Molecular and immunohistochemical characterization of ERBB2 activating mutations in low-grade serous ovarian carcinoma.

Abstract

Aims: Low-grade serous carcinoma (LGSC) of the ovary presents unique therapeutic challenges due to its resistance to platinum-based chemotherapies and a tendency to present at an advanced stage. Approximately 50% of LGSC possess activating mutations in KRAS, NRAS, and BRAF, a finding associated with better overall survival. However, many tumours lack obvious driver alterations against which to direct targeted treatment strategies, necessitating further investigation into molecular drivers of LGSC and their impact on clinical outcomes.

Methods and results: We conducted a retrospective analysis of 84 LGSC patients who underwent tumour-only targeted next-generation sequencing at our institution. Molecular data were correlated with clinical outcomes, HER2 immunohistochemistry, and supplemented with additional tumour sequencing data from the AACR GENIE cohort v15.1 (n = 295). Approximately 5% of LGSC cases across the combined cohort harboured activating alterations in ERBB2 (n = 17/369), which encodes the HER2 receptor tyrosine kinase. These alterations were mutually exclusive of other MAP kinase pathway mutations and included exon 20 insertions (n = 6), extracellular domain/transmembrane domain missense alterations (n = 4), and exon 16 skipping mutations (n = 7). ERBB2 exon 16 emerged as a mutational hotspot in LGSC when compared to other tumour types. Immunohistochemistry revealed variable HER2 expression patterns that were independent of ERBB2 mutational status. In our institutional cohort, patients with RAS/RAF mutant tumours (n = 38) showed better overall survival compared to RAS/RAF wildtype tumours (n = 35). No tumours in our internal cohort (n = 84) harboured ERBB2 amplifications.

Conclusion: As the landscape of HER2-directed therapies continues to evolve, these findings suggest that ERBB2 alterations and HER2 expression may represent a potential therapeutic target in LGSC.