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Originally published as JCO Early Release 10.1200/JCO.2005.97.008 on September 6 2005 © 2005 American Society of Clinical Oncology.
Selecting Patients for Epidermal Growth Factor Receptor Inhibitor Treatment: A FISH Story or a Tale of Mutations?Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA The two articles that appear in this issue of the Journal of Clinical Oncology provide additional information about the role of the mutated epidermal growth factor receptor (EGFR) and gene copy number of EGFR in the response, time to progression, and survival of patients with non–small-cell lung cancer treated with gefitinib.1,2 The article by Takano et al1 includes information on 66 patients with non–small-cell lung cancer (NSCLC) from Japan whose tumors underwent sequencing of exons 18 to 24 of EGFR and determination of EGFR gene copy number by quantitative, real-time polymerase chain reaction (PCR). The article by Hirsch et al2 extends these observations on EGFR copy number assessed by fluorescence in situ hybridization (FISH) and its relationship to response, time to progression, and survival to an additional subset of 81 patients with bronchioloalveolar carcinoma (BAC). The article by Hirsch et al2 reinforces the role of gene copy number assessed by FISH in assessing outcome following treatment with gefitinib, while the article by Takano et al1 provides evidence that the presence of mutations of EGFR—rather than copy number—is more important in determining outcome with gefitinib therapy. Although both of these articles used gefitinib as the EGFR tyrosine kinase inhibitor (EGFR-TKI), some of this Editorial will include some observations with the other EGFR-TKI commonly used for patients with NSCLC, erlotinib. The research community is appropriately left to wonder if EGFR mutations, EGFR copy number, EGFR immunohistochemistry or a combination of these tests should be used to help predict which patients are most likely to respond to gefitinib therapy, and which tests should be done to help identify the appropriate candidates for gefitinib therapy. It is important to point out that there are different end points for successful treatment, with a minority of patients demonstrating a partial response to treatment with gefitinib and erlotinib and a greater proportion with prolonged stable disease that ultimately contribute to a survival benefit. In addition to the two articles in this issue of the Journal of Clinical Oncology, there are two other manuscripts on EGFR mutations in patients from Asia and two manuscripts by the group from the University of Colorado that are particularly pertinent to determining whether this is a FISH story or a tale of mutations, or both.3-6 The data on somatic mutations of EGFR in patients with NSCLC in the article by Takano et al are consistent with that of the two other articles that have appeared in 2005.1,3,4 These studies have been limited to patients from Japan and Korea, where the somatic mutations of EGFR are detected approximately three times more often than in the United States and Europe. The design of the three studies was similar. The patients treated with gefitinib were retrospectively identified, their tumor retrieved from the tumor banks from a previous resection or biopsy, and some or all of exons 18 to 24 of EGFR underwent sequencing of the DNA extracted from the tumor blocks.1,3,4 The differences in response rates, time to progression, and survival were consistent in those with and without EGFR mutations and were highly statistically significant (P = .0053 to <0.0001, respectively; Table 1). The study by Takano et al1 also confirmed the presence of an increased EGFR mutation frequency in specific subgroups of patients, namely in nonsmokers and in those whose tumors have BAC features.7,8 In addition, all of the mutations described by Takano et al1 (exon 19 deletions, L858R and G719S/C) have been previously identified in patients with dramatic clinical responses when treated with gefitinib.9,10 Three additional mutations were detected (L703V, E709K, and S768I), but all occurred in concert with one of the mutations described above, and thus the independent contribution of these three mutations to gefitinib sensitivity remains to be determined.
