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The force of HER2 - A druggable target in NSCLC?
M Jebbink1, A J de Langen1, M C Boelens2
1Department of Thoracic Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
Abstract:
Since several years targeted therapy has been part of treatment in NSCLC in subsets of patients with specific genetic alterations. One of these alterations involves HER2, a member of the ERBB family of tyrosine kinase receptors. Despite that HER2 alterations in NSCLC have been studied for years, there is still no consensus about subgroup definitions. In this review HER2 alterations in NSCLC are discussed, including diagnostic challenges and treatment strategies. Three principal mechanisms of HER2 alterations can be identified: HER2 protein overexpression, HER2 gene amplification and HER2 gene mutations. There are several methods for the detection of HER2 "positivity" in NSCLC, but no gold standard has been established. Laboratory methods for assessment of HER2 positivity in NSCLC include immunohistochemistry (IHC) for protein overexpression and fluorescent in situ hybridization (FISH) and next generation sequencing (NGS) for genetic alterations. Many trials testing HER2 targeted therapy in HER2 altered NSCLC has not lead to a renewed standard of care for this group of patients. Therefore, today the (re)search on how to analyse, define and treat HER2 alterations in NSCLC continues. Still there is no consensus about HER2 subgroup definitions and results of the many trials studying possible treatment strategies are inconclusive. Future research should focus on the most important missing link, whether all HER2 alterations are relevant oncogenic drivers and whether it should be considered as a therapeutic target in NSCLC.
Insights
Targeted therapy for non-small cell lung cancer (NSCLC) with HER2 alterations lacks consensus on subgroup definitions and treatment strategies. Further research is needed to determine if all HER2 alterations are oncogenic drivers for targeted therapy in NSCLC.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Targeted therapy is crucial for subsets of non-small cell lung cancer (NSCLC) patients with specific genetic alterations, including Human Epidermal growth factor Receptor 2 (HER2).
- Despite extensive research, there is no established consensus on defining HER2 subgroups in NSCLC, complicating treatment strategies.
Purpose of the Study:
- This review discusses HER2 alterations in NSCLC, focusing on diagnostic challenges and current treatment strategies.
- It aims to provide an overview of the current understanding and future directions for managing HER2-altered NSCLC.
Main Methods:
- The review synthesizes information on HER2 alterations, diagnostic methods, and therapeutic approaches in NSCLC.
- It covers immunohistochemistry (IHC), fluorescent in situ hybridization (FISH), and next-generation sequencing (NGS) for HER2 assessment.
Main Results:
- Three primary mechanisms of HER2 alterations exist: protein overexpression, gene amplification, and gene mutations.
- Current diagnostic methods lack a gold standard, and numerous clinical trials for HER2-targeted therapies in NSCLC have yielded inconclusive results, failing to establish new standards of care.
Conclusions:
- There is an ongoing need to refine the analysis, definition, and treatment of HER2 alterations in NSCLC.
- Future research must clarify the oncogenic relevance of all HER2 alterations and their potential as therapeutic targets in NSCLC.
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