其它肿瘤中免疫检查点抑制剂(ICI)的阳性预测性生物标志物。我们希望利用替代PD‐L1阈值、MSI和TML确定还有哪些患者可获益于ICI。

方法。用免疫组化分析对肿瘤标本实施新一代测序(NGS)和PD‐L1检测。用NGS确定TML和MSI。

结果。我们分析了581 份G/GEJ 腺癌标本。用PD‐L1染色强度进行评分(0, 无; 1+, 弱; 2+, 中等; 3+, 强)。采用 2+ 染色(5% 阈值),发现9.3% 的肿瘤为PD‐L1阳性;采用1+ 染色( 1%阈值),发现16.2%的肿瘤为PD‐L1 阳性。6.9% 的肿瘤有高MSI。高TML (≥17个突变/百万碱基) 比率为6.9%,中等TML (≥7)比率为56.5%。30份 (5.2%) PD‐L1阴性肿瘤标本(1+染色, 1% 阈值)为高TML或高 MSI。与转移灶相比,原发肿瘤的高TML (8.8% 对比 3.9%; p=0.037 7)和MSI (8.5% 对比 3.9%; p=0.047 1)发生率更高。

结论。单独采用PD‐L1检测无法确定哪些患者可能获益于ICI。未来的临床试验应当考虑更低的PD‐L1阈值以及 TML检测。

实践意义

派姆单抗被美国食品药品监督管理局批准用于难治性胃癌和胃食管癌患者,前提是伴随诊断试验确定肿瘤及其周围组织的程序性死亡配体 (PD‐L1) 蛋白染色结果为阳性。肿瘤基因突变负荷、微卫星不稳定性(MSI)和替代PD‐L1检测阈值可作为免疫检查点抑制剂是否有效的预测性生物标志物,并且标准PD‐L1检测无法识别出所有可能获益于这种治疗方法的患者。

Keywords: Checkpoint inhibitor; Gastric adenocarcinoma; Gastroesophageal adenocarcinoma; Immunotherapy; Programmed death ligand 1.

MeSH terms

  • Adenocarcinoma / genetics*
  • Adenocarcinoma / pathology
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / immunology*
  • Esophageal Neoplasms / genetics*
  • Esophageal Neoplasms / pathology
  • Esophagogastric Junction / pathology
  • Female
  • Humans
  • Male
  • Middle Aged
  • Programmed Cell Death 1 Receptor / genetics*
  • Stomach Neoplasms / genetics*
  • Stomach Neoplasms / pathology
  • Young Adult

Substances

  • Biomarkers, Tumor
  • Programmed Cell Death 1 Receptor

Supplementary concepts

  • Adenocarcinoma Of Esophagus