|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 25, No 36 (December 20), 2007: pp. 5836-5837 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.14.6258
Erlotinib in Pancreatic Cancer: Are Tumor Cells the (only) Target?Cell Biology and Preclinical Models Unit, Istituto Nazionale Tumori-Fondazione Pascale, Naples, Italy To the Editor: We read with great interest the article by Moore et al1 showing that the addition of erlotinib to gemcitabine produced a significant (although small) improvement of overall survival and progression-free survival in patients with advanced pancreatic cancer. Notably, to our knowledge, this is the only phase III trial of a target-based agent in pancreatic cancer that has shown survival benefit. However, the results of these findings open questions on the mechanism of action of erlotinib. Mutations of the K-ras oncogene are an early event in pancreatic carcinogenesis, and they are detected in up to 90% of pancreatic cancer patients at diagnosis.2 In agreement with these findings, molecular characterization of a subgroup of patients enrolled onto the erlotinib trial showed mutations of K-ras in 79% (92 of 117) of the patients.3 Previous studies in non–small-cell lung cancer have demonstrated that patients carrying K-ras mutations are resistant to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors.4,5 Similarly, mutations of K-ras have been associated with resistance to cetuximab in colorectal cancer patients.6,7 No significant correlations were found between K-ras mutations and outcome in the patients enrolled onto the erlotinib trial, although a trend in favor of erlotinib for the patients that carry the wild-type K-ras has been described.3 Nevertheless, the activity of an anti-EGFR agent in a tumor type with so high a frequency of K-ras mutations is definitely an unexpected phenomenon. The findings of the trial by Moore et al1 are even more surprising when one analyzes the hazard ratios in the different subgroups of patients. In particular, the anti-EGFR agent produced a similar advantage in EGFR-positive and EGFR-negative patients. Several studies failed to demonstrate any correlation between EGFR expression and activity of anti-EGFR agents.8 This phenomenon might be due in part to the low sensitivity of the immunohistochemistry techniques that are used routinely, and/or to the fixation and conservation of the tissues that might lead to difficulties in antigen detection. However, some difference between EGFR-negative and EGFR-positive patients are expected when treating a patient with an EGFR-targeting agent such as erlotinib. The data presented by Moore et al1 suggest that erlotinib is functioning through a specific anti-EGFR activity. In fact, a strong correlation was found between development of cutaneous rash and survival in erlotinib-treated pancreatic cancer patients. Therefore, the patients who might benefit from erlotinib treatment fall among the cohort in which the drug efficiently blocks the activation of the EGFR. The question that we put forth is whether the target of erlotinib is represented only by pancreatic cancer cells, given that these cells are expected to be resistant because of K-ras mutations, and patients benefit from erlotinib treatment even if their tumor cells do not express the EGFR. It has been demonstrated that tumor-associated endothelial cells express the EGFR.9-12 Expression of the EGFR in endothelial cells does not depend on the levels of the EGFR in cancer cells, but rather is correlated with the expression of EGFR ligands within the tumor.10 In this regard, it has been long established that pancreatic cancer expresses high levels of EGF-like peptides.13 Several studies have shown that treatment with anti-EGFR agents can induce apoptosis in endothelial cells of experimental tumors of different histologic origin, including pancreatic cancer.9,11,14,15 This effect might be indirect, in part due to the ability of anti-EGFR agents to reduce the levels of secretion of vascular endothelial growth factor (VEGF) in pancreatic cancer cells.9 However, evidence suggests that EGFR-targeting agents might also have a direct effect on endothelial cells. In fact, EGFR tyrosine kinase inhibitors have been shown to block the proliferation and the motility of endothelial cells in vitro.16,17 Furthermore, these agents were found to produce significant levels of apoptosis only in tumor-associated endothelial cells that express activated EGFR.15 The hypothesis of an antiangiogenic effect of erlotinib in pancreatic cancer is apparently in contrast with the negative findings of the phase III trial comparing the anti-VEGF antibody bevacizumab plus gemcitabine versus gemcitabine in pancreatic cancer patients.18 However, it has been shown that EGF plays an important role in endothelial cell proliferation, survival, and sprouting in conditions of limiting VEGF.17 In fact, in