Clinical Cancer Research Vol. 12, 4416s-4420s, July 15, 2006
© 2006 American Association for Cancer Research
Novel Agents in the Treatment of Lung Cancer: Advances in EGFR-Targeted Agents |
Effect of Epidermal Growth Factor Receptor Tyrosine Kinase Domain Mutations on the Outcome of Patients with Non–Small Cell Lung Cancer Treated with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
Pasi A. Jänne and
Bruce E. Johnson
Authors' Affiliation: Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute and Departments of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Requests for reprints: Pasi A. Jänne, Lowe Center for Thoracic Oncology, Department of Medical Oncology, Dana-Farber Cancer Institute, D1234; 44 Binney Street, Boston, MD 02115. Phone: 617-632-6049; Fax: 617-632-5786; E-mail: pjanne{at}partners.org.
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Abstract
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Somatic mutations in the epidermal growth factor receptor (EGFR) have been identified in patients with advanced non–small cell lung cancer who achieve dramatic clinical and radiographic response to the EGFR tyrosine kinase inhibitors (TKI) gefitinib and erlotinib. These mutations in EGFR are found more frequently in patients with adenocarcinomas, nonsmokers, patients of Asian ethnicity, and in females: the same populations that are the most likely to have a clinical response when treated with EGFR TKIs. Retrospective studies comparing the outcomes of patients with and without EGFR mutations treated with EGFR TKIs show a significant clinical benefit of EGFR TKIs in patients with EGFR mutations. These findings suggest that for patients with advanced non–small cell lung cancer bearing EGFR mutations, treatment with an EGFR TKI should be incorporated as at least part of their initial therapy. These approaches are being studied in ongoing clinical trials and will spur the development of additional technology for EGFR mutation detection.
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Clinical Predictors of Response and Survival to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
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The initial studies of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) brought enthusiasm to the field of molecular-targeted therapies for patients with non–small cell lung cancer (NSCLC). These studies provided a proof-of principle demonstration that inhibition of a growth factor receptor, the EGFR, can lead to dramatic tumor regressions in 10% to 15% of all treated patients (1, 2). However, not all patients seemed to benefit from these treatments. A careful examination of patients who benefited from single-agent EGFR TKIs in phase II clinical trials, including unselected patients and those treated in the AstraZeneca gefitinib expanded access program, revealed clinical characteristics associated with an increased likelihood of a clinical or radiographic response (1–8). Patients most likely to achieve a radiographic response to EGFR TKIs were women, never smokers, patients with adenocarcinomas, and Japanese patients. Smoking status seems to be the strongest predictor, with patients who are nonsmokers having the greatest likelihood of a clinical response to an EGFR TKI (3). These clinical predictors of response have been confirmed in randomized clinical trials of both gefitinib (Iressa Survival Evaluation in Lung Cancer) and erlotinib (BR.21; Table 1
; refs. 9, 10). In both studies, the findings are remarkably similar in patients with NSCLC who had previously received chemotherapy, with the response rates being highest in never smokers (9, 10).
The clinical predictors of prolonged survival have also been examined in these studies. Although there was a survival benefit of erlotinib across the majority of clinical characteristics, the magnitude of this benefit varied substantially (9). The same clinical characteristics that were associated with a greater likelihood of a radiographic response to erlotinib are also associated with prolonged survival in both univariate and multivariate analyses (9). In the Iressa Survival Evaluation in Lung Cancer trial, there was no statistically significant survival advantage of treatment with gefitinib compared with placebo in all patients (10). However, exploratory subgroup analyses showed a significantly greater survival duration for patients who were either never smokers or of Asian ethnicity when treated with gefitinib compared with placebo (10). The effect of smoking was also examined in a phase III trial of carboplatin/paclitaxel with or without erlotinib (TRIBUTE; ref. 11). Despite a lack of benefit in the overall patient population, when the analysis was confined to those who had never smoked cigarettes, erlotinib seemed to confer a survival benefit. In this analysis, 105 patients who were identified as never smokers (defined as <100 cigarettes per lifetime) had a median survival of 10 months, similar to the entire study population, when treated with carboplatin and paclitaxel plus placebo. However, for the patients in this subpopulation who were treated with erlotinib in addition to the same chemotherapy regimen, the median survival increased to 22.5 months (P = 0.01). The response rate to chemotherapy with erlotinib was also higher in the never-smoking patients compared with chemotherapy alone (30%; 95% confidence interval, 20-43% for erlotinib versus 11%; 95% confidence interval, 4-25% for placebo; P = 0.02). Taken together, these observations suggested a molecular mechanism underlying the sensitivity to EGFR TKIs that is present more frequently in specific subgroups of patients. The molecular mechanism hypothesis ultimately led to analysis and sequencing of the EGFR gene and to the identification of EGFR mutations (12–14).