Dr Hirsch and colleagues have provided data on the impact of EGFR copy number assessed by FISH on a subset of 81 patients from a trial of 136 patients with BAC treated with gefitinib on a Southwest Oncology Group trial.2 This study showed that patients with EGFR FISH-positive tumors have two-fold increases in their partial response rate, median progression-free survival, and overall survival than those with FISH-negative tumors. Takano et al1 also provide information on the EGFR copy number by quantitative PCR rather than FISH as done by the Colorado group. Patients with NSCLC and more than three copies of EGFR are four times more likely to have a partial response and a doubling in the time to progression, but no more significant difference in survival than that seen in those with fewer than three copies of EGFR. Hirsch et al2 did not find a correlation between increased EGFR copy number and any clinical variable typically seen in patients with an increased chance of response to gefitinib, but their patient population was restricted to patients with BAC. Patients with BAC already share clinical characteristics with patients likely to respond to treatment with gefitinib and erlotinib, including adenocarcinoma histology, female sex, and reduced frequency of smoking in patients with BAC compared with other types of NSCLC—characteristics associated with response to EGFR-TKI. Takano et al1 did not specifically report the clinical characteristics of patients with increased EGFR copy number. It is important to keep in mind the two different end points that are reported in these manuscripts: response and survival. A minority of patients will have a partial response to EGFR-TKI treatment, while a greater proportion of patients with NSCLC likely benefit with prolonged stable disease measured by time to progression, which contributes to a survival benefit. The original observation of somatic mutations of EGFR linked them to the dramatic clinical responses to gefitinib treatment in patients with NSCLC.9,10 Further research has shown that although most patients with dramatic responses have somatic mutations of EGFR, not all NSCLC patients with an EGFR mutation respond to gefitinib and erlotinib therapy. In addition, there are NSCLC patients with stable or progressive disease with EGFR mutations, as well as examples of secondary resistance in patients with NSCLC who either have or have not been treated with gefitinib and erlotinib.11-13 Nonetheless, investigators have typically seen a significant difference in outcome as assessed by response rates, time to progression, and survival duration between NSCLC patients with and without somatic EGFR mutations (Table 1). Therefore, the presence of EGFR mutations appears highly associated with response to gefitinib, and the early evidence from the patients with NSCLC from Asia suggests that those with EGFR mutations have an expected survival of 2 years from the start of treatment with gefitinib. Further research is needed to determine its impact on survival in patients from Europe and North America. Patients treated with both gefitinib and erlotinib can have clinical benefit without having a partial response, as demonstrated in two clinical trials of patients with NSCLC who had been previously treated with one or two chemotherapy regimens and who were randomly assigned to treatment with placebo or either erlotinib (BR.21) or gefitinib (ISEL).14,15 Patients treated with erlotinib had a significantly longer survival than those treated with placebo, while those treated with gefitinib did not live significantly longer than those given placebo. Studies of the characteristics of the tumors from the patients participating in the trials are underway to determine which biologic properties are associated with response and prolongation of survival. The findings from these studies and future prospective studies will help clarify the observations made thus far in the retrospective and single-arm studies. Cappuzzo et al and Hirsch et al have previously provided information about identifying EGFR by immunohistochemistry, gene copy number assessed by FISH, and EGFR mutation in a population of 183 surgically resected NSCLC patients and 102 patients with advanced NSCLC treated with gefitinib.5,6 The studies were used to retrospectively identify subsets of patients with NSCLC who had different outcomes when observed after surgery6 or when treated with gefitinib.5 In their 2005 report, an increased EGFR gene copy number determined by FISH was most closely associated with longer survival in patients with NSCLC, following treatment with gefitinib.5 A review of the information on FISH as presented in their articles identifies issues that may require additional studies. The first is that they use a rather novel and innovative system of categorizing NSCLC specimens that are FISH-positive or -negative. They use six strata: the upper two are considered positive-tumor specimens as defined by high polysomy (four or more copies in more than 40% of the NSCLC cells) and gene amplification (more than two copies of EGFR per chromosome 7 gene, or more than 15 copies) and the lower four strata are considered negative. This splits the group of patients with NSCLC so that approximately one third are FISH-positive and two thirds are FISH-negative. This differed from their initial description in 2003 in which they used a four-category system for FISH.6 This system split their group of 183 patients into approximately 30% positive and 70% negative. Although they had similar percentages of FISH-positive and -negative tumors in these two reports, an explanation on how the six-category system was derived and the reasons for substituting it for their previous four-category system would be helpful in interpreting their current publication. Hirsch et al2 report in their study that the same classification system of EGFR FISH-positive and FISH-negative is used in the study of Cappuzzo et al5 of 102 patients, reported in 2005. The study reported in this article comes from 81 patients with adequate tumor available for study from a total of 136 patients with BAC participating in a prospective clinical study evaluating the efficacy of gefitinib. Once again, the FISH-positive tumors made up approximately one third of patients, while the FISH-negative made up two thirds of the patients. The only other laboratory variable examined was the copy number of HER-2 assessed by FISH, which had no impact. It is reassuring to see that the magnitude of the differences was very similar to that seen in the study of Cappuzzo et al earlier this year.5 In addition, this cohort of patients included both those that had been previously treated with chemotherapy (n = 36) and those who had not (n = 101). There were no analyses done to assess the effect of previous treatment on outcomes. In addition, there is no information given on those who are or are not amplified, but only on FISH positivity and negativity.
