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Cancer Therapy: Clinical |
Authors' Affiliations: Thoracic Oncology Service, Departments of 1 Medicine, 2 Surgery, and 3 Pathology; 4 Human Oncology and Pathogenesis Program; and 5 Biostatistics Service, Memorial Sloan-Kettering Cancer Center, New York, New York
Requests for reprints: Vincent A. Miller, Thoracic Oncology Service, Department of Medicine, Box 437, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021. Phone: 212-639-7243; Fax: 1-212-794-4357; E-mail: millerv{at}mskcc.org.
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Abstract |
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Experimental Design: In patients with NSCLC, EGFR exon 19 deletion mutations and EGFR L858R point mutations were analyzed by nonsequencing PCR-based methods from paraffin blocks of tissue obtained before treatment. The results were correlated with clinical information (sex, pathologic subtype, race/ethnicity, treatment, and overall survival).
Results: The two most common EGFR mutations were identified in 24% (70 of 291; 95% confidence interval, 26%-38%) of tumors from patients with NSCLC. EGFR mutation was associated with Asian ethnicity (P = 0.0023) and being a "never smoker" (P = 0.0001). Among patients with EGFR mutations, 39% (27 of 70) had EGFR L858R, whereas 61% (43 of 70) had an EGFR exon 19 deletion. After treatment with erlotinib (n = 12) or gefitinib (n = 22), patients with EGFR mutations had a median overall survival of 20 months. After treatment with erlotinib or gefitinib, patients with EGFR exon 19 deletions had significantly longer median survival than patients with EGFR L858R (34 versus 8 months; log-rank P = 0.01).
Conclusions: EGFR mutations in exons 19 or 21 are correlated with clinical factors predictive of response to gefitinib and erlotinib. Those with EGFR exon 19 deletion mutations had a longer median survival than patients with EGFR L858R point mutation. These observations warrant confirmation in a prospective study and exploration of the biological mechanisms of the differences between the two major EGFR mutations.
Although many EGFR mutations have been reported, not all have been associated with responsiveness to gefitinib and erlotinib. The two most common EGFR mutations that have been identified, representing 85% to 90% of EGFR mutations, are the EGFR exon 19 deletion that eliminates a leucine-arginine-glutamate-alanine motif in the tyrosine kinase domain of EGFR and a thymine-to-guanine transversion that results in an arginine for leucine substitution at amino acid 858 (L858R). Shortly after the identification of EGFR mutations associated with response to erlotinib or gefitinib, we developed an assay for EGFR exon 19 deletion and EGFR L858R suitable for routine clinical use with greater sensitivity than standard sequencing-based assays (17).
This study was undertaken to explore the relationship between EGFR mutation status and clinical variables, including treatment with EGFR TKIs, and to compare outcomes between patients with the two most common EGFR mutations. Here, we report the results of EGFR genotyping of patients with NSCLC from Memorial Sloan-Kettering Cancer Center and examine clinical factors associated with the two most common EGFR mutations. We compare the clinical and pathologic features of patients with EGFR mutations that have been associated with responsiveness to gefitinib and erlotinib and correlate mutation type with survival after treatment with these agents.
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Materials and Methods |
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Mutational analysis. Tumor specimens were not routinely microdissected before mutational analysis. In some cases where only a small focus of tumor was present in the block, manual microdissection was done. EGFR exon 19 deletions were studied by length analysis of fluorescently labeled PCR products on a capillary electrophoresis device, using the following primers: EGFR-Ex19-FWD1, 5'-GCACCATCTCACAATTGCCAGTTA-3' and EGFR-Ex19-REV1, 5'-Fam-AAAAGGTGGGCCTGAGGTTCA-3'. The cases were also screened for the exon 21 L858R mutation by a PCR RFLP assay, based on a new Sau96I restriction site created by the L858R mutation (2573T 
G). The Sau96I-digested fluorescently labeled PCR products were analyzed by capillary electrophoresis, and the following primers were used: EGFR-Ex21-FWD1, 5'-CCTCACAGCAGGGTCTTCTCTGT-3' and EGFR-Ex21-REV1, 5'-Fam-TCAGGAAAATGCTGGCTGACCTA-3' (17). These assays reliably detect mutations in mixtures containing as little as 5% to 10% tumor DNA (17). Direct sequencing of EGFR was also done in some cases, as previously described (7). In such cases, all sequencing reactions were done in both forward and reverse directions, and all mutations were confirmed by PCR amplification of an independent DNA isolate.
