HER2 mutation profiling in mucinous ovarian carcinoma: Inferences for Enhertu (trastuzumab deruxtecan) as a potential therapeutic approach

Objective

This study aimed to characterize HER2 mutations in Taiwanese mucinous ovarian carcinoma (mOC) and evaluate the potential of Enhertu (T-DXd) as a targeted therapy for HER2-mutant mOC.

Materials and methods

We previously reported a 33.3 % (n = 7/21) HER2 tyrosine kinase domain (TKD) missense mutation rate in mOC using hot-spot PCR and Sanger sequencing. In this study, HER2 mutations were assessed in 18 additional mOC samples using targeted next-generation sequencing (NGS). Data from earlier PCR (n = 21) and current NGS (n = 18) were combined, resulting in all 39 cases. The COSMIC database and PolyPhen-2 (Polymorphism Phenotyping v2) algorithm were used to evaluate the pathogenicity of HER2 mutations identified in the NGS cohort.

Results

HER2 mutations were detected in 43.6 % (n = 17/39) of cases. The PCR cohort (n = 21) from the previous 2 studies using PCR and Sanger sequencing identified seven TKD mutations. On the other hand, the NGS cohort (n = 18) from the present study using targeted NGS detected ten non-TKD mutations, with p.P1170A being the most frequent. PolyPhen-2 pathogenicity predictions indicated that p.P1170A and p.R143Q were likely pathogenic. Combining PCR and NGS data enhanced statistical power; however, the study was limited by the insufficient residual specimens from the PCR cohort for NGS reanalysis.

Conclusion

Our findings reveal a high prevalence of HER2 mutations in mOC, with distinct profiles in TKD and non-TKD regions. These results support further investigation of Enhertu (T-DXd) as a promising targeted therapy for HER2-mutant mOC. Larger, multi-center studies are needed to validate these findings and explore clinical applications.