Comprehensive biomarker analysis of long-term response to trastuzumab in patients with HER2-positive advanced gastric or gastroesophageal adenocarcinoma

Background: 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 re-sponding patient group. Patients and methods: Tumour samples of 19 patients with HER2-positive metastatic gastric and gastroesophageal junction cancer who underwent trastuzumab treatment were retrospec-tively 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 expres-sion analysis were performed along with HER2 and PD-L1 immunohistochemistry. Results: 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. Conclusion: 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. 2023 University Medical Center Mannheim, University of Heidelberg. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons. org/licenses/by-nc-nd/4.0/).

Automated summary

This study aims to identify potential prognostic biomarkers for long-term response to trastuzumab maintenance therapy in HER2-positive metastatic gastric and gastroesophageal junction cancer patients. The results show that long-term responding patients have higher PD-L1 positivity scores, which are associated with longer progression-free survival. ERBB2 copy number and tumor mutational burden cannot discriminate between short-term and long-term responding patients.