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Originally published as JCO Early Release 10.1200/JCO.2008.20.0105 on December 8 2008 © 2009 American Society of Clinical Oncology.
Can Epidermal Growth Factor Receptor–Fluorescent in Situ Hybridization Predict Clinical Benefit From Cetuximab Treatment in Patients With Non–Small-Cell Lung Cancer?
Department of Medical Oncology, Teikyo University School of Medicine, Tokyo, Japan To the Editor: We read with interest the article by Hirsch et al1 reporting that an increased epidermal growth factor receptor (EGFR) gene copy number as detected by fluorescent in situ hybridization (FISH) was associated with better outcomes in non–small-cell lung cancer (NSCLC) patients receiving chemotherapy with cetuximab in a randomized phase II trial (S0342). Although this study suggests the possibility that EGFR-FISH may be a useful test to predict the outcome of cetuximab treatment in NSCLC patients, we think that the findings of the study must be interpreted with caution. First, the S0342 trial was not designed to evaluate the benefit of addition of cetuximab to chemotherapy, but for comparing sequential versus concurrent cetuximab administration with carboplatin-paclitaxel chemotherapy. The possibility cannot be excluded that EGFR-FISH is only a predictive factor for chemotherapy or a prognostic factor independent of the treatment administered. In this study, the response rate, disease control rate, and progression-free survival were superior in the EGFR-FISH–positive subgroup as compared with that in the EGFR-FISH–negative subgroup, in both the sequential and concurrent arms. Because in the sequential arm, these outcomes were affected mostly by chemotherapy alone, the substantially consistent results between the two arms suggest that EGFR-FISH is a predictive factor for the efficacy of chemotherapy rather than that for the efficacy of cetuximab. The EGFR gene copy number may also have prognostic significance in advanced NSCLC patients treated with chemotherapy. In the biomarker analysis of Iressa NSCLC Trials Assessing Combination Therapy-1 and Iressa NSCLC Trials Assessing Combination Therapy-2, phase III trials comparing first-line chemotherapy with and without gefitinib, patients with an increased EGFR gene copy number tended to live longer, independent of the treatment employed.2 Only controlled studies including arms without cetuximab treatment would allow us to distinguish between the predictive and prognostic value of the EGFR gene copy number.
Second, the scoring systems for EGFR-FISH have neither been standardized nor validated yet. Although this study showed a positive result by adopting the scoring system established to identify NSCLC patients who showed better outcomes after gefitinib treatment,3 we cannot generalize the result. Controversy exists in relation to an increased copy number of chromosome 7 without EGFR gene amplification (high polysomy), which is included in the category of EGFR-FISH positive in this scoring system. The biologic significance of high polysomy has not yet been clearly elucidated, and the definition, In patients with metastatic colorectal cancer, predictive factors for the outcomes of cetuximab treatment have been investigated more intensively; however, the predictive value of EGFR protein expression and the EGFR gene copy number still remains controversial. Although cetuximab was approved only for EGFR-expressing colorectal cancer, some studies have suggested that cetuximab showed activity in patients without EGFR expression as determined by immunohistochemistry (IHC),4-6 or that there was no association between the level of EGFR expression as determined by IHC and the sensitivity to cetuximab.7-9 Studies on the association of the EGFR gene copy number with clinical benefit from cetuximab have also yielded inconsistent results.6,9-15 The techniques (FISH, chromogenic in situ hybridization, and quantitative polymerase chain reaction) and scoring systems differed among the studies. For example, Cappuzzo et al6 showed that EGFR-FISH predicted the clinical outcomes in colorectal cancer patients treated with cetuximab if a cutoff of 2.92 EGFR gene copies per cell was used, but not if the scoring system mentioned above3 was used. This situation is quite different from that of human epidermal growth factor receptor 2 (HER-2) evaluation in patients with breast cancer. A significant association has been shown between HER2 gene amplification and HER-2 protein expression; the definition of HER-2–positivity, HER-2 protein overexpression (3+) detected by IHC and/or HER2 gene amplification, has been widely accepted, and a clearer consensus exists for the suggestion that HER-2–targeted agents such as trastuzumab and lapatinib should be used based on the HER-2 status.16 Potential explanations for the differences are: the inaccuracy of currently available methods of EGFR evaluation, different biology between EGFR and HER-2, and different mechanisms of action between cetuximab and trastuzumab. In any event, EGFR evaluation is not yet sufficiently practical to serve as the basis of patient selection for cetuximab treatment. In colorectal cancer, various biomarkers other than EGFR have been investigated as predictors of the efficacy of cetuximab, and the mutational status of KRAS has received the most attention among these. Many studies have consistently shown that KRAS mutations predict cetuximab resistance and that only patients without KRAS mutations benefit from cetuximab treatment.12-15,17-22 Patient selection based on the KRAS mutational status