HER-2 amplification associates with advanced NSCLC and poor prognosis, while Exon 20 mutations show distinct molecular profiles
Investigators retrospectively analyzed targeted next-generation sequencing data from 2,795 non-small cell lung cancer patients to characterize HER-2 genetic variations. HER-2 alterations were detected in 5.3% of cases, predominantly as mutations (86.5%), with amplifications accounting for 10.8% and concurrent events in 2.7%. Patients harboring HER-2 amplifications presented with larger tumors, higher TNM stages, and worse overall prognosis, whereas Exon 20 mutations were more frequent in females and less frequently co-occurred with other driver alterations. The findings underscore the necessity for molecular pathology laboratories to differentiate HER-2 mutation subtypes from amplifications during NGS reporting to guide accurate prognostic stratification and targeted therapy selection.
The original study
[Clinicopathological, molecular characteristics and prognostic analysis of non-small cell lung cancer with HER-2 genetic variations].
- Authors
- Wang YJ, Xu JY, Zhang HZ, Zhao M
- Journal
- Zhonghua zhong liu za zhi [Chinese journal of oncology]
- Type
- English Abstract, Journal Article
- PMID
- 42764221
Original abstract
Objective: To analyze the clinicopathological and molecular characteristics of non-small cell lung cancer (NSCLC) with human epidermal growth factor receptor 2 (HER-2) variations (including mutations and amplifications) and their correlation with prognosis. Methods: Clinicopathological data of NSCLC patients with HER-2 variations who underwent targeted next-generation sequencing (NGS) at Ningbo Clinical Pathology Diagnostic Center from September 2022 to June 2024 were collected. The clinicopathological and molecular features were retrospectively analyzed, and a literature review was conducted. Results: Among 2 795 NSCLC patients, HER-2 variations were identified in 148 cases (5.3%, 148/2 795). Of these, 128 cases had HER-2 mutations [86.5%, 128/148, including 63 exon 20 (Exon20) mutations], 16 cases had HER-2 amplifications (10.8%, 16/148), and 4 cases had concurrent HER-2 mutation and amplification (2.7%, 4/148). Compared with the HER-2 mutation group, patients with HER-2 amplification were more likely to have larger tumor size, lymph node metastasis, distant metastasis and higher TNM stage (all P＜0.05). Among HER-2 mutations, Exon 20 mutations were more common in females and associated with lower risks of larger tumor size, lymph node metastasis and distant metastasis (all P＜0.05). Cox regression analysis indicated that HER-2 amplification, larger tumor size, lymph node metastasis, distant metastasis and higher TNM stage were associated with poor prognosis (P＜0.05). Molecular analysis revealed that Exon20 mutations rarely co-occurred with other gene variations, whereas non-Exon20 mutations were frequently accompanied by other genetic alternations, most commonly epidermal growth factor receptor (EGFR) mutations (55.4%, 36/65). In addition, 16 cases of HER-2 p.A270S mutation were identified, of which 11 were at advanced TNM stage (68.8%, 11/16), and 5 patient died. Conclusions: Different types of HER-2 variations (mutations/amplifications) exhibit distinct clinicopathological and molecular characteristics. Patients with HER-2 amplification have a poor prognosis, and the HER-2 p.A270S mutation may be associated with malignant phenotypes of NSCLC. It is necessary to integrate the characteristics of HER-2 variations to provide references for individualized treatment..