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

ORLANDO-Who is mostlikely to benefit from treatment withgefitinib (Iressa) and erlotinib (Tarceva)?The clinical and demographic predictorsare well known: Lung cancerpatients with adenocarcinoma orbronchioalveolar characteristics, thoseof East Asian ethnicity, never smokers,and women have higher rates ofresponse to the tyrosine kinase inhibitors(TKIs).When it comes to molecular predictors,however, the investigations arejust getting started. Last year's findingthat patients with mutations in theepidermal growth factor receptor(EGFR) were more likely to respondto gefitinib triggered a spate of newEGFR molecular studies, many ofwhich were presented at the 41st annualmeeting of this year's ASCO meeting.Most of these were retrospectiveanalyses of tissue samples from patientstreated with the drugs, and theylooked at EGFR mutations and othermarkers, especially EGFR copy numberor amplification, to see whetherthey correlated with outcome. Becausesome of the study findings were contradictory,discussants at ASCO couldonly agree that it was crucial to learnmore."Molecular profiling is essentialboth in research and ... ultimately, incaring for patients with lung cancer,"commented discussant ThomasLynch, MD, director of thoracic oncologyat Massachusetts General HospitalCancer Center, Boston, at theconclusion of numerous presentationsrelated to EGFR.INTACT and IDEALTwo of the larger correlative studiespresented at ASCO looked at tissuesamples from completed clinical trialsto see whether outcomes could be correlatedwith mutations or some otherfactor related to EGFR. Dr. Lynch andcolleagues analyzed data from the twoINTACT and two IDEAL trials, whichtested gefitinib with chemotherapy inpatients with non-small-cell lung cancer(abstract 7006). Ming-Sound Tsao,MD, professor of laboratory medicineand pathobiology in the Departmentof Pathology at Princess Margaret Hospitalin Toronto, led analysis of moleculardata from the National CancerInstitute of Canada's successful BR.21trial with erlotinib (abstract 7007).Mutations were associated with betteroutcomes in both the IDEAL andINTACT studies, Dr. Lynch reported.In the IDEAL trials' 78 evaluable tissuesamples, the response rate for thosewith mutations was 46%, comparedwith a rate of 10% among those withoutmutations-a highly statisticallysignificant finding. In the INTACTtrials, with more than 300 evaluablesamples, the response rate was higherin the group with mutations-72% vs40%.Progression-free survival also wasimproved among those with mutationsin both trials, reaching statisticalsignificance in the IDEAL trials. Overallsurvival appeared better in bothtrials but again, the difference was notlarge enough to be statistically significant.Amplifications and ResponseDr. Lynch's group also looked atEGFR gene amplification in associationwith outcome. They found thatpatients with amplification seemed todo better but the differences inresponse rate-56% vs 50% in theINTACT trial and 29% vs 15% inIDEAL-did not reach statistical significance.In contrast, the BR.21 analysisshowed that EGFR amplification wasa significantly strong predictor of outcome-more powerful, in fact, thanmutational status. Dr. Tsao and colleaguesfound a high gene copy numberwas associated with a response rateof 20% compared to just 2.4% in patientswith a low gene copy number(P = .03). Though mutations did correlatewith response in BR.21, the differenceswere not significant, and nosurvival benefit was seen among patientswith mutations.Another study presented at ASCOalso found EGFR gene amplificationto be a strong predictor of response(abstract 7030). Fred Hirsch, MD,from the University of Colorado CancerCenter, Aurora, and colleaguesanalyzed samples from patients withbronchioalveolar carcinoma, a uniquetype of NSCLC that is resistant to chemotherapy.They found that an increasedgene copy number, as measuredby fluorescent in situhybridization or FISH, was predictiveof response and survival to gefitinib.This study supported a recent findingfrom the same group, reported byFederico Cappuzzo, MD and colleagues(J Natl Cancer Inst May4;97(9):643-655, 2005). That studyalso found gene copy number, as determinedby FISH, to be a significantpredictor of response and survival togefitinib in patients with advancedNSCLC.EGFR Amplification:A Distinct Subgroup?Both studies showed that EGFRmutations correlate closely with theclinical characteristics associated withbetter outcome.Two other, smaller studies yieldedmixed findings regarding mutationsand amplifications. Toshimi Takano,MD, of the National Cancer CenterHospital in Tokyo, and colleagues analyzedsurgical specimens from 66 patientstreated with gefitinib (abstract7032). They found that EGFR mutationswere a major determinant of responseand survival, but also foundthat EGFR gene copy number was significantlyassociated with mutationalstatus. Dr. Takano noted that he considersEGFR copy number "as a surrogatemarker for EGFR mutations ratherthan a true determinant ofEGFR-TKI sensitivity."On the other hand, no relationshipbetween amplification and responsewas found in a study of tissue samplesfrom 44 patients treated with gefitinibor erlotinib, presented by VincentMiller, MD, of Memorial Sloan-KetteringCancer Center, New York (abstract7031). Amplification in thisstudy was measured with chromogenicin situ hybridization, or CISH. Thisstudy's findings supported the importanceof mutational status, however,in that EGFR mutations were a powerfulpredictor.Discrepant Findings ExploredSpeculating on the reasons for thediscrepant findings related to EGFRmutations, experts suggested severalpossibilities. Pasi Janne, MD, of Dana-Farber Cancer Institute, Boston, notedthat there was a wide range of responserates associated with mutations,from a low of 16% to a high of83%. This suggests that mutations area part, but not all, of the story, he saidand/or that clinical and molecularcontexts could be important as well.It's also possible that "all mutationsare not equal," Dr. Janne noted,and that some have a stronger effecton response. What's more, there maybe differences in the two agents, gefitiniband erlotinib, that account forthe different findings.Different findings on the role ofEGFR amplification also need furtherstudy. Manuel Hidalgo, MD, of SidneyKimmel Comprehensive CancerCenter at Johns Hopkins, Baltimore,noted that the studies' heterogeneouspatient populations and the fact thatthese were all retrospective analyses,with tissue samples selected based onavailability, could contribute to theinconclusive findings. He also said themethods used to determine genecopy-FISH, CISH, and others-might explain differences, as mightdifferent scoring systems and cutoffpoints used to define amplification.Dr. Janne also speculated that thedifferent methods of determiningEGFR gene amplification could be akey issue. "I think additional studiesand characterizations of these groupswill be needed," he said.