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Journal of Clinical Oncology, Vol 25, No 7 (March 1), 2007: pp. 911 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.09.8962
In ReplyClinical Gastrointestinal Cancer Program, Arizona Cancer Center and University of Arizona Cancer Center, Tucson, AZ
University of Cincinnati Medical Center, Cincinnati, OH We thank Dr Personeni for his remarks and thoughtful comments on our article.1 In regard to scoring methodology for epidermal growth factor receptor (EGFR) immunohistochemistry (IHC) in our study, we relied on the staining intensity and not the percentage of positive cells. Strong IHC positivity was present if the intensity of the staining resembled that seen in the positive control (esophageal squamous cell carcinoma cell line). While it is true that the tumors were considered to be positive if any cells were positive, all of the positive tumors in our series showed staining of more than 90% of the cells. We have not encountered tumors in which only a small fraction of the cells were positive. Thus, we felt that the intensity of staining was more helpful for differentiating between tumor samples than was the percentage of positive cells. Tumor samples were provided to us from multiple sites, and it is possible that the site-specific variability in terms of sample collection, storing, and processing affected the reliability of EGFR IHC assessments, an objective limitation of our study. This is even more important for phosphorylated proteins (pAKT) because of more rapid antigen degradation, as we have reported in a related article.2 In regard to EGFR gene amplification, EGFR probe count was compared with the centromeric probe count and a ratio more than 2 was considered to be positive for amplification. Up to 100 cells were counted for the FISH. It is correct in that this would not absolutely rule out the low level of amplification since one is dealing with nuclear slices as compared with whole nuclei. The role of histochemical and molecular markers in predicting the sensitivity to EGFR inhibitors remains controversial. For example, recent experience with cetuximab3 and panitumumab4 suggest that intensity/score and even presence of positive IHC are neither predictive nor necessary for clinical response. We acknowledge that the experience with lung cancer is different, where presence of EGFR mutations and/or amplification appears to be more predictive of clinical outcome in some lung cancer patients. Unfortunately, such a correlation has not been confirmed for patients with colorectal,5,6 head and neck,7 or pancreatic carcinomas.8 It is perplexing that despite the presence of histochemical/genetic predictive markers or the lack thereof, the response rate to EGFR inhibitors across all of these different tumor types is very similar (8% to 12%).This suggest a possibility of the existence of some alternative, but perhaps more important molecular predictors, as Dr Personeni implied. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: N/A Stock: N/A Honoraria: Tomislav Dragovich, Genentech Research Funds: N/A Testimony: N/A Other: N/A REFERENCES
1. Dragovich T, McCoy S, Fenoglio-Preiser CM, et al: Phase II trial of erlotinib in gastroesophageal junction and gastric adenocarcinomas: SWOG 0127. J Clin Oncol 24:4922-4927, 2006 2. Baker A, Dragovich T, Ihle N, et al: Stability of phosphoprotein as a biological marker of tumor signaling. Clin Cancer Res 11:4338-4340, 2005 3. Chung KY, Shia J, Kemeny NE, et al: Cetuximab shows activity in colorectal cancer patients with tumors that do not express the epidermal growth factor receptor by immunohistochemistry. J Clin Oncol 23:1803-1810, 2005 4. Hecht J, Mitchell E, Baranda J, et al: Panitumumab antitumor activity in patients with metastatic colorectal cancer expression low (1%-9%) or negative (< 1%) levels of epidermal growth factor receptor. J Clin Oncol 24:157s, 2006 (abstr 3547) 5. Lenz HJ, Van Custem E, Khambata-Ford S, et al: Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin and fluoropyrimidines. J Clin Oncol 24:4914-4921, 2006 6. Moroni M, Veronese S, Benvenuti S, et al: Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to anti EGFR treatment in colorectal cancer: A cohort study. Lancet Oncol 6:279-286, 2005[CrossRef][Medline] 7. Cohen EW: Role of epidermal growth factor receptor pathway-targeted therapy in patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck. J Clin Oncol 24:2659-2665, 2006 8. Immerwoll H, Hoem D, Kalaiarasy K, et al: Molecular analysis of the EGFR-RAS-RAF pathway in pancreatic ductal adeonacorcinomas: Lack of mutations in the BRAF and EGFR genes. Wirchows Arch 448:788-796, 2006[CrossRef] Related Correspondence
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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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