Favourable Prognostic Significance of HER2 Mutations in Canine Pulmonary Adenocarcinoma Following Surgical Resection.

Abstract

Human epidermal growth factor receptor 2 (HER2) gene mutations have been reported in 5% to 38% of canine pulmonary adenocarcinomas (cPACs), most commonly as V659E mutations in exon 20. However, their prognostic and predictive significance remains unclear. This retrospective, single-centre cohort study investigated the frequency of HER2 mutations in surgically resected cPACs and their association with clinical outcomes. Between 2005 and 2021, lung masses histologically diagnosed as cPACs were collected and subjected to direct sequencing of HER2 exons 20 and 21. A total of 72 dogs were enrolled, with successful HER2 gene analysis in 69 cases. HER2 exon 20 missense mutations were identified in 20 dogs (29.0%), including 18 harbouring the previously reported V659E hotspot mutation within the transmembrane domain. Homozygous mutations were detected in 13 dogs. Univariable analysis revealed associations between progression-free interval (PFI) and clinical signs, tumour size classification, lymph node metastasis, surgical margin status, and histologic grade. Overall survival time (OST) was associated with age, clinical signs, tumour size > 7 cm, histologic subtype, lymph node metastasis, and margin status. In multivariable analysis, tumour size classification and margin status remained significantly associated with PFI, while age, tumour size > 7 cm, and histologic subtype were independently associated with OST. Notably, the presence of HER2 mutations was significantly associated with prolonged PFI in both univariable and multivariable analyses, although no significant association with OST was observed. These findings suggest that HER2 mutation status may serve as a favourable prognostic marker for disease progression in surgically resected cPACs.