Uterine serous carcinoma (USC) has HER2 as a major therapeutic and prognostic target. However, there is a lack of consensus on the best HER2 testing infrastructure, and testing recommendations have evolved. Using chromogenic in situ hybridization (CISH), immunohistochemistry (IHC), and next-generation sequencing (NGS), researchers hoped to evaluate the degree of agreement between these 3 methods of detecting HER2 positivity and to calculate the frequency of downstream mutations that may influence the efficacy of HER2 directed therapy. NGS (NextSeq, 592 Genes, and WES, NovaSEQ), immunohistochemistry (IHC), and comparative in situ hybridization (CISH) were used to study 2,192 tumors from USC found in the Caris tumor registry. 

Using immunohistochemistry, PD-L1 expression was evaluated. Fragment analysis, immunohistochemistry, and next-generation sequencing were all used to check for microsatellite instability. Total somatic mutation count per tumor was used to determine tumor mutational burden (TMB). To determine HER2 positive, investigators used IHC and CISH and referred to the ASCO/CAP HER2 breast cancer guidelines from 2007 and 2018. When comparing the 2018 and 2007 guidelines, the rate of HER2 positive by IHC was greater when following the 2018 guidelines (16.3% vs. 12.3%). There was a 98.9% degree of agreement between the results of IHC and CISH. NGS revealed that amplification of ERBB2 was seen in 10.5% of tumors. 

This corresponds to a  positive predictive value (PPV)  of 60.3% and a concordance rate of 91.6% compared to CISH data. PI3K (33.1%), KRAS (2.5%), and PTEN (1.3%) single-gene changes were found in HER2 amplified tumors, which may be involved in HER2 therapeutic resistance. CISH and immunohistochemistry (IHC) both showed HER2 positive, and there was strong agreement between the 2. The HER2 positive rate is the lowest when using NGS. Finally, the outcome of targeted therapy should be used to verify the accuracy of these testing platforms.-

Source: sciencedirect.com/science/article/abs/pii/S0090825822005923