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EGFR Mutations in NSCLC
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In the spring of 2004, two simultaneously published studies examined series of patients who had had dramatic clinical and/or radiographic responses to gefitinib (12, 13). Thirteen of 14 patients were found to have somatic activating mutations in the EGFR kinase domain, whereas none of the 11 patients who progressed on gefitinib had these EGFR mutations. Subsequently, EGFR mutations have been investigated in several series of NSCLC tumors from surgically resected patients and/or in patients treated with gefitinib or erlotinib. Mutations of EGFR have been examined in several studies of unselected NSCLC tumor specimens (Table 2
; refs. 12, 15–20). The mutation frequency varies based on different patient characteristics but very much mirrors the clinically defined subgroups who were likely to achieve radiographic responses to EGFR TKIs. The mutation frequency also varies within each of the subgroups. For example, the mutation frequency in East Asian females is 58% compared with only 20% in women of other ethnicities (Table 2). Cigarette smoking status is the best predictor of the presence of TKI-sensitive EGFR mutations. The highest EGFR mutation frequency is consistently observed in nonsmokers.
EGFR mutations are found in the first four exons (18–21) of the tyrosine kinase domain of EGFR. Three types of mutations have been described: deletions in exon 19 account for about 60% of all mutations; a common missense mutation in exon 21 (L858R) accounts for another 25%; and, finally, rare point mutations in exons 18, 20, and 21 and insertion/duplications in exon 20 account for the remainder (21).
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Outcome of Patients with EGFR Mutations Treated with EGFR TKIs
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The outcomes of patients with advanced (stage IV) NSCLC harboring EGFR mutations treated with EGFR TKIs have been examined in several retrospective series (Table 3
). No prospective studies have been reported to date. These retrospective studies are all limited by their sample size and sample bias. For example, in a recent large study, mutation analysis was possible only in 177 of 731 (24%) patients, and in only 107 (15%) tumors were exons 18 to 21 analyzed, whereas in 70 specimens, only exons 19 and 21 were analyzed (22). The outcome of patients with EGFR mutations treated with gefitinib seems much better than in those without EGFR mutations (Table 3). The response rates range between 65% and 94%, and the median survival is 
2 years for patients with somatic EGFR mutations in their tumor. To date, no other therapy for NSCLC in any selected subgroup of individuals has shown such impressive findings. Such observations have prompted ongoing clinical trials to document the favorable outcome of patients with EGFR mutations treated with either erlotinib or gefitinib. However, not all retrospective studies have shown an improved outcome for patients with EGFR mutations treated with EGFR TKIs. Two published studies show no improvement in survival for patients with EGFR mutations treated with either gefitinib or erlotinib (22, 23).
There are several possible explanations for these discrepant observations. First, EGFR mutation detection, as currently done by direct sequencing, has limitations for use with most clinical NSCLC specimens. This issue is discussed in detail in the next section. Second, the type and size of specimens available for analyses affect the ability to perform mutation detection studies. Larger surgical specimens or frozen tumor specimens are significantly better sources of genomic DNA than, for example, fine needle aspirates. Some of the recent studies examining EGFR mutations have used surgical specimens and/or frozen tumor specimens as the source material (16). Mutation analysis from DNA extracted from paraffin-embedded tumor specimens has previously been shown to produce false positives when analyzing for BRCA1 mutations (24, 25). However, with appropriate verification studies, such as repeating the PCR and/or original DNA extraction, many such false positives can be avoided. Third, not all EGFR mutations are equal. Since the original discovery of EGFR mutations, they have all been assumed to be similar; that is, the efficacy of gefitinib or erlotinib is presumed to be the same irrespective of the type of mutation. However, emerging data clearly show that there are differences among EGFR mutations. The most common and well-characterized mutations are the exon 19 deletions L858R, L861Q, and G719A/C/S. These have been found in multiple studies, have been examined in NSCLC cell lines or in model systems, and have consistently been shown to be associated with in vivo or in vitro sensitivity to gefitinib or erlotinib. Two mutations are emerging as predictors of resistance. These include T790M and the exon 20 insertion mutations. The T790M mutation, initially identified in patients with dramatic responses to gefitinib who developed disease progression, is associated with both in vitro and in vivo resistance to gefitinib and erlotinib (26, 27). The insertion 20 mutation has recently been shown to be associated with in vitro resistance to gefitinib and erlotinib (28). There are >20 other mutations that have been described, but their significance has not been characterized. That is, they have been identified in patients with NSCLC but not always correlated with efficacy to EGFR TKIs. In addition, such mutations have not been extensively tested in vitro. For example, in the BR.21 trial, 50% of the mutations detected were novel and had not previously been found in patients with NSCLC (22). To date, no in vitro studies have been done on any of these mutations.
