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Molecular and immunohistochemical characterization of ERBB2 activating mutations in low-grade serous ovarian
Alexander J Neil1, Dingani Nkosi1,2, Ju-Yoon Yoon3
1Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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.
Insights
Activating ERBB2 alterations, encoding HER2, were found in 5% of low-grade serous ovarian carcinomas. These ERBB2 alterations may represent a potential therapeutic target for this challenging cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Low-grade serous carcinoma (LGSC) of the ovary is challenging to treat due to platinum resistance and advanced stage at diagnosis.
- Activating mutations in KRAS, NRAS, and BRAF are present in about 50% of LGSC and correlate with better survival.
- Many LGSC tumors lack identifiable driver alterations for targeted therapy, highlighting the need to explore other molecular drivers.
Purpose of the Study:
- To investigate the frequency and clinical significance of ERBB2 alterations in LGSC.
- To correlate molecular findings with clinical outcomes and HER2 expression.
- To identify potential new therapeutic targets for LGSC.
Main Methods:
- Retrospective analysis of 84 LGSC patients with tumor-only targeted next-generation sequencing.
- Correlation of molecular data with clinical outcomes and HER2 immunohistochemistry.
- Supplementation with AACR GENIE cohort data (n=295) for combined analysis.
Main Results:
- Activating ERBB2 alterations were identified in approximately 5% of LGSC cases across the combined cohort (n=17/369).
- These alterations included various mutations (exon 20 insertions, missense, exon 16 skipping) and were mutually exclusive of RAS/RAF mutations.
- ERBB2 exon 16 was a mutational hotspot in LGSC; HER2 expression varied and was independent of ERBB2 mutation status. RAS/RAF mutant tumors showed improved overall survival.
Conclusions:
- ERBB2 alterations, including specific mutations in exon 16, are present in a subset of LGSC.
- HER2 expression patterns are variable and not directly linked to ERBB2 mutational status.
- ERBB2 alterations and HER2 expression represent a potential therapeutic avenue for LGSC as HER2-directed therapies advance.
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