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Clinical Utility of Targeted Next-Generation Sequencing for Determining Human Epidermal Growth Factor Receptor 2
Yoshimi Hara1,2, Kazuki Moro1,2, Hiroshi Ichikawa1
1Division of Digestive and General Surgery, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.
Background:
The development of targeted next-generation sequencing (NGS) technologies has contributed to precision medicine, as evidenced by the growing interest in evaluating human epidermal growth factor receptor 2 (HER2) expression status to treat unresectable/metastatic HER2-low breast cancer (BC). However, the concordance between erb-b2 receptor tyrosine kinase 2 (ERBB2) copy number alteration (CNA) and HER2 immunohistochemistry (IHC) has never been determined. The aim of this study was to evaluate the utility of targeted NGS for determining HER2 status and optimizing targeted therapies for BC.
Methods:
ERBB2 CNAs were examined by targeted NGS in 41 formalin-fixed paraffin-embedded (FFPE) BC tissues. ERBB2 CNA was compared with HER2 status evaluated by IHC in tissue sections, which were identical to those subjected to targeted NGS, using the Ventana 4B5 antibody.
Results:
The median fold changes (FCs) for ERBB2 CNAs in tumors with an IHC score of 3+, 2+, 1+, and 0 were 4.81, 1.49, 1.00, and 1.00, respectively. The difference in the FC for ERBB2 CNA according to HER2 status was statistically significant (P < 0.001). An FC greater than 1.0 for ERBB2 CNA was established as the cutoff value to differentiate between tumors with an IHC score of 3+, 2+, or 1+ and tumors with an IHC score of 0, on the basis of receiver operating characteristic curve analysis. The overall percent agreement, positive percent agreement, negative percent agreement, and Cohen's kappa between ERBB2 CNA and HER2 status were 68.3%, 57.7%, 86.7%, and 0.39, respectively. The numbers of patients with mutations in ERBB2, estrogen receptor 1 (ESR1), phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), serine/threonine kinase 1 (AKT1), and phosphatase and tensin homolog (PTEN) were 7, 3, 6, 1, and 5, respectively. Targeted NGS detected additional gene mutations and presented treatment options for seven of 22 patients (31.8%) with an FC of ERBB2 CNA = 1.00.
Conclusions:
Targeted NGS has the potential in distinguishing HER2 IHC 3+, 2+, and 1+ tumors from IHC 0 in patients with BC; however, differentiating between HER2 IHC 1+ and 0 remains challenging. Additionally, targeted NGS may aid in the identification of actionable mutations, thereby contributing to the selection of optimal treatment strategies in BC management.
Insights
Targeted next-generation sequencing (NGS) shows promise for determining human epidermal growth factor receptor 2 (HER2) status in breast cancer (BC). While NGS can distinguish HER2-expressing tumors, differentiating HER2 IHC 1+ from 0 remains difficult.
Area of Science:
- Oncology
- Genomics
- Precision Medicine
Background:
- Precision medicine advancements rely on accurate human epidermal growth factor receptor 2 (HER2) expression evaluation for treating HER2-low metastatic breast cancer (BC).
- The concordance between erb-b2 receptor tyrosine kinase 2 (ERBB2) copy number alteration (CNA) and HER2 immunohistochemistry (IHC) in BC has not been previously established.
Purpose of the Study:
- To assess the utility of targeted next-generation sequencing (NGS) for determining HER2 status in breast cancer.
- To optimize targeted therapy selection for breast cancer patients based on comprehensive genomic profiling.
Main Methods:
- ERBB2 CNAs were analyzed using targeted NGS in 41 formalin-fixed paraffin-embedded (FFPE) breast cancer tissues.
- ERBB2 CNA results were compared with HER2 status determined by Ventana 4B5 antibody IHC on identical tissue sections.
Main Results:
- A statistically significant difference (P < 0.001) was observed in ERBB2 CNA fold changes (FCs) across HER2 IHC scores (3+: 4.81, 2+: 1.49, 1+: 1.00, 0: 1.00).
- An FC cutoff > 1.0 for ERBB2 CNA effectively differentiated IHC 3+/2+/1+ from IHC 0 tumors (overall agreement: 68.3%, Cohen's kappa: 0.39).
- Targeted NGS identified actionable mutations in 31.8% of patients with an ERBB2 CNA FC of 1.00, suggesting potential therapeutic options.
Conclusions:
- Targeted NGS can potentially distinguish HER2 IHC 3+, 2+, and 1+ tumors from IHC 0 in breast cancer, though differentiating IHC 1+ from 0 is challenging.
- Targeted NGS aids in identifying actionable mutations, thereby supporting optimal treatment strategy selection for breast cancer management.
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