EGFR and HER2 expression in advanced biliary tract cancer

Harder, Jan; Waiz, O.; Otto, Florian; Geißler, Michael; Olschewski, Manfred; Weinhold, Brigitte; Blum, Hubert E.; Schmitt‐Graeff, Annette; Opitz, Oliver G.

doi:10.3748/wjg.15.4511

Cited by 103 publications

(80 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Given the relatively infrequency of EGFR mutations/amplifications, clinical trials of EGFR inhibitor therapy in unselected patients have yielded low objective response rates [16–19], while no trials have been performed with EGFR genomic alterations as a biomarker for patient selection. High ERBB2 amplifications rates are consistent with prior reports of HER2 overexpression in biliary cancers [35, 44–47]. One study of HER2 expression/amplification in 37,992 patients included 194 patients with GBCA.…”

Section: Genomic Alterations In Gallbladder Cancersupporting

confidence: 83%

“…HER family genes include EGFR (i.e., epidermal growth factor receptor or HER1 ), which is mutated altered in about 3.9 % of GBCA [34], but overexpressed in about 38.5 % of cases [44]; ERBB2 and ERBB3 are altered in about 10–16 and 12 % of GBCA, respectively [34, 35]. In fact, in one study of 57 patients, ERBB signaling (including EGFR, ERBB2, ERBB3, ERBB4 , and their downstream targets, such as NRG1 ) was mutated in 36.8 % of tumors [34].…”

Section: Genomic Alterations In Gallbladder Cancermentioning

confidence: 99%

See 1 more Smart Citation

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

Sicklick

Fanta

Shimabukuro

et al. 2016

Cancer Metastasis Rev

View full text Add to dashboard Cite

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.

show abstract

Section: Genomic Alterations In Gallbladder Cancersupporting

confidence: 83%

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

View full text Add to dashboard Cite

show abstract

“…Finally, ZnPC distributes to multiple intracellular loci after uptake of the liposomes [17, 18], from which different cell death pathways but also cell survival pathways are activated [2]. In preliminary experiments it was discovered that epidermal growth factor receptor (EGFR), a receptor overexpressed in a multitude of cancers [19] including perihilar cholangiocarcinoma [20, 21], was afflicted by PDT with ZnPC-liposomes. EGFR constitutes an important druggable target in cancer therapy, as evidenced by the approval status of the monoclonal antibodies cetuximab and panitumumab, as well as the kinase inhibitors gefitinib and erlotinib [22].…”

Section: Introductionmentioning

confidence: 99%

Multi-OMIC profiling of survival and metabolic signaling networks in cells subjected to photodynamic therapy

Weijer

Clavier

Zaal

et al. 2016

Cell. Mol. Life Sci.

View full text Add to dashboard Cite

Photodynamic therapy (PDT) is an established palliative treatment for perihilar cholangiocarcinoma that is clinically promising. However, tumors tend to regrow after PDT, which may result from the PDT-induced activation of survival pathways in sublethally afflicted tumor cells. In this study, tumor-comprising cells (i.e., vascular endothelial cells, macrophages, perihilar cholangiocarcinoma cells, and EGFR-overexpressing epidermoid cancer cells) were treated with the photosensitizer zinc phthalocyanine that was encapsulated in cationic liposomes (ZPCLs). The post-PDT survival pathways and metabolism were studied following sublethal (LC50) and supralethal (LC90) PDT. Sublethal PDT induced survival signaling in perihilar cholangiocarcinoma (SK-ChA-1) cells via mainly HIF-1-, NF-кB-, AP-1-, and heat shock factor (HSF)-mediated pathways. In contrast, supralethal PDT damage was associated with a dampened survival response. PDT-subjected SK-ChA-1 cells downregulated proteins associated with EGFR signaling, particularly at LC90. PDT also affected various components of glycolysis and the tricarboxylic acid cycle as well as metabolites involved in redox signaling. In conclusion, sublethal PDT activates multiple pathways in tumor-associated cell types that transcriptionally regulate cell survival, proliferation, energy metabolism, detoxification, inflammation/angiogenesis, and metastasis. Accordingly, tumor cells sublethally afflicted by PDT are a major therapeutic culprit. Our multi-omic analysis further unveiled multiple druggable targets for pharmacological co-intervention.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-016-2401-0) contains supplementary material, which is available to authorized users.

show abstract

“…Retrospective studies report HER2/neu overexpression ranging from 5 to 76% in cholangiocarcinoma [4,16,17,18], but our prospective correlative analysis reveals no overexpression of HER2/neu. The discrepancy in the reported rates could possibly be attributed to different phenotypic subtypes.…”

Section: Discussionmentioning

confidence: 92%

HER2/neu May Not Be an Interesting Target in Biliary Cancers: Results of an Early Phase II Study with Lapatinib

et al. 2012

View full text Add to dashboard Cite

Purpose: Biliary cancers (BCs) respond poorly to chemotherapy. Lapatinib is a dual inhibitor of epidermal growth factor receptor (EGFR) and HER2/neu, both implicated in cholangiocarcinogenesis. This trial was designed to determine the safety and efficacy of lapatinib in BC. Methods: A Fleming phase II design with a single stage of 25 patients was used. The dose of lapatinib was 1,500 mg/day administered orally in 28-day cycles. Tumor and blood specimens were analyzed for expression of HER2/neu and EGFR.Results:Nine patients with BC enrolled in this study. The study was terminated early because of futility. The most common toxicities were nausea and fatigue (78%) and diarrhea (67%). No responses were observed. Of 8 evaluable patients, 4 (50%) had stable disease. Median progression-free survival was 2.6 months (95% CI 1.6–4.4) and median overall survival was 5.1 months (95% CI 2.0–16.5). No somatic mutations in EGFR (exons 18–21) or HER2/neu were found. We did not find evidence of HER2 overexpression. Conclusions:Lapatinib is well tolerated but failed to show activity as a single agent in treating patients with BC. Despite the small patient population, our study is consistent with previous findings, suggesting that targeting HER2/neu does not appear to be an effective therapy for BC.

show abstract

EGFR and HER2 expression in advanced biliary tract cancer

Abstract: Our data suggest that routine testing and therapeutic targeting of HER2 does not seem to be useful in patients with BTC, while targeting EGFR may be promising.

Cited by 103 publications

References 25 publications

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

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

Multi-OMIC profiling of survival and metabolic signaling networks in cells subjected to photodynamic therapy

HER2/neu May Not Be an Interesting Target in Biliary Cancers: Results of an Early Phase II Study with Lapatinib

Contact Info

Product

Resources

About