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Journal of Clinical Oncology, Vol 23, No 25 (September 1), 2005: pp. 6274-6275 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.01.9174
Target-Treatment and Patients' Selection: Can We Still Neglect the Timing of Tissue Collection?Departments of Medical Oncology, Pathology, and Thoracic Surgery, European Institute of Oncology, Milan, Italy To the Editor: We read with interest the report by Chung et al1 that explores the potential role of cetuximab in epidermal growth factor receptor (EGFR) –negative patients with advanced colorectal cancer. The authors identified patients treated with cetuximab-based therapy who had experienced failure with a prior irinotecan-based regimen and who had a pathology report indicating an EGFR-negative tumor by immunohistochemistry (IHC). In 16 patients, six major/minor objective responses were seen. According to these data, they conclude that "...the exclusion of patients for cetuximab therapy on the basis of currently available EGFR IHC does not seem warranted." We believe that this study is not adequate to support the evidence of cetuximab activity in IHC-determined EGFR-negative tumors. We are concerned that the EGFR status assigned to each patient in the analysis does not correspond to the real EGFR status of the tumor at the time of cetuximab-based treatment. All patients received at least two different chemotherapy regimens before cetuximab. The authors do not specify whether the tissues used for EGFR evaluation were collected before or after chemotherapy administration. Four specimens were from primary tumor, with a testing-time interval of at least 14 months, and one specimen was from liver metastases with a testing-time interval of 37 months. According to these data, we suppose that at least five of the six responders received chemotherapy after the tissue collection. In our experience,2 systemic chemotherapy can induce EGFR expression in EGFR-negative tumors. We observed a switch from an EGFR-score of 0 to 2+/3+ from the time of diagnosis in four of six patients with NSCLC stage IIIa/b pN2/3 who underwent surgical resection after induction chemotherapy. According to these observations, we raise the hypothesis that patients responding to cetuximab-based treatment in the Chung et al report could have become EGFR positive before receiving cetuximab. Furthermore, as discussed by the authors, the site of tissue collection could also be an important issue contributing to a misleading interpretation of results. EGFR status was evaluated on the primary tumor in four of the six responders, and the authors assumed the methacronous metastases to be EGFR negative as well. This assumption does not fit with the data by Scartozzi et al,3 who showed that 15% of EGFR-negative colorectal tumors regained EGFR expression in metastases. The activity of an antibody as a target agent is unexpected in the absence of the target antigen. Our major concern about EGFR status assessment in this report is not only related to the limits of IHC, but most of all, to the timing and site of tissue collection. In clinical practice and in prospective studies, a major effort should be done to perform a postchemotherapy metastases rebiopsy to asses EGFR expression. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. 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
2. De Pas T, Pelosi G, de Braud F, et al: Modulation of epidermal growth factor receptor (EGFR) status by chemotherapy in patients with locally advanced non small cell lung cancer is rare. J Clin Oncol 22:4966-4970, 2004
3. Scartozzi M, Bearzi I, Berardi R, et al: Epidermal growth factor receptor (EGFR) status in primary colorectal tumors does not correlate with EGFR expression in related metastatic sites: implications for treatment with EGFR-targeted monoclonal antibodies. J Clin Oncol 22:4772-4778, 2004
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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