Background

On October 14, 2024, official website, National Medical Products Administration, China (NMPA) announced the marketing approval of a new indication for lung cancer for Trastuzumab deruxtecan (Enhertu). The new drug is an antibody-coupled drug (ADC) targeting HER2 that is targeted at unresectable or metastatic adult non-small cell lung cancer (NSCLC) patients with HER2 activation mutations who have received at least one systemic treatment in the past.

Understanding the characteristics of HER2 gene variation is essential to guide the accurate treatment of NSCLC with this gene variation.

01. Incidence of HER2 variation and distribution characteristics of patient population

In a retrospective analysis of the population cohort of 1281 patients with NSCLC in China who carried HER2 somatic variation (including amplification), the incidence of HER2 variation in NSCLC was 5.6% (1281/22,905), 55% of whom were women with a median age of 58 years. The majority of patients with HER2 variation were nonsmokers (70.9%) and had histologic types of adenocarcinoma (94.9%).

02. Molecular characteristics of HER2 variation

Among 1281 patients with HER2 mutations, 930 had either point mutations or small-fragment insertion mutations with a frequency of 4.0% (930/22,905), were annotated with a public database of detected mutation types, and 920 carried pathogenic mutations. The incidence of amplification variants harboring only HER2 was 1.5%(351/22,905). The simultaneous incidence of point mutation/amplification was 5.5% (70/1281).

Common mutations of HER2 occurred mainly in the tyrosine kinase domain of exon 20 (80.1% [737/920]), with Y772_A775dup being the most common (58%[534/920]), followed by G776delins (10.7%[98/920]) and S310F/Y (10.5% [97/920]) (Figure 1).

Figure 1. Types and proportions of HER2 pathogenic mutations

Among 70 patients who had both HER2 amplification and mutation at the same time, the pathogenic HER2 mutation was found in 61 patients (Figure 2a). Of these, Y772_A775dup was the most common mutation (50.8%[31/61]) (Figure 2b).

Figure 2. Proportional and Distribution of Pathogenic Point Mutations Coincidence with HER2 Amplification

03. Molecular atlas analysis of HER2 co-mutation

Genetic information for co-mutations with HER2 was also evaluated and the distribution of co-mutated genes between HER2 mutations and HER2 amplification was compared in detail. TP53, EGFR, and CDKN2A mutations occurred significantly more frequently with HER2 amplification, and increases in copy numbers of the CDK12, FGFR1, and EGFR genes were significantly higher in the HER2 amplification group compared with the HER2 mutation (Figure 3).

Figure 3. Distribution of co-mutated genes between HER2 mutation and HER2 amplification

(a. Molecular atlas of HER2 mutation and HER2 amplification co-mutation b. Distribution comparison of SNV/Indel variation types in different subgroups c. Distribution comparison of copy number variation in different subgroups)

04. Comparison of clinical features of patients with 04．HER2 mutation/amplification

The clinical features of the two groups were compared based on the fact that the HER2 mutation group and the HER2 amplification group showed different molecular patterns of co-mutation (Table 1). Patients with HER2 mutations were younger (mean 53.6 vs 63 years, p<0.001), had more women (66% vs 31%, p<0.001), and had never smoked (79% vs 50%, p<0.001). The majority of HER2-mutated tumors were adenocarcinoma (98.6%), while the squamous cell carcinoma was more abundant in HER2-amplified tumors (15.4% vs 0.7%, p<0.001), and TMB values were higher than those in the HER2-mutated group (mean 8.9 vs 3.5;  p < 0.001)。

Table 1. Comparison of clinical features of patients with HER2 system mutation/amplification

05. Summary

There were three types of HER2 changes, such as gene mutation, gene amplification, and HER2 protein overexpression. There are two main forms of HER2 variation in non-small cell lung cancer (NSCLC): One is the amplification of HER2 gene; Second, HER2 gene activation and mutation. Ninety-six percent of patients with HER2 mutations had an insertion mutation in exon 20 (the most common form being the insertion of YVMA four amino acids at position 775 in exon 20 of the HER2 gene). HER2 gene mutation is mainly found in female, non-smoking and lung adenocarcinoma patients. The indication of Trastuzumab deruxtecan monoclonal antibody is approved for patients with lung cancer, which provides more powerful guarantee for clinical medication prescriptions for patients based on HER2 mutation. The need for detection of HER2 mutation based on multiple genes or single genes will become clearer.

XIAMEN SPACEGEN Co., Ltd. independently developed “Oncology Multi-Gene Mutations Detection Kit” which can detect multiple key gene mutations in tumor tissues of patients with non-small cell lung cancer. Gene testing will help drive the development of precision medicine by enabling more precise identification of patients who are suitable for treatment with HER2 variant ADCs.

References

Hong L, Patel S, Drusbosky LM, Xiong Y, Chen R, Geng R, Heeke S, Nilsson M, Wu J, Heymach JV, Wang Y, Zhang J,  Le X. Molecular landscape of ERBB2 alterations in 3000 advanced NSCLC patients. NPJ Precis Oncol. 2024 Oct 1; 8(1):217.

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