Overexpression and gene amplification of EGFR, HER2, and HER3 in biliary tract carcinomas, and the possibility for therapy with the HER2-targeting antibody pertuzumab

Kawamoto, Toru; Ishige, Kazunori; Thomas, Melanie B.; Yamashita-Kashima, Yoriko; Shu, Sei; Ishikura, Nobuyuki; Ariizumi, Shun‐ichi; Yamamoto, Masakazu; Kurosaki, Kunihiko; Shoda, Junichi

doi:10.1007/s00535-014-0984-5

Cited by 34 publications

(27 citation statements)

References 53 publications

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“…When all studies were included (regardless of applying ISH for “selected” or “unselected” population), mean HER2 amplification rate was statistically significantly higher in patients with EH-BTCs compared to IHCCs (Table 4). Interestingly, the mean HER2 amplification rate was higher in the five studies [59, 68, 72, 73, 78] in which ISH test was performed in “selected” population when compared to the 12 studies in which ISH test was applied to “unselected population” only [17.9 % (95 % CI 0.1–35.4 %) vs. 57.6 % (95 % CI 16.2–99 %), p value 0.0072] [55, 56, 59, 63, 64, 66, 77, 80–83, 85] (Table 4). Nakazawa et al reported data from 221 patients, 71 of whom had FISH testing performed: meaningful differences in HER2 amplification rate were shown between “unselected” [15/71 (21 %)] and “selected” [15/19 (79 %)] populations [59] (Table 2).…”

Section: Resultsmentioning

confidence: 99%

“…Ten studies [55, 56, 59, 63, 64, 77, 80, 82, 83, 85] and five studies [59, 68, 72, 73, 78] had data for both HER2 expression and amplification in the “unselected” and “selected” population, respectively. While no statistically significant correlation was observed in studies with the “selected” population (five studies; Spearman rho = −0.9; p value 0.037), a better correlation (although not statistically significant) was shown in “unselected” patients (10 studies; Spearman rho 0.38; p value 0.2763) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…All four studies had a HQ HER3 expression assessment (Table 3). The pooled mean overall HER3 overexpression rate was 27.9 % (95 % CI 9.7–46.1 %) [51, 76, 81, 83]; only one study reported HER3 amplification rate (26.5 %) [83] (Table 2). …”

Section: Resultsmentioning

confidence: 99%

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HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?

Galdy

Lamarca

McNamara

et al. 2016

Cancer Metastasis Rev

145

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Human epidermal growth factor receptor 2 (HER2) overexpression and amplification have been reported as predictive markers for HER2-targeted therapy in breast and gastric cancer, whereas human epidermal growth factor receptor 3 (HER3) is emerging as a potential resistance factor. The aim of this study was to perform a systematic review and meta-analysis of the HER2 and HER3 overexpression and amplification in biliary tract cancers (BTCs). An electronic search of MEDLINE, American Society of Clinical Oncology (ASCO), European Society of Medical Oncology Congress (ESMO), and American Association for Cancer Research (AACR) was performed to identify studies reporting HER2 and/or HER3 membrane protein expression by immunohistochemistry (IHC) and/or gene amplification by in situ hybridization (ISH) in BTCs. Studies were classified as “high quality” (HQ) if IHC overexpression was defined as presence of moderate/strong staining or “low quality” (LQ) where “any” expression was considered positive. Of 440 studies screened, 40 met the inclusion criteria. Globally, HER2 expression rate was 26.5 % (95 % CI 18.9–34.1 %). When HQ studies were analyzed (n = 27 studies), extrahepatic BTCs showed a higher HER2 overexpression rate compared to intrahepatic cholangiocarcinoma: 19.9 % (95 % CI 12.8–27.1 %) vs. 4.8 % (95 % CI 0–14.5 %), respectively, p value 0.0049. HER2 amplification rate was higher in patients selected by HER2 overexpression compared to “unselected” patients: 57.6 % (95 % CI 16.2–99 %) vs. 17.9 % (95 % CI 0.1–35.4 %), respectively, p value 0.0072. HER3 overexpression (4/4 HQ studies) and amplification rates were 27.9 % (95 % CI 9.7–46.1 %) and 26.5 % (one study), respectively. Up to 20 % of extrahepatic BTCs appear to be HER2 overexpressed; of these, close to 60 % appear to be HER2 amplified, while HER3 is overexpressed or amplified in about 25 % of patients. Clinical relevance for targeted therapy should be tested in prospective clinical trials.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?

