EGFR-exon-20-insertion-mutations-耐药突变.pdf

Vol 13 January 2012 e23ReviewLancet Oncol 2012;13:e2331Published OnlineJuly 18,2011DOI:10.1016/S1470-2045(11)70129-2This publication has been corrected.The corrected version fi rst appeared at on November 25,2011Department of Medicine,Division of Hematology/Oncology,Beth Israel Deaconess Medical Center,Harvard Medical School,Boston,MA,USA(H Yasuda MD,S Kobayashi MD,D B Costa MD)Correspondence to:Dr Daniel B Costa,Division of Hematology/Oncology,Beth Israel Deaconess Medical Center,Boston,MA,USA 02215dbcostabidmc.harvard.eduEGFR exon 20 insertion mutations in non-small-cell lung cancer:preclinical data and clinical implicationsHiroyuki Yasuda,Susumu Kobayashi,Daniel B CostaLung cancer is the leading cause of cancer-related death.The identifi cation of epidermal growth factor receptor(EGFR)somatic mutations defi ned a new,molecularly classifi ed subgroup of non-small-cell lung cancer(NSCLC).Classic EGFR activating mutations,such as inframe deletions in exon 19 or the Leu858Arg(L858R)point mutation in exon 21 are associated with sensitivity to fi rst generation quinazoline reversible EGFR tyrosine kinase inhibitors(TKIs).EGFR exon 20 insertion mutations,which are typically located after the C-helix of the tyrosine kinase domain of EGFR,may account for up to 4%of all EGFR mutations.Preclinical models have shown that the most prevalent EGFR exon 20 insertion mutated proteins are resistant to clinically achievable doses of reversible(gefi tinib,erlotinib)and irreversible(neratinib,afatinib,PF00299804)EGFR TKIs.Growing clinical experience with patients whose tumours harbour EGFR exon 20 insertions corresponds with the preclinical data;very few patients have had responses to EGFR TKIs.Despite the prevalence and biological importance of EGFR exon 20 insertions,few reports have summarised all preclinical and clinical data on these mutations.Here,we review the literature and provide an update with an emphasis on the structural,molecular,and clinical implications of EGFR exon 20 insertions.IntroductionLung cancer is the leading cause of cancer-related death worldwide,with more than 16 million cases diagnosed and 13 million deaths per year.1 Therefore,even small subgroups of non-small-cell lung cancer(NSCLC)contribute to signifi cant morbidity and mortality.In 2004,the identifi cation of somatic mutations in the epidermal growth factor receptor(EGFR)provided a glimpse into a clinically relevant oncogene and a new molecularly classifi ed subgroup of NSCLC.24 Among the multitude of mutations found in the EGFR gene(fi gure 1),the most common cluster in two regions and are often termed classic activating mutations.These include inframe deletions around the LeuArgGluAla motif(residues 746750)of exon 19(roughly 4550%of all EGFR mutations),and the Leu858Arg(L858R)point mutation in exon 21(about 4045%of EGFR mutations).57 Classic EGFR mutations are more common in tumours in women,Asians,never smokers,and those with adenocarcinoma histology.5,7,8 About 15%of all NSCLCs in western Europeans,30%in East Asians,and 50%in never smokers are EGFR mutation-positive.5,7,8 Most patients with exon 19 deletions or Leu858Arg EGFR activating mutations have substantial clinical and radiographic responses to monotherapy with the reversible anilinoquinazoline,ATP-mimetic EGFR tyrosine kinase inhibitors(TKIs)gefi tinib and erlotinib.9 Response rates(RRs)exceed 70%,with median progression-free survival(PFS)of longer than 9 months and overall survival(OS)that reaches 24 months.917 At least three randomised phase 3 trials have shown a better RR and PFS with gefi tinib or erlotinib compared with chemotherapy in patients with classic EGFR mutation-positive NSCLC.1821 Additional EGFR mutations(fi gure 1)have been associated with some sensitivity to gefi tinib and erlotinib,although their ability to predict a radiographic and clinical response to gefi tinib or erlotinib is less striking than that of classic EGFR mutations.22 These include point mutations in position Gly719 of exon 18(Gly719Ala,Cys,or Ser),which account for about 3%of EGFR mutations,and a recurrent Leu861Gln mutation in exon 21 that represents about 2%of EGFR mutations.23,24 The frequency of classic EGFR mutations in patients with diff erent ethnic backgrounds has not been completely established;however,EGFR genotyping of large prospective cohorts of western Europeans with NSCLC shows a higher frequency of exon 19 deletions than Leu858Arg mutations,11 compared with similar cohorts or clinical trials of east Asian populations where exon 19 deletions are only slightly more prevalent than Leu858Arg mutations.18 Some EGFR mutations are not often associated with radiographic responses and clinical benefi t with reversible EGFR TKIs.This is the case for most exon 20 EGFR insertions reported so far.2527 Exon 20 insertion mutations might account for up to 4%of all EGFR mutations,22,24,28 and therefore as many as 10 000 new yearly cases of NSCLC worldwide.1 The latter estimate is based on data f