Statistical Analysis. The variables measured in the study were investigated for association using the Fisher's exact test when two categories existed for a variable and Pearson's 
2 test when three or more categories existed for a variable. Statistical significance was determined by a two-tailed P < 0.05. Median duration of overall survival and progression-free survival were calculated using the Kaplan-Meier method. Comparison of survival between groups was made using the log-rank test. Survival analysis was done using Stata version 8 for Windows.
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Results |
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70 pack-year history of smoking were found to have EGFR mutations.
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29 months), and the median overall survival after initiation of gefitinib or erlotinib was 20 months (95% confidence interval, 16 months to not reached; range, 4 to 34 months). Comparison of patients treated with erlotinib to those treated with gefitinib revealed no difference in overall survival (log-rank P = 0.54). To explore whether the two major EGFR mutation genotypes respond differently to treatment with gefitinib and erlotinib, we determined the progression-free survival and overall survival of patients with these genotypes from the time of initiation of treatment (Fig. 1). In this subset of patients, there was no significant difference in proportion of women, never smokers, adenocarcinoma histology, or bronchioloalveolar carcinoma features (Table 3). At the time of initiation of treatment, whereas patients with EGFR exon 19 deletion were more likely to have a site of at least one extrathoracic metastasis (14 of 23 versus 2 of 11; P = 0.03), there was no significant difference in the incidence of metastases to individual sites of bone, brain, or liver. There was no significant difference in the baseline Karnofsky performance status of these patients. Patients with EGFR exon 19 deletion had a median progression-free survival of 12 months compared with 5 months for patients with EGFR L858R (P = 0.01). Patients with EGFR exon 19 deletion had a median overall survival of 34 months compared with 8 months for patients with EGFR L858R (P = 0.01).
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8 pack-years (n = 10; Fig. 2). The median overall survival for never smokers was 20 months. The median survival of former smokers who smoked <8 pack-years has not been reached, whereas the median survival of former smokers with 8 pack-year history of smoking was 8 months.
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Discussion |
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We report a relatively high proportion (24%) of patients with one of the two most common EGFR mutation genotypes. As clinical factors predictive of sensitivity to EGFR TKIs antedated identification of EGFR mutations, clinicians tended to request mutational studies of patients with such factors. The group of patients studied is enriched for never smokers, women, patients with adenocarcinoma, and patients of Asian ethnicity. Only 8% (24 of 291) patients tested had nonadenocarcinoma histology. Additionally, this series has a relatively large proportion of patients who presented with metastatic disease. Many of the previous series were made up almost solely of patients who had resections for early-stage NSCLC.
Multiple prior international reports have confirmed the association of mutations with those clinical characteristics known to predict response to gefitinib or erlotinib (i.e., Asian ethnicity, history of never smoking, and adenocarcinoma histology). In this large group of patients from North America, we confirmed the association of EGFR mutation with some of the clinical predictors of response, including history as a never smoker and Asian ethnicity. Women were not more likely to have tumors with EGFR mutations in this series that included a disproportionate number of women (51% of patients with NSCLC referred to our medical oncology service are women). This observation has been made by other groups as well. However, some have found gender to be predictive in multivariate analyses.
Since the initial reports of partial responses with gefitinib, researchers have noted a significant geographic and ethnic variability in the sensitivity of patients to this class of agents. After the identification of somatic mutations in EGFR and their association with response, it became clear that these two factors were linked. A significantly higher proportion of patients from East Asia have mutations in EGFR based on multiple reports from Japan, China, Taiwan, and Europe, as well as smaller studies from North America. Accordingly, obtaining accurate information about each patient's country of origin, race, and ethnicity is vital. In contrast to a previous report that noted a relatively low incidence of EGFR mutations in patients of African-American ethnicity (2%, 1 of 41), 43% (6 of 14) of African-American patients in our series had EGFR mutations. Clearly, a variety of factors could modify this incidence with the most obvious being smoking history. Fifty-seven percent (8 of 14) of African-American patients in our series were never smokers.
These data extend the observation that a heavy smoking history in patients with NSCLC is associated with a poorer survival to this subpopulation of NSCLC patients with EGFR mutations (21, 22). The cause of this difference is not fully understood, although repeated exposure to tobacco-related carcinogens is thought to lead to a more genetically complex tumor in patients with heavy smoking history. Although EGFR mutations and KRAS mutations, the most well-studied genetic lesion in smokers, are thought to be mutually exclusive, it remains possible that other mutations caused by tobacco-related carcinogens may be present in heavy smokers and lead to decreased overall survival (23). More comprehensive molecular analysis of tumors from patients with NSCLC and EGFR mutations will be helpful to clarify this issue.
