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Journal of Clinical Oncology, Vol 23, No 4 (February 1), 2005: pp. 921-922 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.700
Immunohistochemical Detection of HER1/HER2 Can Be Considered a Predictive Marker of Gefitinib Activity in Non-Small-Cell Lung Cancer?New Drugs Development Unit, European Institute of Oncology, Milan, Italy To the Editor:
We read with interest the article by M. Fukuoka et al1 in the June 15 issue of the Journal of Clinical Oncology and the related Editorial,2 in which D.H. Johnson and C.L. Arteaga focused on cross-talk pathways that could be involved in the therapeutic response of non-small-cell lung cancer (NSCLC) to gefitinib, underlining that epidermal growth factor receptor (EGFR) expression as determined by current methods is not a valid predictor of gefitinib activity. In our series of patients, we tried to demonstrate a relationship between EGFR and HER2 expression and response to gefitinib. Our hypothesis was that HER1/HER2 heterodimerization should have a more sustained proliferative activity in NSCLC cells predicting a better response to gefitinib. From March 2001 to February 2002, we evaluated 79 patients (51 men, 28 women) with pretreated metastatic NSCLC. Median age was 56 years (range, 31 to 77 years), and most of the tumors were classified as adenocarcinoma (65%). Patients were treated with gefitinib 250 mg/d within an expanded access program as second- or third-line therapy. Of 65 patients assessable for response, we observed five partial responses (8%; all of them adenocarcinoma) and 19 instances of stable disease (29%). Median duration of response was 7 months for responders, and median duration of stable disease was 4 months. Twenty-three cases were studied for immunohistochemical overexpression of EGFR and HER2 in relation to clinical activity of gefitinib: 11 patients who achieved a partial response or stable disease DAKO score for HER2 overexpression was +++ only in one patient (group B), and + in three patients (two for group A and one group B). According to these data, the incidence of HER2 overexpression is too rare to consider it relevant in predicting response to gefitinib. Although all responders were positive to EGFR in at least 20% of cells with a median staining intensity of 80%, a high expression of EGFR seemed not to be a predictive factor of response to gefitinib. Among the 23 patients studied, only five had less than 10% of cells expressing EGFR, and all of them were nonresponders. With such a small number of cases, no definitive conclusion can be drawn. At present, the significance of EGFR expression by currently available assays in predicting response to EGFR-targeted therapies is unclear. The lack of quantitative standardization of different assays for EGFR expression, the few available data on the role of receptor phosphorylation and of the transactivation of downstream or upstream signaling pathways (MAP-kinase), and the complexity of different cellular mechanisms able to increase EGFR signal activation aside from the level of receptor expression are gaps to be bridged to validate a target for gefitinib. In all future trials, patients assigned to gefitinib should be assessed for EGFR, phospho-EGFR, related MAP-kinases, and other intermediate biomarkers.3 Is activity rate of gefitinib disappointing? Medical oncologists do not have the luxury of being disappointed in the presence of exciting responses and symptom improvements, even if in a small number of patients. Accordingly, we should give priority to the definition of a predictive profile of response to gefitinib: which way to optimize a molecular targeted therapy if not through validation of the target? Authors' Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have 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. Honoraria: Fillippo de Braud, AstraZeneca. For a detailed description of these 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 of Information for Contributors found in the front of every issue. REFERENCES
1. Fukuoka M, Yano S, Giaccone G, et al: Multi-institutional randomized phase II trial of gefitinib for previously treated patients with advanced non-small-cell lung cancer. J Clin Oncol 21:2237-2246, 2003
2. Johnson D, Arteaga C: Gefitinib in recurrent non-small-cell lung cancer: An IDEAL trial? J Clin Oncol 21:2227-2229, 2003
3. Arteaga CL, Baselga J: Clinical trial design and end points for epidermal growth factor receptor-targeted therapies: Implications for drug development and practice. Clin Cancer Res 9:1579-1589, 2003
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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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4 months, all progressive on previous treatment (group A), and 12 patients with progressive disease (group B). EGFR was detected using the monoclonal antiboby 31G7, and HER2, using HercepTest (DAKO, Carpinteria, CA). Results were expressed as the percentage of membrane-labeled immunoreactive cells for EGFR and according to the DAKO system for HER2. Mean and median relative staining intensity for EGFR was higher in patients grouped as A (mean ± standard deviation, 69.54% ± 26.96%; median, 80% [range, 20 to 95]; P = .2412) compared with group B (mean ± standard deviation, 47.08% ± 43.40%; median, 37.5% [range, 0 to 95]; P = .9059). These relationships were not statistically significant. 
