KRAS mutation as a predictor of insufficient trastuzumab efficacy and poor prognosis in HER2-positive advanced gastric cancer

Shimozaki, Keitaro; Shinozaki, Eiji; Yamamoto, Norio; Imamura, Yu; Osumi, Hiroki; Nakayama, Izuma; Wakatsuki, Takeru; Ooki, Akira; Takahari, Daisuke; Ogura, Mariko; Chin, Keisho; Watanabe, Masayuki; Yamaguchi, Kensei

doi:10.1007/s00432-022-03966-7

Cited by 7 publications

(5 citation statements)

References 50 publications

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“…The most commonly mutated genes were TP53 (64%), followed by CDH1 (20%), ARID1A (18%), HMCN1 (15%), KMT2D (11%), and PIK3CA (11%). The results were coincident with previously reports that alterations in some genes, such as TP53 , 24 KRAS , 25 PIK3CA , ERBB2 , ERBB4 , and NF1 26 were commonly mutated and may be associated with drug resistance. Copy Number Variation analysis showed that the somatic CNV gain was the dominant type in Chinese GC patients and the top somatic CNV genes were MYC (20%), RAC1 (14%), GSTM1 (13%), MCL1 (13%), and CCNE1 (12%) (Figure 1A ).…”

Section: Resultssupporting

confidence: 91%

The genomic and immune landscapes of gastric cancer and their correlations with HER2 amplification and PD‐L1 expression

Jing,

Luo,

et al. 2023

Cancer Medicine

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BackgroundAnti‐PD1/PD‐L1 antibody plus human epidermal growth factor receptor 2 (HER2) antibody and chemotherapy have become the new first‐line therapy for HER2 overexpression‐positive advanced gastric cancers (GC), suggesting that HER2 and PD‐L1 play a vital role in guiding systemic treatment for patients with GC. This study aimed to depict the genomic and immune landscapes of Chinese patients with GC and investigate their correlations with HER2 amplification and PD‐L1 expression.Patients and MethodsNext‐generation targeted sequencing and PD‐L1 immunohistochemistry were performed on tumor samples from 735 patients with pathologically diagnosed GC. The genomic and immune landscapes and their correlations with HER2 amplification and PD‐L1 expression were analyzed.ResultsThe most commonly mutated genes in Chinese GC were TP53 (64%), CDH1 (20%), ARID1A (18%), HMCN1 (15%), KMT2D (11%), and PIK3CA (11%). Seventy‐six (10%) patients were HER2 amplification, and 291 (40%) had positive PD‐L1 expression. Classifying the total population based on HER2 amplification and PD‐L1 expression level, 735 patients were divided into four subgroups: HER2+/PD‐L1+ (4.5%), HER2+/PD‐L1− (5.9%), HER2−/PD‐L1+ (35.1%), and HER2−/PD‐L1− (54.5%). The HER2+/PD‐L1− and HER2+/PD‐L1+ subgroups exhibited dramatically higher rate of TP53 mutations, CCNE1 and VEGF amplifications. The HER2+/PD‐L1− subgroup also had a markedly higher rate of MYC amplification and KRAS mutations. The HER2−/PD‐L1+ subgroup had significantly higher rate of PIK3CA mutations. HER2+/PD‐L1− subgroup had the highest TMB level and HER2−/PD‐L1+ subgroup had the highest proportion of patients with microsatellite instability‐high than other subgroups. Furthermore, we observed that different HER2 amplification levels had distinct impacts on the correlations between PD‐L1 expression and therapeutic genomic alterations, but no impact on the prognosis.ConclusionThe combination of HER2 amplification and PD‐L1 expression in Chinese patients with GC could stratify the total populations into several subgroups with distinctive genomic and immune landscapes, which should be considered when making personalized treatment decisions.

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Section: Resultssupporting

confidence: 91%

The genomic and immune landscapes of gastric cancer and their correlations with HER2 amplification and PD‐L1 expression

Jing,

Luo,

et al. 2023

Cancer Medicine

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“…However, many patients do not respond or may acquire resistance following treatment with HER2 inhibitors [9,10]. The heterogeneous nature of stomach cancer, loss of HER2 expression, expression and mutation of other growth factor receptors, and the activation of alternative pathways or mutations in downstream cell signaling pathways genes such as KRAS or PTEN may be some of the factors contributing to no, or poor response to the treatment with HER2 inhibitors in patients with stomach cancer [12,[24][25][26].…”

Section: Discussionmentioning

confidence: 99%

The Combination of Afatinib With Dasatinib or Miransertib Results in Synergistic Growth Inhibition of Stomach Cancer Cells

