The identification of HER2 overexpression in a subset of gastric cancer (GC) patients represents a significant step forward in unveiling the molecular complexity of this disease. The predictive and prognostic value of HER2 amplification in advanced HER2 inhibitor-treated GC patients has been investigated. However, its predictive value in early stage resectable patients remains unclear. In this study we interrogated the correlation between HER2 copy number (CN) and disease-free survival (DFS).
We enrolled 98 treatment-naïve resectable (stage I-III) Chinese GC patients with HER2 overexpression assessed using IHC. Capture-based targeted sequencing using a panel consisting of 41 gastrointestinal cancer -related genes was performed on FFPE samples. Furthermore, we also investigated the correlation between HER2 CN and DFS. This cohort had 81 males and 17 females, with a median age of 64. 12, 62 and 24 patients had diffuse, intestinal and mixed GC respectively.
Of the 98 HER2-overexpressed patients assessed using IHC, 91 had HER2 CN amplification assessed using next-generation sequencing, achieving 93% concordance. In addition, 10 had concurrent HER2 missense mutations, including 4 with S310X. All patients except for two had at least one concurrent mutation. The most commonly seen concurrent mutations were TP53, EGFR and PIK3CA, occurring in 85%, 13% and 12% patients, respectively. Furthermore, 23 patients had mutations in EGFR, MET, PDGFRA or KIT, which may participate in the activation of bypass pathways. We also revealed that patients with concurrent TP53 (p = 0.05) or PI3KCA (p = 0.02) mutations were significantly older than patients without. Next, dichotomous analysis was performed to investigate the association between HER2 CN and DFS. Stage I patients did not undergo adjuvant chemotherapy and all stage II-III patients underwent adjuvant chemotherapy. Our study revealed that patients with high HER2 CN had a significantly shorter DFS than patients with low HER2 CN (p = 0.002).
We elucidated the mutation spectrum of HER2-amplified resectable Chinese GC patients and the association between HER2 CN and DFS. Our study revealed the predictive value of HER2 CN and allowed us to further stratify HER2-positive patients.
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All authors have declared no conflicts of interest.