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Originally published as JCO Early Release 10.1200/JCO.2008.20.0873 on December 8 2008 © 2009 American Society of Clinical Oncology.
In Reply
University of Colorado Cancer Center, Aurora, CO
The University of Texas M. D. Anderson Cancer Center, Houston, TX
University of Colorado Cancer Center, Aurora, CO
Southwest Oncology Group, San Antonio, TX
University of Kansas Cancer Center, Kansas City, KS
University of Colorado Cancer Center, Aurora, CO
University of California Davis Cancer Center, Davis, CA We thank Takano et al for their constructive comments to our article about the predictive role of increased epidermal growth factor receptor (EGFR) gene copy number detected by fluorescent in situ hybridization (FISH) for cetuximab in combination with chemotherapy for patients with advanced non–small-cell lung cancer (NSCLC), based on the Southwest Oncology Group study S0342.1 We agree with that the study was not designed to specifically evaluate the benefit of adding cetuximab to chemotherapy. Instead, it was a randomized phase II "pick the winner" trial designed to test the feasibility of adding cetuximab to chemotherapy either concomitantly or sequentially. The clearly stated goal was to pick one of the regimens to compare with chemotherapy alone in a subsequent prospective phase III study. However, as all the patients received cetuximab, the study gave us the opportunity to compare the response and outcome in EGFR-FISH–positive and –negative patients. Takano et al mention the possibility that EGFR-FISH is only a predictive factor for chemotherapy or a prognostic factor independent of therapy. They conclude that because EGFR-FISH–positive patients had better outcome in both the concomitant and the sequential arm, outcome in the sequential arm was affected mostly by chemotherapy alone. Furthermore, they conclude that the consistent results between the two arms suggest that EGFR-FISH is a predictive factor for efficacy of chemotherapy rather than for cetuximab. As support for their suggestion they refer to the results from the Iressa NSCLC Trials Assessing Combination Therapy-1 and Iressa NSCLC Trials Assessing Combination Therapy-2 studies, in which the patients were randomly assigned to chemotherapy with or without gefitinib as first-line therapy, and in which patients with increased EGFR gene copy number (by quantitative real-time polymerase chain reaction [qPCR]) tended to live longer independent of therapy given.2,3 We agree with Takano et al that it is important to distinguish between the prognostic and the predictive association to outcome, and also to distinguish various methods of assessing gene copy number. To summarize, studies to date suggest that EGFR-FISH is neither prognostic for a good outcome in NSCLC (ie, after surgery alone), nor predictive of benefit from chemotherapy alone. We have previously reported that increased EGFR gene copy number by FISH is not associated with better outcome with chemotherapy alone.4 We have also previously reported that increased EGFR gene copy number detected by FISH is associated with a worse prognosis in surgically resected NSCLC patients, not treated with EGFR inhibitors.5 We propose that this finding is similar to the bad prognosis for patients with HER-2–expressing breast cancer after surgery, which is transformed into an improved outcome when HER-2–FISH–positive patients are treated with trastuzumab.6 Thus, we find it unlikely that our findings should be explained by a predictive association to chemotherapy alone and independent of cetuximab therapy. In the most recent update of results from the National Cancer Institute of Canada BR-21 study comparing erlotinib to placebo increased EGFR gene copy number by FISH was associated with poor prognosis without erlotinib therapy, and an improved outcome with erlotinib therapy.7 Takano et al say that the scoring system for EGFR-FISH has never been standardized nor validated, and because this is the first and only study, to our knowledge, showing an association between EGFR gene copy number and the outcome in NSCLC patients treated with cetuximab, the results cannot be generalized. We agree that results of