New Analyses Explore Roles of EGFR Amplification, Mutations in Response to TKIs

ORLANDO-Who is most likely to benefit from treatment with gefitinib(Drug information on gefitinib) (Iressa) and erlotinib (Tarceva)? The clinical and demographic predictors are well known: Lung cancer patients with adenocarcinoma or bronchioalveolar characteristics, those of East Asian ethnicity, never smokers, and women have higher rates of response to the tyrosine kinase inhibitors (TKIs). When it comes to molecular predictors, however, the investigations arejust getting started. Last year's finding that patients with mutations in the epidermal growth factor receptor (EGFR) were more likely to respond to gefitinib triggered a spate of new EGFR molecular studies, many of which were presented at the 41st annual meeting of this year's ASCO meeting. Most of these were retrospective analyses of tissue samples from patients treated with the drugs, and they looked at EGFR mutations and othermarkers, especially EGFR copy number or amplification, to see whether they correlated with outcome. Because some of the study findings were contradictory, discussants at ASCO could only agree that it was crucial to learn more. "Molecular profiling is essential both in research and ... ultimately, in caring for patients with lung cancer," commented discussant Thomas Lynch, MD, director of thoracic oncology at Massachusetts General Hospital Cancer Center, Boston, at the conclusion of numerous presentations related to EGFR. INTACT and IDEAL Two of the larger correlative studies presented at ASCO looked at tissue samples from completed clinical trials to see whether outcomes could be correlated with mutations or some other factor related to EGFR. Dr. Lynch and colleagues analyzed data from the two INTACT and two IDEAL trials, which tested gefitinib with chemotherapy in patients with non-small-cell lung cancer (abstract 7006). Ming-Sound Tsao, MD, professor of laboratory medicine and pathobiology in the Department of Pathology at Princess Margaret Hospital in Toronto, led analysis of molecular data from the National Cancer Institute of Canada's successful BR.21 trial with erlotinib (abstract 7007). Mutations were associated with better outcomes in both the IDEAL and INTACT studies, Dr. Lynch reported. In the IDEAL trials' 78 evaluable tissue samples, the response rate for those with mutations was 46%, compared with a rate of 10% among those without mutations-a highly statistically significant finding. In the INTACT trials, with more than 300 evaluable samples, the response rate was higher in the group with mutations-72% vs 40%. Progression-free survival also was improved among those with mutations in both trials, reaching statistical significance in the IDEAL trials. Overall survival appeared better in bothtrials but again, the difference was not large enough to be statistically significant. Amplifications and Response Dr. Lynch's group also looked at EGFR gene amplification in association with outcome. They found that patients with amplification seemed to do better but the differences in response rate-56% vs 50% in the INTACT trial and 29% vs 15% in IDEAL-did not reach statistical significance. In contrast, the BR.21 analysis showed that EGFR amplification wasa significantly strong predictor of outcome- more powerful, in fact, than mutational status. Dr. Tsao and colleagues found a high gene copy number was associated with a response rate of 20% compared to just 2.4% in patients with a low gene copy number (P = .03). Though mutations did correlate with response in BR.21, the differences were not significant, and no survival benefit was seen among patients with mutations. Another study presented at ASCO also found EGFR gene amplification to be a strong predictor of response (abstract 7030). Fred Hirsch, MD, from the University of Colorado Cancer Center, Aurora, and colleagues analyzed samples from patients with bronchioalveolar carcinoma, a unique type of NSCLC that is resistant to chemotherapy. They found that an increased gene copy number, as measured by fluorescent in situ hybridization or FISH, was predictiveof response and survival to gefitinib. This study supported a recent finding from the same group, reported by Federico Cappuzzo, MD and colleagues (J Natl Cancer Inst May 4;97(9):643-655, 2005). That study also found gene copy number, as determined by FISH, to be a significant predictor of response and survival to gefitinib in patients with advanced NSCLC. EGFR Amplification: A Distinct Subgroup? Both studies showed that EGFR mutations correlate closely with the clinical characteristics associated with better outcome. Two other, smaller studies yielded mixed findings regarding mutations and amplifications. Toshimi Takano, MD, of the National Cancer Center Hospital in Tokyo, and colleagues analyzed surgical specimens from 66 patients treated with gefitinib (abstract 7032). They found that EGFR mutations were a major determinant of response and survival, but also found that EGFR gene copy number was significantly associated with mutational status. Dr. Takano noted that he considers EGFR copy number "as a surrogate marker for EGFR mutations rather than a true determinant of EGFR-TKI sensitivity." On the other hand, no relationship between amplification and response was found in a study of tissue samples from 44 patients treated with gefitinib or erlotinib, presented by Vincent Miller, MD, of Memorial Sloan-Kettering Cancer Center, New York (abstract 7031). Amplification in this study was measured with chromogenic in situ hybridization, or CISH. This study's findings supported the importance of mutational status, however, in that EGFR mutations were a powerful predictor. Discrepant Findings Explored Speculating on the reasons for the discrepant findings related to EGFR mutations, experts suggested severalpossibilities. Pasi Janne, MD, of Dana- Farber Cancer Institute, Boston, noted that there was a wide range of response rates associated with mutations, from a low of 16% to a high of 83%. This suggests that mutations are a part, but not all, of the story, he said and/or that clinical and molecular contexts could be important as well. It's also possible that "all mutations are not equal," Dr. Janne noted, and that some have a stronger effect on response. What's more, there maybe differences in the two agents, gefitinib and erlotinib, that account for the different findings. Different findings on the role of EGFR amplification also need further study. Manuel Hidalgo, MD, of Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, noted that the studies' heterogeneous patient populations and the fact that these were all retrospective analyses, with tissue samples selected based on availability, could contribute to theinconclusive findings. He also said the methods used to determine gene copy-FISH, CISH, and others- might explain differences, as might different scoring systems and cutoff points used to define amplification. Dr. Janne also speculated that the different methods of determining EGFR gene amplification could be a key issue. "I think additional studies and characterizations of these groups will be needed," he said.