Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, 68167 Mannheim, Germany.
Eur J Cancer. 2023 Apr;183:119-130. doi: 10.1016/j.ejca.2023.01.022. Epub 2023 Feb 3.
A subgroup of patients with HER2-positive metastatic gastric and gastroesophageal junction cancers shows long-term response under trastuzumab maintenance monotherapy. Obviously, HER2 status alone is not able to identify these patients. We performed this study to identify potential new prognostic biomarkers for this long-term responding patient group.
Tumour samples of 19 patients with HER2-positive metastatic gastric and gastroesophageal junction cancer who underwent trastuzumab treatment were retrospectively collected from multiple centres. Patients were divided into long-term responding (n = 7) or short-term responding group (n = 12) according to progression-free survival (PFS≥12 months vs. PFS < 12 months). Next-generation sequencing and microarray-based gene expression analysis were performed along with HER2 and PD-L1 immunohistochemistry.
Long-term responding patients had significantly higher PD-L1 combined positive scores (CPS) and CPS correlated with longer progression-free survival. PD-L1 positivity (CPS ≥ 1) was further associated with an increased CD4+ memory T-cell score. The ERBB2 copy number as well as the tumour mutational burden could not discriminate between short-term and long-term responding patients. Genetic alterations and coamplifications in HER2 pathway associated genes such as EGFR, which were connected to trastuzumab resistance, were present in 10% of the patients and equally distributed between the groups.
The study highlights the clinical relevance of PD-L1 testing also in the context of trastuzumab treatment and offers a biological rational by demonstrating elevated CD4+ memory T-cells scores in the PD-L1-positive group.
曲妥珠单抗维持单药治疗可使部分 HER2 阳性转移性胃和胃食管交界癌患者获得长期缓解。显然，HER2 状态本身并不能识别这些患者。我们进行这项研究是为了确定这种长期缓解患者群体的潜在新预后生物标志物。
从多个中心回顾性收集了 19 例接受曲妥珠单抗治疗的 HER2 阳性转移性胃和胃食管交界癌患者的肿瘤样本。根据无进展生存期（PFS≥12 个月与 PFS<12 个月），将患者分为长期缓解组（n=7）和短期缓解组（n=12）。进行了下一代测序和基于微阵列的基因表达分析，以及 HER2 和 PD-L1 免疫组化。
长期缓解患者的 PD-L1 联合阳性评分（CPS）显著更高，CPS 与更长的无进展生存期相关。PD-L1 阳性（CPS≥1）与增加的 CD4+记忆 T 细胞评分进一步相关。ERBB2 拷贝数和肿瘤突变负担不能区分短期和长期缓解患者。在 HER2 通路相关基因（如与曲妥珠单抗耐药相关的 EGFR）中存在遗传改变和共扩增，在 10%的患者中存在，并且在两组之间分布均匀。
该研究强调了 PD-L1 检测在曲妥珠单抗治疗中的临床相关性，并通过在 PD-L1 阳性组中显示出升高的 CD4+记忆 T 细胞评分提供了生物学依据。