EGFR gene copy number by FISH or by qPCR can produce divergent results. We also agree that our S0342 results are hypothesis-generating, as stated in our paper, and that they merit prospective validation. To this end, a large randomized phase III prospective validation study (S0819) will be undertaken of chemotherapy with or without cetuximab, statistically powered for EGFR-FISH. We also disagree that the classification of EGFR-FISH results has not been standardized. Although some aspects of the standardization process is still needed and is ongoing (ie, more data on the interlaboratorial reproducibility), several retrospective analyses from NSCLC patient cohorts treated with EGFR tyrosine kinase inhibitors have used this same classification and consistent results have been reported.8-11 Also a prospective validation study has been performed in the Oncobell study showing outcome benefit of gefitinib added to chemotherapy in the FISH-positive patients.12 Further, a recently activated intergroup study (MARVEL) is designed to validate the predictive value of EGFR-FISH in selecting NSCLC patients for second line therapy with erlotinib. This trial will be highly complementary to the S0819 cetuximab study described in this correspondence. Takano et al stress the fact that the EGFR-FISH classification of NSCLC patients is different from suggested EGFR-FISH classification in colorectal cancer (CRC) and the HER-2 classification in breast cancer. We are well aware of the differences in classification systems from one disease to another. In fact, our group at the University of Colorado Cancer Center (Aurora, CO) has been involved in the EGFR-FISH studies in CRC, and we have emphasized that the basis for the scoring system is different from one organ system to another.13 Furthermore, as noted, we have previously demonstrated that the predictive capability of increased EGFR gene copy number detected by FISH cannot be compared with the predictive capability of PCR detection in patients with NSCLC.14 Takano et al refer to the results from the recently presented randomized First-line in Lung Cancer with Erbitux study with chemotherapy with or without cetuximab and say that the "clinical benefit was modest, if any, in the unselected patients and the cost is high."15 We answer that EGFR-FISH provides a potential biomarker capable of preselecting a large patient subset who are most likely to benefit—this is the basis for S0819. Takano et al mention KRAS mutation as a possible better selection marker based on CRC studies.16 However, the role of KRAS mutation in CRC might be different from NSCLC. In NSCLC, KRAS mutation is related to tobacco-associated carcinogenesis, and is largely mutually exclusive from EGFR mutation.17 EGFR mutation is essentially nonexistent in CRC. Further, while the prevalence of KRAS mutation is 40% to 50% in CRC, it is around 20% in unselected NSCLC.16,17 The lower incidence of KRAS mutations in NSCLC might limit the clinical usefulness of this marker as a selection marker for EGFR inhibitors in NSCLC. KRAS mutation has also a significant prognostic association in NSCLC patients.18 Our own KRAS data from S0342, as well as from the large randomized trials with cetuximab and chemotherapy in NSCLC, will soon be presented and will shed a better light on the clinical usefulness of KRAS and other markers for patient selection for cetuximab therapy in NSCLC. The data will also suggest that CRC and NSCLC are quite different diseases in this regard. Lastly, we completely agree with Takano et al that standardization and validation of biomarkers is essential. The results of S0342 are hypothesis-generating; the hypothesis will be tested in a phase III setting in Southwest Oncology Group S0819. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: None Consultant or Advisory Role: Fred R. Hirsch, AstraZeneca (C), Lilly Oncology (C), Roche (C), Merck Serono (C), Pfizer (C); Roy S. Herbst, ImClone Systems Inc (C), Bristol-Myers Squibb Co (C); Karen Kelly, ImClone Systems Inc (C), Bristol-Myers Squibb Co (C); Paul A. Bunn, ImClone Systems Inc (C), Bristol-Myers Squibb Co (C), AstraZeneca (C), Eli Lilly & Co (C), OSI Pharmaceuticals (C), Genentech (C), Sanofi-aventis (C) Stock Ownership: None Honoraria: None Research Funding: Fred R. Hirsch, AstraZeneca, Genetech, OSI Pharmaceuticals; Roy S. Herbst, ImClone Systems Inc, Bristol-Myers Squibb Co; David R. Gandara, Bristol-Myers Squibb Co Expert Testimony: None Other Remuneration: Fred R. Hirsch, Wilbur A. Franklin, Paul A. Bunn Jr, and Marileila Varella-Garcia are co-inventors of a University of Colorado–owned patent "EGFR-FISH As a Predictive Marker for EGFR Inhibitors" (patent licensed to Abbott Diagnostics). NOTES published online ahead of print at www.jco.org on December 8, 2008 REFERENCES
