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In Reply

Karmanos Cancer Institute, Wayne State University, Detroit, MI

Michelle R. Mahoney, Cristine Allmer

Mayo Clinic, Rochester, MN

James Thomas

University of Wisconsin Comprehensive Cancer Center, Madison, WI

Henry C. Pitot

Mayo Clinic, Rochester, MN

George Kim

Mayo Clinic Jacksonville, Jacksonville, FL

Ross C. Donehower

Bunting Blaustein Cancer Research Building, Baltimore, MD

Tom Fitch

Mayo Clinic Scottsdale, Scottsdale, AZ

Joel Picus

Washington University School of Medicine, St Louis, MO

Charles Erlichman

Mayo Clinic, Rochester, MN

We appreciate very much the comments of Leone et al with respect to further studying the epidermal growth factor receptor (EGFR) pathway in our patients with advanced biliary cancer who were treated with erlotinib.¹ The potential benefit of targeting of EGFR makes it a rational platform for combinations of targeted agents. Further improvements in the use of those agents will also be dependent on better selection of patients who are more likely to respond to such therapy.

Our study¹ included the analysis of EGFR expression by immunohistochemistry, because at the time of its inception the expression level was considered to be a potential predictor of response to erlotinib. It is now recognized that tumoral EGFR expression is unlikely to predict response to EGFR blockers, as was confirmed in larger studies of diseases such as lung and colorectal cancers. A review of published literature reveals very few reports of EGFR gene mutations in biliary cancers. Leone et al's data from 40 patients demonstrated mutations in the kinase domain in 15% of patients. One patient had one missense point mutation in exon 19, two in exon 20, and three in exon 21. Another study of 22 patients with biliary cancers revealed mutations in 13.6% of patients, all being deletions in exon 19. Some similarities in mutation patterns to patterns in non–small-cell lung cancer have also been shown.

Studies to define the gene mutations in patients with biliary cancers that are predictive of activation of the EGFR signaling pathway face several challenges. First, biliary cancers are rather heterogenous in their molecular signatures, probably a result of the varying carcinogenic processes within the different parts of the biliary tree. It is possible that those mutations may vary in the different locations within the biliary system, as was suggested by Gwak et al.² Second, testing the hypotheses relating the known and yet undiscovered EGFR gene mutations to clinical response to therapy will be limited by the relatively small number of patients within individual clinical trials who received or who are currently receiving EGFR tyrosine kinase (TK) inhibitors. This underscores the need for national and international collaborative efforts to ensure the pooling of tumor specimens and clinical data from different studies, as it would allow for more definitive statistical analyses to determine the correlations between specific gene mutations and therapy outcome. In addition, performing prospective trials of EGFR-TK inhibitors in patients with prespecified gene mutations will require major collaborations given the small number of eligible patients.

Considerations should also be given to define the role of other molecular events that relate to EGFR signaling, such as the expression of the ligands, HER-2 activity, downstream molecules (eg, BRAF), and other survival pathways as suggested by Leone et al.³ Analyses and quantifications focused on protein expression and phosphorylation status are challenged by the need for fresh tissue and the performance of assays for phosphorylated proteins.

AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The authors indicated no potential conflicts of interest.

REFERENCES

1. Philip PA, Mahoney MR, Allmer C, et al: Phase II study of erlotinib in patients with advanced biliary cancer. J Clin Oncol 24:3069-3074, 2006[Abstract/Free Full Text]

2. Gwak G-Y, Yoon J-H, Shin CM, et al: Detection of response-predicting mutations in the kinase domain of the epidermal growth factor receptor gene in cholangiocarcinoma. J Cancer Res Clin Oncol 131:649-652, 2005[CrossRef][Medline]

3. Leone F, Cavalloni G, Pignochino Y, et al: Somatic mutations of epidermal growth factor receptor in bile duct and gallbladder carcinoma. Clin Cancer Res 12:1680-1685, 2006[Abstract/Free Full Text]

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