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Journal of Clinical Oncology, Vol 23, No 16 (June 1), 2005: pp. 3866-3867 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.233
In Reply:Department of Experimental Oncology, National Cancer Institute, Fondazione Pascale, Via Mariano Semola, Naples, Italy We read with great interest the comments by Kanazawa et al to our correspondence. In fact, their observations raise important questions on the mechanisms involved in the antitumor activity of gefitinib. The authors reported that treatment with gefitinib produced an increase in plasma concentrations of soluble markers (P-selectin and E-selectin) that are associated with activation of platelets. Since platelets and platelet-precursors do not express the epidermal growth factor receptor (EGFR), this observation clearly raises the question of whether the activity of gefitinib might be mediated by non–EGFR-related effects. On the other hand, Kanazawa et al suggested that the antitumor activity of gefitinib is not due to its ability to reduce the proliferative activity of cancer cells, but rather to the blockade of angiogenesis and to the activation of an immune response through activation of platelets and release of regulated on activation, normal T cells expressed and secreted (RANTES). We agree with Kanazawa et al on one fundamental aspect: we all are looking at the characteristics of the tumor cells in order to find out markers of response to gefitinib and, more generally, to anti-EGFR agents. However, the EGFR is expressed in all cell types with the exception of differentiated hematologic cells.1 Since the growth of cancer cells depends on their interactions with the surrounding tissues, it is conceivable that any effect of anti-EGFR agents on nontumor cells within or close to the tumor mass (endothelial cells, stromal cells, etc.) might have an important role in determining the response to these agents. For example, recently we have found that gefitinib affects the proliferation and the production of selected cytokines in bone marrow stromal cells, which have an important role in the pathogenesis of bone metastasis.2 Starting from these observations, we believe that there are no formal proofs of non–EGFR-related activities of gefitinib. We cannot comment in detail on the data reported by Kanazawa et al on activation of platelets, since they have not been published yet. However, activation of platelets in patients receiving gefitinib might represent a secondary event, due to necrosis of either tumor cells or endothelial cells. In this regard, Kanazawa et al have hypothesized an important role of platelet-derived RANTES in inducing an immune response to tumor cells. Secretion of RANTES has been also demonstrated to occur in non–small-cell lung cancer (NSCLC) cells and in human lung fibroblasts following stimulation with appropriate cytokines.3,4 Therefore, an immune response to tumor cells could be turned on by RANTES produced by different sources. In particular, the effects of gefitinib on the ability of both lung cancer cells and lung fibroblasts to produce RANTES have not been assessed yet. Finally, we do not agree with the hypothesis of the authors on the mechanisms of action of gefitinib that does not take in account the direct effect of this drug on tumor cells. In fact, striking evidence suggests that the EGFR and its ligands are involved in the autonomous growth of cancer cells.1,5 Several in vitro and in vivo studies have demonstrated that gefitinib is able to block the growth of cancer cells.5 Therefore, we believe that the antitumor activity of gefitinib is due, at least in part, to its ability to affect tumor cell proliferation and survival. In this respect, cancer cells' sensitivity and resistance to this agent is clearly related to the presence of molecular alterations that have been shown to render tumor cell growth dependent or independent on EGFR signaling.5-8 In conclusion, several different mechanisms of action are likely be involved in the antitumor activity of anti-EGFR agents, including effects on nontumor cell types. This observation makes even more difficult the identification of markers to predict the probability of cancer patients to respond to gefitinib. 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. Other Remuneration: Nicola Normanno, 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. 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] 2. Normanno N, De Luca A, Aldinucci D, et al: Expression and functional role of the epidermal growth factor receptor and its ligands in human bone marrow stromal cells. Proc Am Assoc Cancer Res 43:783, 2002 (abstr 3882)
3. Moran CJ, Arenberg DA, Huang C-C, et al: RANTES expression is a predictor of survival in stage I lung adenocarcinoma. Clin Cancer Res 8:3803-3812, 2002 4. Koyama S, Sato E, Masubuchi T, et al: Human lung fibroblasts release chemokinetic activity for monocytes constitutively. Am J Physiol 275:L223-L230, 1998 5. 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 10:1-22, 2003[Abstract]
6. Lynch TJ, Bell DW, Sordella R, et al: Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 350:2129-2139, 2004
7. Paez JG, Janne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004
8. Janmaat ML, Kruyt FAE, Rodriguez JA, et al: Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: Limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. Clin Cancer Res 9:2316-2326, 2003
Related Correspondence
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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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