EGFR mutations and increased copy number have been treated as separate molecular events, but they are, in fact, not mutually exclusive. In the study of Takano et al1, 22 (56%) of 39 patients with EGFR mutations also had increased EGFR copy number, and all of the patients with high copy numbers ( The contribution made by both Takano et al1 and Hirsch et al2 have been welcome indeed. Takano et al1 provided another patient cohort that showed a difference in outcome for those with somatic mutations of EGFR treated with gefitinib. The FISH scoring system generated by the Colorado group provided a second group of patients with NSCLC and increased copy number of EGFR assessed by FISH who, once again, were more likely to respond and have a longer survival duration than those with a low copy number when treated with gefitinib. Takano et al 1 have also shown that those with an increased copy number of EGFR as assessed by real-time PCR have both an increased response rate and longer time to progression. In their Japanese population, the somatic EGFR mutations are more common than amplification and more predictive of outcome. Thus, EGFR mutations may be a more important predictor of outcome in Asian patients than in the patients from the United States and Europe. The frequency of EGFR mutations in the populations of Italy and the United States are one third of that seen in Japan. Therefore, determining copy number may be important for defining the larger group that will benefit from gefitinib therapy, with both partial response and prolonged time to progression leading to longer survival. The identification of EGFR mutations may help identify those who are likely to respond to gefitinib therapy and survive for a median of approximately 2 years from the start of gefitinib therapy. The obvious way to determine whether copy number or quantity of EGFR receptor assessed by FISH or PCR, EGFR detected by immunohistochemistry, EGFR mutation, or other unknown factors affect the outcomes of patients treated with gefitinib will be to design trials to assess these prospectively. It will be important to continue to look at populations of patients with NSCLC from Asia, Europe, and North America because the clinical significance of the different methods used to assess EGFR could vary between these populations. We anticipate that in another few years, we will be able to use the ongoing clinical research to determine if the selection of patients for treatment with an EGFR-TKI will be a FISH story, a tale of mutations, or a compilation of other predictive factors. Authors' Disclosures of Potential Conflicts of Interest Although all authors completed the disclosure declaration, the following authors or their immediate family members 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. 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.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C)
REFERENCES
1. Takano T, Ohe Y, Sakamoto H, et al: Epidermal growth factor receptor gene mutations and increased copy numbers predict gefitinib sensitivity in patients with recurrent non-small-cell lung cancer. J Clin Oncol 23:6829-6837, 2005
2. Hirsch FR, Varella-Garcia M, McCoy J, et al: Increased EGFR gene copy number detected by FISH associates with increased sensitivity to gefitinib in patients with bronchioloalveolar carcinoma subtypes: A Southwest Oncology Group Study. J Clin Oncol 23:6838-6845, 2005
3. Mitsudomi T, Kosaka T, Endoh H, et al: Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence. J Clin Oncol 23:2513-2520, 2005
4. Han SW, Kim TY, Hwang PG, et al: Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small-cell lung cancer patients treated with gefitinib. J Clin Oncol 23:2493-2501, 2005
5. 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
6. 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
7. Marchetti A, Martella C, Felicioni L, et al: EGFR mutations in non-small-cell lung cancer: Analysis of a large series of cases and development of a rapid and sensitive method for diagnostic screening with potential implications on pharmacologic treatment. J Clin Oncol 23:857-865, 2005
8. Shigematsu H, Lin L, Takahashi T, et al: Clinical and biological features associated with epidermal growth factor receptor gene mutations in lung cancers. J Natl Cancer Inst 97:339-346, 2005
9. 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
10. Paez JG, Jänne PA, Lee JC, et al: EGFR mutations in lung cancer: Correlation with clinical response to gefitinib therapy. Science 304:1497-1500, 2004 11. Pao W, Miller VA, Politi KA, et al: Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med 2:e73, 2005[CrossRef][Medline]
12. Kobayashi S, Boggon TJ, Dayaram T, et al: EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med 352:786-792, 2005
13. Kosaka T, Yatabe Y, Endoh H, et al: Mutations of the epidermal growth factor receptor gene in lung cancer: Biological and clinical implications. Cancer Res 64:8919-8923, 2004
14. Shepherd FA, Pereira J, Ciuleanu TE, et al: Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123-132, 2005 15. Thatcher T, Chang A, Parikh P, et al: Results of a phase III placebo-controlled study (ISEL) of gefitinib (IRESSA) plus best supportive care (BSC) in patients with advanced non-small-cell lung cancer (NSCLC) who had received 1 or 2 prior chemotherapy regimens. Annual Meeting of the American Association for Cancer Research, Anaheim, CA, 2005, pp LB-6
16. Amann J, Kalyankrishna S, Massion PP, et al: Aberrant epidermal growth factor receptor signaling and enhanced sensitivity to EGFR inhibitors in lung cancer. Cancer Res 65:226-235, 2005
17. Tracy S, Mukohara T, Hansen M, et al: Gefitinib induces apoptosis in the EGFR L858R non-small-cell lung cancer cell line H3255. Cancer Res 64:7241-7244, 2004 Related Articles
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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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6.0 per cell) also had EGFR mutations. Similarly, in a previous publication by Cappuzzo et al, 67% (six of nine) patients with EGFR amplification also had EGFR mutations.