Many recent series have compared NSCLC patients with EGFR mutations to those patients with no detectable EGFR mutations to explore the clinical relevance of EGFR mutations for sensitivity to gefitinib or erlotinib. Some series show an improvement in overall survival for patients with EGFR mutations who have been treated with gefitinib or erlotinib (10, 24). Mitsudomi et al. studied 59 patients with disease recurrence after surgery who had been treated with gefitinib (25) and found that patients with EGFR mutations had a prolonged survival (P = 0.005). Similarly, Chou et al. examined 54 patients, 61% of whom had mutations in EGFR and showed longer progression-free survival (P = 0.011) and overall survival (P = 0.046) after treatment with gefitinib when compared with patients with wild-type EGFR (26). Cappuzzo et al., in examining a group of 89 patients who had been treated with gefitinib, found 15 patients with mutations in EGFR with a median survival of 21 months as opposed to a median survival of 8 months for the 74 patients without mutations (P = 0.09; ref. 27). Similarly, Tokumo et al. looked at 21 gefitinib treated patients, 9 with mutations in EGFR, and noted a 25-month survival for patients with mutations and 14 months for those without mutations (P = 0.15; ref. 15). A variety of pitfalls are associated with comparing patients with EGFR mutations to those without detectable mutations, including potential sensitivity issues in the use of direct sequencing to detect EGFR mutations (whereby patients with EGFR mutations are included in the wild-type group) and the uncertainty of association of EGFR mutations other than exon 19 deletions and L858R with response to erlotinib or gefitinib. To avoid these problems, our survival analysis included only patients with detectable mutations and compared the two most common subtypes of mutations, EGFR L858R and EGFR exon 19 deletion.
Our results suggest that specific EGFR mutation genotypes may be predictive of survival after treatment with EGFR TKI in patients with NSCLC, showing that EGFR exon 19 deletion patients treated with erlotinib or gefitinib lived longer than patients with EGFR L858R (P = 0.01). This survival benefit was observed in spite of the higher frequency of extrathoracic metastases for patients with EGFR exon 19 deletions. A previous report of patients treated with gefitinib or erlotinib noted a difference in response rate, which favored patients with EGFR exon 19 deletion, but differences in survival were not detected (25). Mitsudomi et al. noted a 62% (8 of 13) response rate in patients with EGFR point mutations compared with 100% (16 of 16) response rate in patient with EGFR exon 19 deletion (P = 0.0108). In contrast, Shigematsu et al. reported data from patients, never treated with EGFR TKI, who had surgically resected NSCLC (14). They compared 62 patients with EGFR mutations (31 with EGFR L858R and 31 with EGFR exon 19 deletion) and noted a relatively prolonged survival for those patients with L858R (P = 0.05). If prospectively confirmed, our data suggest that treatment with gefitinib or erlotinib alters the natural history of patients with EGFR-mutated NSCLC, converting the EGFR exon 19 deletion subtype of NSCLC from a disease with a worse prognosis to one with a more favorable prognosis.
Differences in response rate determined by different mutations and prolonged survival for TKI therapy has also been observed with imatinib in the treatment of patients with gastrointestinal stromal tumors. After the initial identification of KIT mutations and their association with response to imatinib, it was noted that particular mutations conferred greater sensitivity to imatinib (28–30). Recently, an analysis of tumor specimens from an intergroup trial of imatinib showed a longer time to treatment failure and overall survival in patients with KIT exon 9 mutations compared with those patients with KIT exon 11 mutations (31).
Our data highlight the need for a prospective analysis of EGFR genotype in a larger study of patients treated with erlotinib or gefitinib. Unfortunately, recent results of EGFR genotyping from the largest trial of erlotinib to date suffered from low levels of tissue acquisition, obtaining usable tissue for EGFR sequence analysis on only 177 patients of 731 patients randomized, and a relatively low total number of mutations identified (n = 40, of which only 21 were L858R mutations or exon 19 deletions, the mutations previously associated with sensitivity to erlotinib), making analysis of these data problematic (32). Future analyses should incorporate the prospective collection of tumor blocks and an attempt to correlate other factors, which may be predictive of response to gefitinib or erlotinib, including EGFR amplification, EGFR expression, KRAS mutations, and phospho-AKT expression (27).
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Acknowledgments |
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Footnotes |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 8/23/05; revised 11/ 3/05; accepted 11/11/05.
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