Human epidermal growth factor receptor 2 expression loss after neoadjuvant chemotherapy in localized gastroesophageal
Jean-Baptiste Demigné1, Marie Heinisch2, Julia Gilhodes3
1Department of Medical Oncology, Paoli-Calmettes Institute & AP-HM, Marseille, France.
Background:
Human epidermal growth factor receptor 2 (HER2) overexpression/ERBB2 amplification represents an established therapeutic target in advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma. However, the reliability of HER2 assessment between diagnostic biopsies and surgical specimens (SS), and the potential impact of neoadjuvant therapy on HER2 status, remain incompletely characterized in localized disease. This study aimed to evaluate HER2 concordance between pre-treatment biopsies (PTB) and matched SS, and to describe HER2 changes following neoadjuvant treatment in localized gastric and GEJ adenocarcinoma.
Methods:
We conducted a retrospective single-center cohort study including patients with localized gastric or GEJ adenocarcinoma who underwent curative-intent surgery between 2017 and 2021. HER2 status was assessed on PTB and matched SS using immunohistochemistry (IHC) with reflex in situ hybridization (ISH) for IHC-2+ cases, according to gastric cancer guidelines. Concordance between PTB and SS, the impact of biopsy sampling adequacy, and dynamic changes in HER2 status following neoadjuvant therapy were analyzed descriptively.
Results:
Fifty-seven patients were included. Median age was 67 years; 77% were male. Neoadjuvant treatment was administered in 89.5% of patients, while 10.5% underwent upfront surgery. HER2 positivity was observed in 21.1% of biopsies and 15.8% of SS. Overall concordance of HER2 status between PTB and SS was 87.7% [95% confidence interval (CI): 76.3-94.9%]. Seven discordant cases were identified, including five cases of HER2 loss (biopsy-positive/resection-negative) and two cases of HER2 gain. Among the 12 tumors initially classified as HER2-positive on biopsy, HER2 positivity was maintained in seven cases (58.3%) but lost in five (41.7%; 95% CI: 15.2-72.3%). When restricted to patients receiving neoadjuvant therapy, HER2 loss occurred in 5 of 10 HER2-positive cases (50.0%; 95% CI: 18.7-81.3%). Increasing the number of biopsy fragments did not significantly reduce discordance between biopsy and SS.
Conclusions:
HER2 status shows overall good concordance between diagnostic biopsies and SS in localized gastric and GEJ adenocarcinomas. However, a substantial proportion of initially HER2-positive tumors exhibited loss of HER2 expression following neoadjuvant chemotherapy. These findings suggest that HER2 expression/ERBB2 amplification may evolve during perioperative treatment and support further evaluation of HER2 reassessment on SS.
