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Journal of Clinical Oncology, Vol 23, No 30 (October 20), 2005: pp. 7746-7748 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.02.7755
Modulation of Epidermal Growth Factor Receptor–Positive Circulating Tumor Cells by Chemotherapy in Non–Small-Cell Lung Cancer PatientsCell Biology and Preclinical Models Unit, INT-Fondazione Pascale, Naples, Italy
Division of Medical Oncology, "S.G. Moscati" Hospital, Avellino, Italy To the Editor: We read with great interest the article by De Pas et al on the modulation of epidermal growth factor receptor (EGFR) expression by chemotherapy in patients with locally advanced non–small-cell lung cancer (NSCLC).1 In this study, the authors assessed the expression of EGFR protein by immunohistochemistry in mediastinal nodes and primary tumors of advanced NSCLC patients at diagnosis and after administration of chemotherapy. They found that none of 34 patients who had high levels of EGFR expression (2+/3+) at diagnosis experienced a change to zero EGFR immunoreactivity after therapy. Only one of seven patients with 1+ EGFR reactivity became negative. More interestingly, four of six patients who had no expression of EGFR at diagnosis became positive following administration of chemotherapy. The authors concluded that induction chemotherapy does not affect expression of EGFR in EGFR-positive NSCLC, whereas it might induce expression of the receptor in EGFR-negative tumors.
We have recently obtained results that might sustain the hypothesis of De Pas et al. We have previously established a reverse transcriptase-polymerase chain reaction (RT-PCR) Southern blot assay for the detection of circulating tumor cells (CTC) expressing EGFR mRNA in the peripheral blood of carcinoma patients.2 Briefly, total RNA was obtained from peripheral blood nucleated cells and was subsequently analyzed by nested PCR for expression of EGFR mRNA. By using this assay, EGFR-positive CTCs were found in 59% of peripheral blood samples obtained from 75 patients with either metastatic breast, colon, or lung carcinoma, and in approximately 10% of healthy volunteers (P < .001; More recently, we have analyzed the expression of EGFR mRNA in peripheral blood samples obtained from advanced NSCLC patients at diagnosis and during administration of chemotherapy. We selected for this analysis 17 patients for which at least three blood samples were available: one at diagnosis, one before the II cycle of therapy and one before the III cycle of therapy. Patients were treated with different chemotherapy regimens containing either gemcitabine, navelbine, and/or cis-platinum (Table 1). Consistently with previous findings, EGFR-positive CTCs were detected in approximately 50% untreated NSCLC patients (eight of 17; Table 1 and Fig 1). No correlation was found between presence or absence of EGFR-positive CTCs and either histologic type or response to therapy in this small group of patients. Of the eight patients positive at diagnosis, only two (25%) became negative by cycle III of therapy. In contrast, EGFR-positive CTC were detected by cycle III in six (66%) of nine patients with either adenocarcinoma or squamous carcinoma that were negative at diagnosis (Table 1 and Fig 1). Interestingly, this frequency of conversion from EGFR-negative to -positive status is identical to that observed by De Pas et al by analyzing the expression of EGFR in the tumor and in mediastinal nodes.
Results of clinical trials of anti-EGFR agents in NSCLC suggest that markers to select patients that are likely to respond to such drugs are definitely required.6 Recent reports have suggested that amplification or high polysomy of the EGFR gene, which is usually associated with increased levels of expression of EGFR mRNA and protein, correlates with response to anti-EGFR agents in NSCLC patients.7 However, determination of EGFR gene copy number by FISH or protein expression by immuohistochemistry requires a biopsy of the tumor tissue. Furthermore, the observation of De Pas et al that a change in EGFR status might occur following administration of chemotherapy implies that repeated measurements of EGFR expression in NSCLC patients are necessary. In this respect, detection of EGFR-positive CTCs might represent a novel approach to determining the EGFR status in NSCLC patients following chemotherapy. In fact, this is a simple technique that can be performed on peripheral blood samples, allowing patients to spare an additional biopsy. Furthermore, this approach might be more reliable as compared with immunohistochemical detection of EGFR, for which a standardized and reproducible assay has not yet been established. Of course, whether determination of EGFR status by detecting EGFR-positive CTCs might be useful to select patients that are likely to respond to EGFR targeting drugs needs to be addressed in specific clinical trials. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
Acknowledgment N.N. was supported in part by a grant from the Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.). REFERENCES
1. De Pas T, Pelosi G, de Braud F, et al: Modulation of epidermal growth factor receptor status by chemotherapy in patients with locally advanced non-small-cell lung cancer is rare. J Clin Oncol 22:4966-4970, 2004
2. De Luca A, Pignata S, Casamassimi A, et al: Detection of circulating tumor cells in carcinoma patients by a novel epidermal growth factor receptor reverse transcription-PCR assay. Clin Cancer Res 6:1439-1444, 2000
3. Castaldo G, Tomaiuolo R, Sanduzzi A, et al: Lung cancer metastatic cells detected in blood by reverse transcriptase-polymerase chain reaction and dot-blot analysis. J Clin Oncol 15:3388-3393, 1997
4. Castaldo G, Tomaiuolo R, Sanduzzi A, et al: Carcinoembryonic antigen mRNA analysis detects micrometastatic cells in blood from lung cancer patients. Eur Respir J 22:418-421, 2003
5. Sher YP, Shih JY, Yang PC, et al: Prognosis of non-small cell lung cancer patients by detecting circulating cancer cells in the peripheral blood with multiple marker genes. Clin Cancer Res 11:173-179, 2005 6. Di Maio M, Gridelli C, Normanno N, et al: Trying to compose the puzzle with all the pieces: Epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. J Cell Physiol. Published Online 13 May 2005
7. 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
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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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2 test). In particular, EGFR-positive CTCs were detected in 17 (57%) of 30 untreated stage IV NSCLC patients. In this respect, CTCs have been found in 40% to 80% of NSCLC patients by using different mRNA markers.
