Genomic characterization between <scp>HER2</scp>‐positive and negative gastric cancer patients in a prospective trial

Hu, Qingjiang; Oki, Eiji; Yamada, Teppei; Kashiwada, Tomomi; Sonoda, Hideto; Kataoka, Masato; Kawanaka, Hirofumi; Tsuji, Yasushi; Makiyama, Akitaka; Nakashima, Yasuhiro; M, Ota; Kimura, Yasue; Yoshizumi, Tomoharu

doi:10.1002/cam4.6269

Cited by 3 publications

(1 citation statement)

References 37 publications

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“…Molecular mechanisms of resistance to trastuzumab therapy include AMP of receptor tyrosine kinases other than HER2 and genetic alterations within HER2 DPs, such as the PI3K-AKT-mTOR and MAPK pathways [ 31 – 34 ]. NGS-based tumour sequencing tests target multiple genes, facilitating concurrent evaluation of genetic alterations within these pathways [ 35 ]. In this study, patients who displayed CNAs in HER2 DPs exhibited a diminished response rate and poorer PFS to trastuzumab therapy.…”

Section: Discussionmentioning

confidence: 99%

Clinical application of targeted tumour sequencing tests for detecting ERBB2 amplification and optimizing anti-HER2 therapy in gastric cancer

Ichikawa,

Usui,

Aizawa

et al. 2024

BMC Cancer

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Background Evaluation of human epidermal growth factor receptor 2 (HER2) overexpression caused by erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification (AMP) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) is essential for treating unresectable metastatic gastric cancer (GC). A targeted tumour sequencing test enables comprehensive assessment of alterations in cancer-related genes, including ERBB2. This study aimed to evaluate the concordance between the targeted tumour sequencing test and IHC/FISH for detecting HER2-positive GC and to clarify the significance of ERBB2 AMP and concomitant genetic alterations in HER2 downstream pathways (DPs) in anti-HER2 therapy for unresectable metastatic GC patients. Methods ERBB2 copy number alteration (CNA) was examined via a targeted tumour sequencing test in 152 formalin-fixed paraffin-embedded (FFPE) GC tissues. ERBB2 CNA was compared to HER2 status evaluated by IHC/FISH in FFPE block sections, which were identical to those subjected to the targeted tumour sequencing test. Treatment outcomes of anti-HER2 therapy in 11 patients with unresectable metastatic GC was evaluated. Results ERBB2 AMP (≥ 2.5-fold change) was detected by the targeted tumour sequencing test in 15 patients (9.9%), and HER2 positivity (IHC 3 + or IHC 2+/FISH positive) was detected in 21 patients (13.8%). The overall percent agreement, positive percent agreement, negative percent agreement and Cohen’s kappa between ERBB2 CNA and HER2 status were 94.7%, 66.7%, 99.2% and 0.75, respectively. Progression-free survival for trastuzumab therapy in patients with ERBB2 AMP was significantly longer than that in patients with no ERBB2 AMP detected by the targeted tumour sequencing test (median 14 months vs. 4 months, P = 0.007). Treatment response to trastuzumab therapy was reduced in patients with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs. One patient with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs achieved a durable response to trastuzumab deruxtecan as fourth-line therapy. Conclusions A targeted tumour sequencing test is a reliable modality for identifying HER2-positive GC. ERBB2 AMP and concomitant genetic alterations detected through the targeted tumour sequencing test are potential indicators of treatment response to trastuzumab therapy. The targeted tumour sequencing test has emerged as a plausible candidate for companion diagnostics to determine indications for anti-HER2 therapy in the era of precision medicine for GC.

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Section: Discussionmentioning

confidence: 99%

Clinical application of targeted tumour sequencing tests for detecting ERBB2 amplification and optimizing anti-HER2 therapy in gastric cancer

Ichikawa,

Usui,

Aizawa

et al. 2024

BMC Cancer

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Assessing clinical pathological characteristics and gene expression patterns associated with hepatoid adenocarcinoma of the stomach

Ge,

Wang,

et al. 2024

Clin Transl Oncol

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Efficacy of immunotherapy in ARID1A-mutant solid tumors: a single-center retrospective study

Zhou,

Sun,

Song

et al. 2024

Discov Onc

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Background Immune checkpoint inhibitors (ICIs), especially those targeting programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1), have introduced a new treatment landscape for many types of tumors. However, they only achieve a limited therapeutic response. Hence, identifying patients who may benefit from ICIs is currently a challenge. Methods 47 tumor patients harboring ARID1A mutations were retrospectively studied. The genomic profiling data through next-generation sequencing (NGS) and relevant clinical information were collected and analyzed. Additionally, bioinformatics analysis of the expression of immune checkpoints and immune cell infiltration levels was conducted in ARID1A-mutant gastric cancer (GC). Results ARID1A mutations frequently co-occur with mutations in DNA damage repair (DDR)-associated genes. Among the 35 ARID1A-mutant patients who received immunotherapy, 27 were evaluable., with the objective response rate (ORR) was 48.15% (13/27), and the disease control rate (DCR) was 92.59% (25/27). Moreover, survival assays revealed that ARID1A-mutant patients had longer median overall survival (mOS) after immunotherapy. In ARID1A-mutated GC patients, receiving ICIs treatment indicated longer progressive-free survival (PFS). Additionally, the incidence of microsatellite instability-high (MSI-H), high tumor mutation burden (TMB-H) and Epstein‒Barr virus (EBV) infection was elevated. Bioinformatic analysis showed significant enrichment of immune response and T cell activation pathway within differentially expressed genes in ARID1A-mutant GC group. Finally, ARID1A mutations status was considered to be highly correlated with the level of tumor infiltrating lymphocytes (TILs) and high expression of immune checkpoints. Conclusions Patients with tumors harboring ARID1A mutations may achieve better clinical outcomes from immunotherapy, especially in GC. ARID1A mutations can lead to genomic instability and reshape the tumor immune microenvironment (TIME), which can be used as a biomarker for immunotherapy.

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Genomic characterization between HER2‐positive and negative gastric cancer patients in a prospective trial

Cited by 3 publications

References 37 publications

Clinical application of targeted tumour sequencing tests for detecting ERBB2 amplification and optimizing anti-HER2 therapy in gastric cancer

Clinical application of targeted tumour sequencing tests for detecting ERBB2 amplification and optimizing anti-HER2 therapy in gastric cancer

Assessing clinical pathological characteristics and gene expression patterns associated with hepatoid adenocarcinoma of the stomach

Efficacy of immunotherapy in ARID1A-mutant solid tumors: a single-center retrospective study

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