seems to be reasonable. Loss of phosphatase and tensin homolog protein expression, a decreased PTEN gene copy number and PIK3CA mutations have also been suggested as predictors of resistance to cetuximab.14,15,23 High gene expression levels of the EGFR ligands epiregulin and amphiregulin,13 and immunoglobin G fragment c gamma receptor polymorphisms24 are also candidate predictive biomarkers. Recently, in a phase III trial conducted in patients with advanced NSCLC, the survival benefit of cetuximab in combination with first-line chemotherapy was shown.25 Cetuximab is certainly a promising drug for NSCLC, but overall, the clinical benefit is modest, if any, in unselected patients, and the cost is high. Therefore, one of the most important research questions that needs to be addressed is how can we select patients who might truly benefit from cetuximab. We think that the mutational status of KRAS is the most suitable candidate as a predictor of cetuximab efficacy and should be investigated in well-designed studies. EGFR-FISH is another expected candidate; however, standardization and validation are needed until it can be used in the clinical setting. Other predictive biomarkers should also need to be investigated actively from here on. 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: None Stock Ownership: None Honoraria: Toshimi Takano, Bristol-Myers Squibb Co, AstraZeneca Research Funding: None Expert Testimony: None Other Remuneration: None 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 fluorescent 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. Bell DW, Lynch TJ, Haserlat SM, et al: Epidermal growth factor receptor mutations and gene amplification in non–small-cell lung cancer: Molecular analysis of the IDEAL/INTACT gefitinib trials. J Clin Oncol 23:8081-8092, 2005 3. 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 4. 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 5. Hebbar M, Wacrenier A, Desauw C, et al: Lack of usefulness of epidermal growth factor receptor expression determination for cetuximab therapy in patients with colorectal cancer. Anticancer Drugs 17:855-857, 2006[CrossRef][Medline] 6. 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 7. Cunningham D, Humblet Y, Siena S, et al: Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351:337-345, 2004 8. Saltz LB, Meropol NJ, Loehrer PJ Sr, et al: Phase II trial of cetuximab in patients with refractory colorectal cancer that expresses the epidermal growth factor receptor. J Clin Oncol 22:1201-1208, 2004 9. Italiano A, Follana P, Caroli FX, et al: Cetuximab shows activity in colorectal cancer patients with tumors for which FISH analysis does not detect an increase in EGFR gene copy number. Ann Surg Oncol 15:649-654, 2008[CrossRef][Medline] 10. Moroni M, Veronese S, Benvenuti S, et al: Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: A cohort study. Lancet Oncol 6:279-286, 2005[CrossRef][Medline] 11. Lenz HJ, Van Cutsem E, Khambata-Ford S, et al: Multicenter phase II and translational study of cetuximab in metastatic colorectal carcinoma refractory to irinotecan, oxaliplatin, and fluoropyrimidines. J Clin Oncol 24:4914-4921, 2006 12. 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 13. Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of epiregulin and amphiregulin and KRAS mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230-3237, 2007 14. Frattini M, Saletti P, Romagnani E, et al: PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. Br J Cancer 97:1139-1145, 2007[CrossRef][Medline] 15. Perrone F, Lampis A, Orsenigo M, et al: PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients. Ann Oncol doi:10.1093/annonc/mdn541 [epub ahead of print on July 31, 2008] 16. Wolff AC, Hammond ME, Schwartz JN, et al: American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer. J Clin Oncol 25:118-145, 2007 17. Lièvre A, Bachet JP, Boige V, et al: KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol 26:374-379, 2008 18. Benvenuti S, Sartore-Bianchi A, Di Nicolantonio F, et al: Oncogenic activation of the RAS/RAF signaling pathway impairs the response of metastatic colorectal cancers to anti–epidermal growth factor receptor antibody therapies. Cancer Res 67:2643-2648, 2007 19. Di Fiore F, Blanchard F, Charbonnier F, et al: Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by cetuximab plus chemotherapy. Br J Cancer 96:1166-1169, 2007[CrossRef][Medline] 20. De Roock W, Piessevaux H, De Schutter J, et al: Kras wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 19:508-515, 2008 21. Cutsem EV, Lang I, D'haens G, et al: KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: The CRYSTAL experience. J Clin Oncol 26:5s, 2008 (suppl; abstr 2)[CrossRef] 22. Bokemeyer C, Bondarenko I, Hartmann JT, et al: KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: The OPUS experience. J Clin Oncol 26:178s, 2008 (suppl; abstr 4000) 23. Jhawer M, Goel S, Wilson AJ, et al: PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. Cancer Res 68:1953-1961, 2008 24. Zhang W, Gordon M, Schultheis AM, et al: FCGR2A and FCGR3A polymorphisms associated with clinical outcome of epidermal growth factor receptor expressing metastatic colorectal cancer patients treated with single-agent cetuximab. J Clin Oncol 25:3712-3718, 2007 25. 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 (NSCLC). J Clin Oncol 26:6s, 2008 (suppl; abstr 3)[CrossRef]
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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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four EGFR gene copies in 
