Associations of HER2 Mutation With Immune-Related Features and Immunotherapy Outcomes in Solid Tumors

Abstract

BackgroundHER2 is one of the most extensively studied oncogenes in solid tumors. However, the association between tumor microenvironment (TME) and HER2 mutation remains elusive, and there are no specific therapies for HER2-mutated tumors. Immune checkpoint inhibitors (ICIs) have been approved for some tumor subgroups that lack targeted therapies, while their effects are still unclear in HER2-mutated tumors. We examined whether HER2 mutation impacts treatment outcomes of ICIs in solid tumors via its association with anticancer immunity.MethodsMulti-omics data of solid tumors from The Cancer Genome Atlas (TCGA), the Asian Cancer Research Group and the Affiliated Hospital of Jiangsu University were used to analyze the association between HER2 mutations and tumor features. Data of patients with multiple microsatellite-stable solid tumors, who were treated by ICIs including antibodies against programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), or cytotoxic T lymphocyte-associated protein 4 (CTLA-4) in eight studies, were collected to investigate the effects of HER2 mutations on immunotherapy outcomes.ResultsThe mutation rate of HER2 varied in solid tumors of TCGA, with an overall incidence of 3.13%, ranged from 0.39% to 12.2%. Concurrent HER2 mutations and amplifications were rare (0.26%). HER2 mutation was not associated with HER2 protein expression but was positively associated with microsatellite instability, tumor mutation and neoantigen burdens, infiltrating antitumor immune cells, and signal activities of antitumor immunity. Of 321 ICI-treated patients, 18 carried HER2 mutations (5.6%) and showed improved objective response rates compared with those with HER2 wild-type (44.4% vs. 25.7%, p=0.081), especially in the anti-PD-1/anti-PD-L1 subgroup (62.5% vs. 28.4%, p=0.04). Heterogeneity was observed among tumor types. Patients with HER2 mutations also had superior overall survival than those with HER2 wild-type (HR=0.47, 95%CI: 0.23-0.97, p=0.04), especially in the presence of co-mutations in ABCA1 (HR = 0.23, 95% CI: 0.07-0.73, p=0.013), CELSR1 (HR = 0.24, 95% CI: 0.08-0.77, p=0.016), LRP2 (HR = 0.24, 95% CI: 0.07-0.74, p=0.014), or PKHD1L1 (HR = 0.2, 95% CI: 0.05-0.8, p=0.023).ConclusionsHER2 mutations may improve the TME to favor immunotherapy. A prospective basket trial is needed to further investigate the impacts of HER2 mutations on immunotherapy outcomes in solid tumors.

Whether specific genetic feature predicted immunotherapy efficacy: A case report

“…The ErbB2 amplification subgroup displayed increased ErbB2 protein expression, a higher abundance of tumor-infiltrating regulatory T cells, and a lower abundance of activated NK cells and CD8+ T cells compared to the standard ErbB2 control, according to the analysis of the Cancer Genome Atlas pan-cancer cohort data. [ 15 ] Some preclinical and clinical investigations have revealed that Treg cells may impair individual immune surveillance against cancer, delay cancer patients from acquiring efficient antitumor immunity, and improve tumor growth. [ 16 ] PD-1 blockade promotes the recovery of malfunctioning PD-1+/CD8+ T cells and improves PD-1 + Treg cell–mediated immunosuppression, which might explain how immunotherapy benefits ErbB2 amplification patients.…”

Prognostic value of PD‑L1 expression and CD68 macrophages in tumor nest of patients with primary gastric cancer

“…Yamashita et al ( 26 ) showed that trastuzumab can upregulate PD-L1 in HER2-amplified GC cells by interacting with NK cells through the secretion of IFN-γ. Altogether, there is a complex regulatory network between HER2 and PD-L1 expression, which is not only affected by the tumor cells themselves, but also closely related to the TME ( 36 ). The relationship between molecular subtypes of GC and PD-L1, HER2 and combined HER2 and PD-L1 expression, requires further investigation.…”

An oncogene regulating chromatin favors response to immunotherapy

“…Data from other cohorts have been previously published and were acquired and preprocessed as described elsewhere. 19 , 20 Immune-associated indices, including tumor mutation burden (TMB), tumor neoantigen burden (TNB), microsatellite instability (MSI), and immune subtype, have been previously defined and determined. 19 , 20 , 23 …”

“… 19 , 20 Immune-associated indices, including tumor mutation burden (TMB), tumor neoantigen burden (TNB), microsatellite instability (MSI), and immune subtype, have been previously defined and determined. 19 , 20 , 23 …”