Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padova, Italy.
Unit of Pathology, Fondazione IRCCS Ospedale Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.
J Clin Pathol. 2023 Dec;76(12):815-821. doi: 10.1136/jcp-2023-208767. Epub 2023 Apr 13.
In the DESTINY-Gastric01 trial, a novel HER2-targeted antibody-drug conjugate trastuzumab deruxtecan proved to be effective in HER2-low gastro-oesophageal adenocarcinomas. The aim of our study is to investigate the clinicopathological and molecular features of HER2-low gastric/gastro-oesophageal junction cancers in the real-world setting of a large multi-Institutional series.
We retrospectively evaluated 1210 formalin-fixed paraffin-embedded samples of gastro-oesophageal adenocarcinomas which were analysed by immunohistochemistry for HER2 protein expression in 8 Italian surgical pathology units from January 2018 to June 2022. We assessed the prevalence of HER2-low (ie, HER2 1+ and HER2 2+ without amplification) and its correlation with clinical and histopathological features, other biomarkers' status, including mismatch repair/microsatellite instability status, Epstein-Barr encoding region (EBER) and PD-L1 Combined Positive Score.
HER2 status could be assessed in 1189/1210 cases, including 710 HER2 0 cases, 217 HER2 1+, 120 not amplified HER2 2+, 41 amplified HER2 2+ and 101 HER2 3+. The estimated prevalence of HER2-low was 28.3% (95% CI 25.8% to 31.0%) overall, and was higher in biopsy specimens (34.9%, 95% CI 31.2% to 38.8%) compared with surgical resection specimens (21.0%, 95% CI 17.7% to 24.6%) (p<0.0001). Moreover, HER2-low prevalence ranged from 19.1% to 40.6% among centres (p=0.0005).
This work shows how the expansion of the HER2 spectrum might raise problems in reproducibility, especially in biopsy specimens, decreasing interlaboratory and interobserver concordance. If controlled trials confirm the promising activity of novel anti-HER2 agents in HER2-low gastro-oesophageal cancers, a shift in the interpretation of HER2 status may need to be pursued.
在 DESTINY-Gastric01 试验中，一种新型的靶向 HER2 的抗体药物偶联物曲妥珠单抗 deruxtecan 已被证明对 HER2 低表达的胃食管腺癌有效。本研究的目的是在意大利 8 个外科病理学单位的一个大型多机构系列的真实世界环境中，研究 HER2 低表达胃/胃食管交界处癌的临床病理和分子特征。
我们回顾性评估了 1210 例福尔马林固定石蜡包埋的胃食管腺癌样本，这些样本于 2018 年 1 月至 2022 年 6 月在意大利 8 个外科病理学单位通过免疫组织化学方法分析 HER2 蛋白表达。我们评估了 HER2 低表达（即 HER2 1+和无扩增的 HER2 2+）的发生率及其与临床病理特征、其他生物标志物状态（包括错配修复/微卫星不稳定性状态、EB 病毒编码区（EBER）和 PD-L1 联合阳性评分）的相关性。
在 1210 例病例中，1189 例可评估 HER2 状态，其中 710 例 HER2 0 ，217 例 HER2 1+，120 例非扩增 HER2 2+，41 例扩增 HER2 2+和 101 例 HER2 3+。总体而言，HER2 低表达的估计发生率为 28.3%（95%CI 25.8%至 31.0%），活检标本中的发生率（34.9%，95%CI 31.2%至 38.8%）高于手术切除标本（21.0%，95%CI 17.7%至 24.6%）（p<0.0001）。此外，HER2 低表达的发生率在各中心之间从 19.1%到 40.6%不等（p=0.0005）。
这项工作表明，HER2 谱的扩展可能会在可重复性方面引起问题，尤其是在活检标本中，会降低实验室间和观察者间的一致性。如果对照试验证实新型抗 HER2 药物在 HER2 低表达胃食管癌中的活性，可能需要对 HER2 状态的解释进行调整。