Galdy

Lamarca

McNamara

et al. 2016

Cancer Metastasis Rev

145

View full text Add to dashboard Cite

show abstract

“…However, we failed to identify reliable antibodies for HER3 and FGFR2, which are other frequently amplified RTKs in GCs. The amplification of these RTKs can be accessed using fluorescence in situ hybridization [22–25], which can be time-consuming and expensive. In this respect, we evaluated the clinicopathologic characteristics of RA-GCs for three RTKs, EGFR, HER, and MET, and sought to develop a screening algorithm for the detection of a subgroup enriched with RA-GCs.…”

Section: Discussionmentioning

confidence: 99%

Receptor tyrosine kinase amplified gastric cancer: Clinicopathologic characteristics and proposed screening algorithm

Park

Kim

et al. 2016

Oncotarget

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Although targeted therapy for receptor tyrosine kinases (RTKs) of advanced gastric cancers (AGCs) has been in the spotlight, guidelines for the identification of RTK-amplified gastric cancers (RA-GCs) have not been established. In this study, we investigate clinicopathologic characteristics of RA-GCs and propose a screening algorithm for their identification. We performed immunohistochemistry (IHC) for MLH1, MSH2, PMS2, MSH6, key RTKs (EGFR, HER2, MET), and p53, in situ hybridization for Epstein-Barr virus encoding RNA, and silver in situ hybridization (SISH) for EGFR, HER2, and MET using tissue microarrays of 993 AGCs. On IHC, 157 (15.8%) 61, (6.15%), and 85 (8.56%) out of 993 cases scored 2+ or 3+ for EGFR, HER2, and MET, respectively. On SISH, 31.2% (49/157), 80.3% (49/61), and 30.6% (26/85) of 2+ or 3+ cases on IHC showed amplification of the corresponding genes. Of the 993 cases, 104 were classified as RA-GCs. RA-GC status correlated with older age (P < 0.001), differentiated histology (P = 0.001), intestinal or mixed type by Lauren classification (P < 0.001), lymphovascular invasion (P = 0.026), and mutant-pattern of p53 (P < 0.001). The cases were divided into four subgroups using two classification systems, putative molecular classification and histologic-molecular classification, based on Lauren classification, IHC, and SISH results. The histologic-molecular classification showed higher sensitivity for identification of RA-GCs and predicted patient prognosis better than the putative molecular classification. In conclusion, RA-GCs show unique clinicopathologic features. The proposed algorithm based on histologic-molecular classification can be applied to select candidates for genetic examination and targeted therapy.

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“…Of the subset, 9.8 % had HER2 overexpression (IHC) with a 92 % concordance with fluorescence in situ hybridization [35]. Preclinical experiments suggest that targeting HER2 induces apoptosis and inhibition of subcutaneous biliary tract tumors [48]. To date, small studies with lapatinib in unselected patients with biliary tract cancers have been unsuccessful [20].…”

Section: Genomic Alterations In Gallbladder Cancermentioning

confidence: 99%

Genomics of gallbladder cancer: the case for biomarker-driven clinical trial design

Sicklick

Fanta

Shimabukuro

et al. 2016

Cancer Metastasis Rev

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Background and aims Gallbladder carcinoma is a rare, aggressive malignancy of the biliary tract associated with a poor prognosis. Despite the deployment of targeted therapies that have demonstrated marked survival benefits in many tumor types, traditional cytotoxic chemotherapy has remained the mainstay of treatment for unresectable and metastatic gall-bladder cancer. Methods Systematic review of ongoing and prior clinical studies shows a paucity of biomarker-driven therapeutic trials using targeted agents in gallbladder cancer. In fact, over the past 6 years, of the 38 therapeutic biliary tract protocols listed on clinicaltrials.gov, only 6 (21 %) utilized targeted therapies based upon tumor biomarkers or genomics. Now that we have entered the era of next-generation sequencing and precision medicine, we are beginning to identify common and specific genetic alterations in gallbladder carcinomas. Results A review of the literature reveals alterations in ARID1A, BRAF, CDKN2A/B, EGFR, ERBB2-4, HKN-RAS, PIK3CA, PBRM1, and TP53. Given the widespread use of tumor genomic profiling and the fact that most of the aforementioned alterations are pharmacologically tractable, these observations suggest the potential for new therapeutic strategies in this aggressive malignancy. Conclusions Taken together, further understanding of the genomic landscape of gallbladder cancer coupled with biomarker-driven clinical trials that match therapies to targets are urgently needed.

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Overexpression and gene amplification of EGFR, HER2, and HER3 in biliary tract carcinomas, and the possibility for therapy with the HER2-targeting antibody pertuzumab

Abstract: Pertuzumab exerts potent antitumor activity in BTC cells co-overexpressing HER2 and HER3. Pertuzumab provides a new therapeutic option against BTC.

Cited by 34 publications

References 53 publications

HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?

HER2/HER3 pathway in biliary tract malignancies; systematic review and meta-analysis: a potential therapeutic target?

Receptor tyrosine kinase amplified gastric cancer: Clinicopathologic characteristics and proposed screening algorithm

Genomics of gallbladder cancer: the case for biomarker-driven clinical trial design

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