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Journal of Clinical Oncology, Vol 25, No 9 (March 20), 2007: pp. 1145 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.3427
Targeting of Epidermal Growth Factor Receptor in Patients Affected by Biliary Tract CarcinomaDivision of Medical Oncology, Institute for Cancer Research and Treatment, Candiolo, Torino, Italy To the Editor: A study by Philip et al published in the July 1, 2006, issue of the Journal of Clinical Oncology1 shows the therapeutic benefit of epidermal growth factor receptor (EGFR) blockade with erlotinib in patients with biliary tract carcinoma. The results are interesting because in a cohort composed of 24 chemotherapy-refractory patients and 18 chemotherapy-naive patients, erlotinib as a single agent can achieve disease control in 50% of patients with a median duration of disease control of 5.1 months. However, the authors conclude that the activity of erlotinib is modest because only 17% of the patients achieved the primary end point of the study, which was progression-free survival at 24 weeks. Although gefitinib and erlotinib are active in unselected patients with non–small-cell lung cancer (NSCLC), clinical characteristics and tumor molecular markers associated with enhanced benefit have been identified. Notably, mutations in the tyrosine kinase domain of EGFR were subsequently found to be associated with sensitivity to small molecule inhibitors in NSCLC.2-4 Emerging data also suggest that increased EGFR copy number is a predictor of response to gefitinib therapy, regardless of EGFR kinase domain mutational status.5 Furthermore, in contrast to wild-type EGFR, the EGFR mutations are mutually exclusive of K-Ras mutations,6-8 which are found in biliary tract carcinomas with a particularly high incidence in some geographical areas.9-11 Mutations of the EGFR kinase domain have recently been described by our group in 15% of biliary tract carcinoma specimens.12 One of these mutations was a T790M substitution, which is known to correlate with an acquired resistance to small molecule inhibitor treatment in NSCLC. Whereas 28% of the EGFR-positive patients were progression free at 24 weeks, the study by Philip et al, based on the lack of correlation between EGFR expression level and treatment outcome in other tumor types, includes six undetermined and seven EGFR-negative patients. This patient number is too small to provide evidence of any correlation. Thus, it would be of interest to know if other molecular analyses, such as sequencing of EGFR tyrosine kinase or of downstream members of the signaling pathway, like K-Ras, B-Raf or PTEN, or EGFR gene amplification, have been planned in this group of biliary tract cancer patients treated with erlotinib. This finding will have extraordinary implications and will serve as a critical step toward individualized patient-specific treatment plans based on the molecular constitution of the tumor of each individual. 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 2. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004 3. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004 4. Pao W, Miller V, Zakowski M, et al: EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A 101:13306-13311, 2004 5. Cappuzzo F, Hirsch FR, Rossi E, et al: Epidermal growth factor receptor gene and protein and gefitinib sensitivity in non-small-cell lung cancer. J Natl Cancer Inst 97:643-655, 2005 6. Pao W, Wang TY, Riely GJ, et al: KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med 2:e17, 2005 [E-Pub: February 22, 2005][CrossRef][Medline] 7. Shigematsu H, Lin L, Takahashi T, et al: Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97:339-346, 2005 8. Soung YH, Lee JW, Kim SY, et al: Mutational analysis of EGFR and K-RAS genes in lung adenocarcinomas. Virchows Arch 446:483-488, 2005[CrossRef][Medline] 9. Tannapfel A, Benicke M, Katalinic A, et al: Frequency of p16 (INK4A) alterations and K-ras mutations in intrahepatic cholangiocarcinoma of the liver. Gut 47:721-727, 2000 10. Tada M, Omata M, Ohto M: High incidence of ras gene mutation in intrahepatic cholangiocarcinoma. Cancer 69:1115-1118, 1992[CrossRef][Medline] 11. Itoi T, Takei K, Shinohara Y, et al: K-ras codon 12 and p53 mutations in biopsy specimens and bile from biliary tract cancers. Pathol Int 49:30-37, 1999[CrossRef][Medline] 12. 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
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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