Al-Janaby,

Nahi,

Seddon

et al. 2024

World J Oncol

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Background Of various human epidermal growth factor receptor (HER) inhibitors, only the anti-HER2 monoclonal antibody (mAb) Herceptin/trastuzumab and the antibody-drug conjugate trastuzumab deruxtecan (T-Dxd) has been approved for the treatment of patients with stomach cancer. However, the duration of response may be short in many patients, with tumor heterogeneity being one contributing factor. Methods We investigated the effect of various types of targeted agents on growth in vitro and migration of a panel of human stomach cancer cells (HSCCLs) and the impact of cell proliferation rate on the anti-tumor activities of these agents. We also investigated the association between the cell surface expression of the HER family members, hepatocyte growth factor receptor (c-Met), anaplastic lymphoma kinase (ALK)7 and cancer stem cell markers CD44 and CD133, and the response to the targeted agents. Results Of the 18 agents examined, the cyclin dependent kinase (CDK) 1/2/5/9 inhibitor dinaciclib was the most effective and inhibited the growth of all human HSCCLs at 50% inhibitory concentration (IC 50 ) values between 9 nM to 23 nM. Of various HER inhibitors, the irreversible pan-HER family inhibitors (e.g., afatinib) were more effective than the reversible dual epidermal growth factor receptor (EGFR)/HER2 tyrosine kinase inhibitor (TKI) lapatinib and the EGFR-specific TKI erlotinib in inhibiting the growth of HSCCLs. Of agents targeting different downstream cell signaling molecules, dasatinib targeting Ab1/Src/C-Kit, trametinib targeting MERK1/2 and miransertib targeting AKT1/2/3 inhibited growth of majority of HSCCLs, with the IC 50 values ranging from 2 nM to 7 µM. Many of these agents were more effective in inhibiting the growth of HSCCLs when they were proliferating at a slower rate. Treatment with neratinib, afatinib, dinaciclib, dasatinib, stattic, miransertib and paclitaxel significantly inhibited migration of stomach cancer cells. Interestingly, treatment with a combination of afatinib and dasatinib or afatinib and miransertib resulted in synergistic and additive growth inhibition of stomach cancer cells. Conclusions These results suggest that treatment with a combination of these agents may be of therapeutic value in stomach cancer and warrants further investigations.

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“…Regarding the treatment effect according to the investigated biomarkers, several preclinical works showed that dual HER2 blockade with trastuzumab plus pertuzumab or lapatinib is more effective than single-agent trastuzumab, especially in HER2 "hyper-amplified" models, whereas the presence of co-drivers such as MET, EGFR or KRAS amplifications is associated with cross-resistance to either single-agent or dual HER2 targeted strategies [14,[17][18][19][20][21].…”

Section: Discussionmentioning

confidence: 99%

HER2 Copy Number and Resistance Mechanisms in Patients with HER2-positive Advanced Gastric Cancer Receiving Initial Trastuzumab-based Therapy in JACOB Trial

Pietrantonio

Manca

Bellomo

et al. 2022

Clinical Cancer Research

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Purpose: In JACOB trial, pertuzumab added to trastuzumab-chemotherapy did not significantly improve survival of patients with HER2-positive metastatic gastric cancer, despite 3.3 months increase versus placebo. HER2 copy number variation (CNV) and AMNESIA panel encompassing primary resistance alterations (KRAS/PIK3CA/MET mutations, KRAS/EGFR/MET amplifications) may improve patients’ selection for HER2 inhibition. Experimental design: In a post-hoc analysis of JACOB on 327 samples successfully sequenced by NGS (Oncomine Focus DNA), HER2 CNV, HER2 expression by IHC and AMNESIA were correlated with ORR, PFS and OS by uni/multivariable models. Results: Median HER2 CNV was 4.7 (IQR 2.2-16.9). HER2 CNV-high vs low using the median as cut-off was associated with longer median PFS (10.5 vs 6.4 months; HR=0.48, 95%CI: 0.38-0.62; p<.001) and OS (20.3 vs 13.0 months; HR=0.54, 0.42-0.72; p<.001). Combining HER2 CNV and IHC improved discriminative ability, with better outcomes restricted to HER2-high/HER2 3+ subgroup. AMNESIA positivity was found in 51 (16%), with unadjusted HR=1.35 (0.98-1.86) for PFS; 1.43 (1.00-2.03) for OS. In multivariable models, only HER2 CNV status remained significant for PFS (p<.001)/OS (p=.004). Higher ORR was significantly associated with IHC 3+ [61% vs 34% in 2+; odds ratio (OR)=3.11 (1.89-5.17)] and HER2-high [59% vs 43% in HER2-low; OR=1.84 (1.16-2.94)], with highest OR in the top CNV quartile. These biomarkers were not associated with treatment effect of pertuzumab. Conclusions: HER2 CNV-high assessed by NGS may be associated with better ORR, PFS, OS in a JACOB subgroup, especially if combined with HER2 3+. The negative prognostic role of AMNESIA requires further clinical validation.

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KRAS mutation as a predictor of insufficient trastuzumab efficacy and poor prognosis in HER2-positive advanced gastric cancer

Cited by 7 publications

References 50 publications

The genomic and immune landscapes of gastric cancer and their correlations with HER2 amplification and PD‐L1 expression

The genomic and immune landscapes of gastric cancer and their correlations with HER2 amplification and PD‐L1 expression

The Combination of Afatinib With Dasatinib or Miransertib Results in Synergistic Growth Inhibition of Stomach Cancer Cells

HER2 Copy Number and Resistance Mechanisms in Patients with HER2-positive Advanced Gastric Cancer Receiving Initial Trastuzumab-based Therapy in JACOB Trial

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