Genomic landscape of ERBB3 alterations in metastatic solid tumours: a real-world data analysis
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1Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
Background:
Although human epidermal growth factor receptor 2 (ERBB2/HER2) is a validated therapeutic target, the significance of ERBB3 (HER3) alterations across solid tumours remains poorly defined. We characterised such alterations to clarify the genomic landscape relevant to HER3-directed strategies, distinguishing somatic events from germline polymorphisms.
Patients And Methods:
We analysed real-world data from 5416 patients with metastatic solid tumours who underwent next-generation sequencing. As tumour-only sequencing cannot separate germline from somatic variants, recurrent germline-pattern variants were reclassified using gnomAD and Korean population databases, and remaining somatic variants were annotated for oncogenicity using OncoKB (v7.3, Memorial Sloan Kettering Cancer Center, New York, NY). Overall survival (OS) was analysed via Cox regression analysis stratified according to tumour type.
Results:
ERBB3 alterations were initially identified in 12.9% of patients, dominated by mutations (12.3%) rather than amplifications (0.8%). However, the two most common variants, K498I and R1127H, proved to be common germline polymorphisms, and germline-pattern variants accounted for 63% of all mutation calls. After germline exclusion, the prevalence of somatic mutations was 4.5%, and oncogenic/likely-oncogenic mutations only 1.6%, matching a large pan-cancer series. Oncogenic mutations clustered in extracellular domains, were tumour-type-specific (V104M/L in colorectal and urothelial; G284R in gastric and biliary tract cancer), and persisted in nonhypermutated tumours. The ERBB3 mutation status was not prognostic (adjusted hazard ratio [HR] 0.97, P = 0.52), whereas ERBB3 amplification was independently associated with a worse OS (HR 1.43, P = 0.024).
Conclusions:
Most apparent ERBB3 mutations in this East Asian tumour-only cohort were likely germline polymorphisms; true somatic oncogenic mutations were uncommon and tumour-type-specific, whereas amplification was rare but prognostically adverse. As HER3-directed antibody-drug conjugates depend on HER3 protein expression, the integration of such data with HER3 immunohistochemistry and outcomes is essential to define the target population.