Approximately 10% to 13% of patients who are EGFR wild type still obtain partial responses to gefitinib treatment (Table 3). What are the possible explanations for these observations? First it is possible that some of those patients in fact harbored an EGFR mutation but was not detected using conventional sequencing. This is discussed further in the next section. Second, it is possible that there are other determinants of gefitinib's benefit. Recent studies have identified increased EGFR copy number as a predictor for the efficacy of gefitinib (23, 29). Increased EGFR copy number occurs often concurrently with EGFR amplification, and limited data exist on tumors that have increased EGFR copy number (or amplification) but do not harbor a concurrent mutation (23). In a recent study by Takano et al., three patients were identified who achieved a partial response with gefitinib but who did not harbor an EGFR mutation (30). Two of the patients had a moderately increased EGFR copy number and had prolonged responses (
10.9 and 21.1 months, respectively). Third, it is possible that the presence of other ErbB family members contributes to the efficacy of gefitinib in a subset of EGFR wild-type tumors. It is becoming increasingly clear that erbB-2 and erbB-3 are important components of EGFR-dependent cancers, and that they may modulate and/or are required for the efficacy of gefitinib (31–33). Additional studies focusing on EGFR copy number and the concurrent presence of other erbB family members need to be incorporated into future studies of EGFR inhibitors.
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EGFR Mutation Detection
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Presently, the most common method of EGFR mutation detection is direct sequencing. This is a multistep process requiring a relatively pure tumor specimen with abundant DNA, typically at least a core needle biopsy or surgical specimen, and is difficult to perform when the tumor is very heterogeneous. In addition, direct sequencing lacks sensitivity. To detect a mutation, the dissected tumor material must contain at least 40% tumor cells. Furthermore, direct sequencing can take a significant amount of time to perform. These shortcomings of direct DNA sequencing have led to alternative methods for EGFR mutation detection. These methods include allele-specific PCR, PCR-based single-strand conformation polymorphism, and the use of a DNA endonuclease Surveyor (Transgenomic, Inc., Omaha, NE) for screening of EGFR mutations. Sasaki et al. examined 118 fresh frozen tumor specimens using an allele-specific real-time reverse transcription-PCR assay system (34). They examined for mutations at three sites: point mutations at G719 and L858 and deletions in exon 19. A variation of allele-specific PCR, peptide nucleic acid–locked nucleic acid PCR clamp, is a very sensitive method that can detect EGFR mutations in the presence of 100- to 1,000-fold background of wild-type EGFR (35). Pan et al. have also used a PCR-based method but only examined mutations in exons 19 and 21 (36). Although these methods may be faster than direct sequencing, allele-specific PCR methods rely on a priori knowledge of potential mutations, a limitation when scanning for new mutations or when examining for rare events. New EGFR mutations continue to be reported, including the T790M mutation found in patients who develop acquired resistance to EGFR TKIs (26, 27). To detect such mutations, the method should be unbiased towards any particular EGFR mutation. Marchetti et al. compared direct sequencing and PCR single-strand conformation polymorphism for detecting EGFR mutations in DNA prepared from frozen NSCLC specimens (18). No false-positive or false-negative results were observed with single-strand conformation polymorphism, and eight additional mutations (all point mutations; seven in exon 21 and one in exon 18) not detected by direct sequencing were identified. The majority of specimens examined in the abovementioned studies have been derived from fresh frozen tumors or from NSCLC cell lines (18, 34, 35). However, a significant majority of patients with advanced NSCLC have diagnostic specimens that are formalin fixed and paraffin embedded. Thus, if EGFR mutation detection is going to be used in clinical decision making, the development of a method that allows accurate testing of formalin-fixed, paraffin-embedded specimens will be necessary. Recently, a new method for EGFR mutation screening using a DNA endonuclease (Surveyor) has been described by our group (37). This method uses the properties of Surveyor to digest heteroduplexes formed between EGFR mutant and wild-type sequences. The digested products can then be separated using high-performance liquid chromatography and analyzed further for specific mutations. This technique can be used to analyze undissected tumor specimens and was also found to be more sensitive than direct DNA sequencing (37).
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Conclusions and Future Directions
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EGFR mutations are currently a strong predictive marker for radiographic and clinical responses to EGFR TKIs gefitinib and erlotinib. Since their initial identification, additional potential molecular markers, including increased EGFR copy number and tumor EGFR expression detected by immunohistochemistry, have also emerged as predictors of efficacy to EGFR TKIs (22, 23). The limitations in all of these studies to date is that they are retrospective. In addition, the analytic methods for determining EGFR mutations, EGFR copy number, or EGFR expression have not been standardized or compared between different investigators and/or institutions. The next generation of clinical trials will prospectively evaluate the efficacy of EGFR TKIs in clinically or molecularly enriched patient populations. These studies, combined with ongoing advances in technology for detecting EGFR mutations and copy number, will help further refine the population of patients with NSCLC who are likely to derive the greatest benefit from EGFR TKIs.