1. Hirsch FR, Herbst RS, Olsen C, et al: Increased EGFR gene copy number detected by fluorescence in situ hybridization predicts outcome in non–small-cell lung cancer patients treated with cetuximab and chemotherapy. J Clin Oncol 26:3351-3357, 2008 2. Giaccone G, Herbst RS, Manegold C, et al: Gefitinib in combination with gemcitabine and cisplatin in advanced non–small-cell lung cancer: A phase III trial—INTACT 1. J Clin Oncol 22:777-784, 2004 3. Herbst RS, Giaccone G, Schiller JH, et al: Gefitinib in combination with paclitaxel and carboplatin in advanced non–small-cell lung cancer: A phase III trial–INTACT 2. J Clin Oncol 22:785-794, 2004 4. Dziadziuszko R, Holm B, Skov BG, et al: Epidermal growth factor receptor gene copy number and protein level are not associated with outcome of non–small-cell lung cancer patients treated with chemotherapy. Ann Oncol 18:447-452, 2007 5. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al: Epidermal growth factor receptor in non–small-cell lung carcinomas: Correlation between gene copy number and protein expression and impact on prognosis. J Clin Oncol 21:3798-3807, 2003 6. Press MF, Bernstein L, Thomas PA, et al: HER-2/neu gene amplification characterized by fluorescence in situ hybridization: Poor prognosis in node-negative breast carcinomas. J Clin Oncol 15:2894-2904, 1997[Abstract] 7. Zhu C-Q, Santos G, Ding K, et al: Role of KRAS and EGFR as biomarkers for response to erlotinib in National Cancer Institute of Canada Clinical Trials Group study BR-21. J Clin Oncol 26:4268-4275, 2008 8. Hirsch FR, Varella-Garcia M, Bunn PA Jr, et al: Molecular predictors of outcome with gefitinib in a phase III placebo-controlled study in advanced non–small-cell lung cancer. J Clin Oncol 24:5034-5042, 2006 9. Tsao MS, Sakurada A, Cutz JC, et al: Erlotinib in lung cancer: Molecular and clinical predictors of outcome. N Engl J Med 353:133-144, 2005 10. 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 11. Hirsch FR, Varella-Garcia M, McCoy J, et al: Increased epidermal growth factor receptor gene copy number detected by fluorescence in situ hybridization associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: A Southwest Oncology Group Study. J Clin Oncol 23:6838-6845, 2005 12. Cappuzzo F, Ligorio C, Janne PA, et al: Prospective study of gefitinib in epidermal growth factor receptor fluorescence in situ hybridization–positive/phospho-Akt–positive or never-smoker patients with advanced non–small-cell lung cancer: The ONCOBELL trial. J Clin Oncol 25:2248-2255, 2007 13. Cappuzzo F, Finocchiaro G, Rossi E, et al: EGFR FISH assay predicts for response to cetuximab in chemotherapy refractory colorectal cancer patients. Ann Oncol 19:717-723, 2008 14. Dziadziuszko R, Witta SE, Cappuzzo F, et al: Epidermal growth factor receptor messenger RNA expression, gene dosage, and gefitinib sensitivity in non–small-cell lung cancer. Clin Cancer Res 12:3078-3084, 2006 15. Pirker R, Szczesna A, von Pawel J, et al: FLEX: A randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non–small-cell lung cancer. J Clin Oncol 26:6s, 2008 (suppl; abstr 3)[CrossRef] 16. Lièvre A, Bachet JB, Le Corre D, et al: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992-3995, 2006 17. Shigematsu H, lin L, Takashi T, et al: Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancer. J Natl Cancer Inst 97:339-346, 2005 18. Slebos R, Kibbelar R, Dalesio O, et al: K-RAS oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med 323:561-565, 1990[Abstract]
Related Correspondence
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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