About 5% of NSCLCs have overexpression and amplification of HER2 or its mutations, mostly exon 20 insertions. There are still few data available on roles of HER2 alterations in NSCLCs.
To determine the frequency and characteristics of HER2 alterations in NSCLCs and to identify patients (pts) eligible for clinical trial of trastuzumab (HOT1303-B), we conducted a prospective observational study of HER2 alterations in pts with advanced NSCLCs without EGFR or ALK mutations. We determined HER2 overexpression by IHC, amplification by dual color in situ hybridization (DISH), and mutation of exons 8, 19, 20 and 21 by direct sequence and that of all the exons by NGS. We also analyzed 48 cancer-related genes by NGS using targeted sequencing kits.
Until completion of enrollment of HOT1303-B, 129 eligible pts with advanced NSCLCs including 108 adenocarcinoma pts were enrolled to this study. IHC3+ was observed in 6 pts (4.6%), all of whom showed DISH+. IHC2+/DISH+ were also observed in 6 pts (4.6%). Hotspot mutations (5 exon 20 YVMA insertions and 2 S310F mutations) were detected in 7 pts (5.4%), and non-hotspot mutations including a previously unknown L755_N758delinsPST mutation were detected in 12 pts (9.3%). Amplifications and hotspot mutations were mutually exclusive except a case with IHC2+/DISH+ and S310F. When we defined amplifications and hotspot mutations narrowly as HER2 alterations (18 pts, 14%), they correlated with smoking inversely (p = 0.03), but not with age, sex, chemotherapy response or overall survival from 1st line therapy. The 48 gene NGS analysis was conducted in 91 pts. Number of mutated genes per pt (median, 2; range, 0-23) did not correlate with HER2 alterations. The most frequently mutated gene was TP53, mutations of which tended to correlate with HER2 alterations (11/14, 79% vs. 41/77, 53%; p = 0.08). Although there were no genes mutations of which were significantly associated with HER2 alterations, HER2 altered tumors had no oncogenic driver mutations including K-RAS and B-RAF.
HER2 alterations were relatively frequently observed. Hotspot mutations and amplifications were almost mutually exclusive and tended to be associated with TP53 mutations. Precise roles of distinct HER2 alterations should be determined in larger cohorts.
Clinical trial identification
Legal entity responsible for the study
Ministry of Health, Labor and Welfare, Japan.
I. Kinoshita: Honoraria: Chugai Pharma, Novartis. S. Oizumi: Honoraria: AstraZeneca Japan, Lilly Japan. Research funding from Kyowa Hakko Kirin, Pfizer, BMS UK, ONO Pharmaceutial. T. Harada: Honoraria: Taiho Pharmaceutical, AstraZeneca KK, Boehringer Ingelheim, Hisamitu Pharmaceutical. S. Sugawara: Honoraria: AstraZeneca, Chugai Pharma, Nippon Boehringer Ingelheim, Taiho Pharmaceutical, Pfizer, Eli Lilly and Campany, Novartis, Kyowa Hakko Kirin, Bristol-Myers Squibb, Ono Pharmaceutical, MSD K.K. Y. Hatanaka: Advisory Role: GeneticLab, Medicinal Cheistry Pharmaceutical Co.; Speakers' Bureau: Merck Sharp & Dohme, Chugai Pharma, Pfizer; Honoraria: Ono Pharmaceutical, AstraZeneca KK; Research fuding: Roche, Taiho Pharmaceutical, Eisai, Merck Sharp & Dohme. H. Isobe: Speakers' Bureau: Chugai Pharma, Bristol-Myers Squibb Japan, Pfizer. All other authors have declared no conflicts of interest.