HER2-low in gastroesophageal adenocarcinoma: a real-world pathological perspective

Introduction: Trastuzumab in combination with cytotoxic chemotherapy is the first-line therapy of choice in HER2-overexpressing metastatic gastroesophageal cancers. In the DESTINY-Gastric01 trial, a novel HER2-targeted antibody-drug conjugate Trastuzumab deruxtecan proved to be effective also in HER2-low disease, paving the way for novel therapeutic scenarios. Materials and methods: we retrospectively selected a large series of 1109 formalin-fixed paraffin-embedded (FFPE) samples of gastroesophageal adenocarcinoma (n = 375 gastroesophageal junctional adenocarcinomas and 707 gastric adenocarcinomas; 502 surgical resection specimens and 607 biopsy specimens) analyzed by IHC for HER2 protein expression in seven Italian surgical pathology units from January 2018 to June 2022. We assessed the prevalence of HER2-low (i.e., HER2 1+ and HER2 2+ without amplification) and its correlation with clinical and histopathological features, other biomarkers’ status, including MMR/MSI status, EBER and PD-L1 Combined Positive Score. Results: out of 1089 assessable cases, 662 (60.8%) cases were HER2 0, 298 (27.4%) were HER2-low and 129 (11.8%) were HER2-high. Biopsy samples were enriched in HER2-low cases in comparison with surgical resection specimens (34.5% versus 18.9%; p<0.00001). The prevalence of HER2-low and HER2-high cases was higher in Lauren intestinal cases than in diffuse cases and lower in pure signet-ring cell carcinomas (SRC) (p=0.002). The distribution of HER2 0, HER2-low and HER2-high cases among the centers where the evaluation was performed was significantly different (p=0.007). HER2-low status did not correlate with localization, histotype and grading according to WHO, Ming classification, staging, other biomarkers’ status and year of diagnosis. Conclusions: in this work, we showed how the expansion of the HER2 spectrum might decrease reproducibility, especially in biopsy specimens, increasing inter-laboratory and interobserver variability. If controlled trials confirm the promising activity of novel anti-HER2 agents in HER2-low gastroesophageal cancers, a shift in the interpretation of HER2 status may need to be pursued, including a modification of existing HER2 assays and a well-defined characterization of HER2 expression beyond the current dichotomic HER2-positive and HER2-negative status.