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Open Discussion
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Dr. Thomas Lynch: I'm struggling with how to put all this together: the relationship between polysomy, gene copy number, amplification, and mutations. Where you think we are with understanding that relationship?
Dr. Jänne: I think, and I believe, the literature would support this; the majority of truly amplified tumors are also mutated. That is true in Dr. Takano's paper [J Clin Oncol 2005; 23:6829-37], in Dr. Cappuzzo's paper [J Natl Cancer Inst 2005;97:643-55], and in a large series of papers. So we are not dealing with separate molecular events; we are dealing with concomitant events.
Dr. Paul Bunn: The majority of amplified tumors are mutated? Not true. Let's not mix quantitative PCR and FISH.
Dr. Jänne: If you look at the true amplified ones, or the ones that have a very high copy number by quantitative PCR, you are going to find that a significant proportion of those have mutations as well.
Dr. Matthew Meyerson: In the cell lines, isn't it correct that all of the high-level amplifications are associated with mutations? Three out of the four?
Dr. Daniel Haber: It is possible that very high amplifications might be mutated. But if you look at all amplifications, in those that are 4-fold by real-time PCR, about 20% are mutant and 80% are wild type. In our hands, they track quite separately in terms of the types of tumors. We haven't done the question of looking at, say, 50-fold amplification versus 4-fold. The number that we can really see are amplified is only about 8%; it is much smaller than what you see by FISH.
Dr. Jänne: So one of the questions is, for patients who have polysomy but not amplification, are these individuals going to do a little bit better with EGFR tyrosine kinase inhibitors than those who don't have these alterations, but not quite as good as people who have extreme genetic alterations? Is it a spectrum of responses, or are these different populations?
Dr. Bunn: When we first started doing progesterone and estrogen receptors, it was easy to see that there was a difference, but more and more studies were needed to validate the techniques, and then we needed to determine a cutoff value. Are the cutoff values that we are choosing now going to be the final cut offs when we have data on thousands of patients? Probably not. I think we are just back where the hormone receptor people were 20 years ago. We have found some principles that are true, but we have to refine the methodologies and refine the cutoffs.
Dr. David Johnson: Dr. Bunn, when you showed your in vitro data, the polysomy had the same lack of sensitivity as all the other genetic variables. It was only in amplified that you saw real sensitivity.
Dr. Bunn: That's correct, although when you actually count the copy number, the Spearmann correlation between copy number and the IC50 was pretty good. Just looking at the boxes of low polysomy versus high polysomy, there wasn't too much difference. But if you can actually count the copy number, six copies may be different than five, which may be different than two. It is hard to say. I would submit that we don't actually know the best cutoff values for immunohistochemistry or for FISH, and I think that work needs to be done.
Dr. Haber: You could argue that a cell that specifically has a mutation in EGFR with specific amplification is a marker that the pathway is really quite relevant, whereas polysomy, whether high, low, or intermediate, is more of a marker of an anaploid cell where the link to the EGFR pathway is much more questionable. Clinically, the data go one way versus the other, but scientifically, the rationale makes much more sense toward targeting gene amplification.
Dr. Jänne: Dr. Haber, as a breast cancer geneticist, do you want to comment on how that relates to HER2? In HER2, FISH- positive, HER2 amplification versus HER2 polysomy, can we draw some parallels from that?
Dr. Haber: It is my understanding that, if you can document specific HER2 amplification by FISH, using other controls that are on the same chromosome and elsewhere, that is the highest predictor of response to trastuzumab.
Dr. Bunn: In breast cancer, the FISH positivity includes high polysomy. It is not just amplification.
Dr. David Johnson: In breast cancer, we're talking about copy numbers that are manyfold higher compared to lung. We're talking about 4- or 5-fold amplification here; in breast cancer, it is thousand-fold.
Dr. Bunn: Even in high polysomy in our definition, >40% of the cells have more than four copies. As we can get more data, we can probably look and see the actual copy number whether there is a good correlation. Again, we don't know the cutoff, but I'm not disagreeing with that.
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Footnotes
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Presented at the Third Cambridge Conference on Novel Agents in the Treatment of Lung Cancer: Advances in EGFR-Targeted Agents, September 23-24, 2005 in Cambridge, Massachusetts.
Received 3/ 7/06;
revised 4/25/06;
accepted 5/ 5/06.
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Abstract
Clinical Predictors of Response...