the presence of high levels of VEGF, EGF did not induce cell proliferation of endothelial cells, and anti-EGFR agents had no effect on endothelial cell sprouting.17 Taken together, these findings suggest that in selected patients, with low intratumoral levels of VEGF, blockade of EGFR in endothelial cells might result in a significant antiangiogenic effect and, therefore, in an antitumor activity even in tumors that do not express the EGFR. These considerations also represent the rationale for the use of combinations of anti-EGFRand anti-VEGF therapies that are currently being explored in pancreatic cancer. In conclusion, the EGFR is expressed in different nontransformed cell types of the neoplastic environment that are involved in tumor growth and progression, including endothelial cells. Studying the effects of anti-EGFR agents in the different components of the tumor microenvironment might improve our knowledge of the mechanism of action of these drugs. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. ACKNOWLEDGMENTS N. Normanno is supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC); A. De Luca is supported by a fellowship from AIRC. REFERENCES
1. Moore MJ, Goldstein D, Hamm J, et al: Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: A phase III trial of the National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol 25:1960-1966, 2007 2. Löhr M, Kloppel G, Maisonneuve P, et al: Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: A meta-analysis. Neoplasia 7:17-23, 2005[CrossRef][Medline] 3. Moore MJ, da Cunha Santos G, Kamel-Reid S, et al: The relationship of K-ras mutations and EGFR gene copy number to outcome in patients treated with Erlotinib on National Cancer Institute of Canada Clinical Trials Group trial study PA.3. J Clin Oncol 25:202s, 2007 (suppl; abstr 4521) 4. 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[CrossRef][Medline] 5. Massarelli E, Varella-Garcia M, Tang X, et al: KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res 13:2890-2896, 2007 6. Lièvre A, Bachet JB, Le Corre D, et al: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992-3995, 2006 7. Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230-3237, 2007 8. Normanno N, Bianco C, De Luca A, et al: Target-based agents against ErbB receptors and their ligands: A novel approach to cancer treatment. Endocr Relat Cancer 10:1-21, 2003[Abstract] 9. Bruns CJ, Solorzano CC, Harbison MT, et al: Blockade of the epidermal growth factor receptor signaling by a novel tyrosine kinase inhibitor leads to apoptosis of endothelial cells and therapy of human pancreatic carcinoma. Cancer Res 60:2926-2935, 2000 10. Baker CH, Kedar D, McCarty MF, et al: Blockade of epidermal growth factor receptor signaling on tumor cells and tumor-associated endothelial cells for therapy of human carcinomas. Am J Pathol 161:929-938, 2002 11. Weber KL, Doucet M, Price JE, et al: Blockade of epidermal growth factor receptor signaling leads to inhibition of renal cell carcinoma growth in the bone of nude mice. Cancer Res 63:2940-2947, 2003 12. Yokoi K, Sasaki T, Bucana CD, et al: Simultaneous inhibition of EGFR, VEGFR, and platelet-derived growth factor receptor signaling combined with gemcitabine produces therapy of human pancreatic carcinoma and prolongs survival in an orthotopic nude mouse model. Cancer Res 65:10371-10380, 2005 13. Salomon DS, Brandt R, Ciardiello F, et al: Epidermal growth factor-related peptides and their receptors in human malignancies. Crit Rev Oncol Hematol 19:183-232, 1995[Medline] 14. Kim SJ, Uehara H, Karashima T, et al: Blockade of epidermal growth factor receptor signaling in tumor cells and tumor-associated endothelial cells for therapy of androgen-independent human prostate cancer growing in the bone of nude mice. Clin Cancer Res 9:1200-1210, 2003 15. Baker CH, Pino MS, Fidler IJ: Phosphorylated epidermal growth factor receptor on tumor-associated endothelial cells in human renal cell carcinoma is a primary target for therapy by tyrosine kinase inhibitors. Neoplasia 8:470-476, 2006[CrossRef][Medline] 16. Hirata A, Ogawa S, Kometani T, et al: ZD1839 (Iressa) induces antiangiogenic effects through inhibition of epidermal growth factor receptor tyrosine kinase. Cancer Res 62:2554-2560, 2002 17. Sini P, Wyder L, Schnell C, et al: The antitumor and antiangiogenic activity of vascular endothelial growth factor receptor inhibition is potentiated by ErbB1 blockade. Clin Cancer Res 11:4521-4532, 2005 18. Kindler HL, Niedzwiecki D, Hollis D, et al: A double-blind, placebo-controlled, randomized phase III trial of gemcitabine (G) plus bevacizumab (B) versus gemcitabine plus placebo (P) in patients (pts) with advanced pancreatic cancer (PC): A preliminary analysis of Cancer and Leukemia Group B (CALGB). ASCO Meeting Abstracts 25:199s, 2007 (suppl; abstr 4508)
Related Article
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
