Context.-A subset of lung adenocarcinomas appears preferentially sensitive to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). EGFR-activating mutations and never smoking are associated with response to TKIs. Objectives.-To describe the morphology of adenocarcinomas responsive to TKIs, compare it to tumors in nonresponding patients, and correlate findings with EGFR mutations, gene copy number, and protein expression. Design.-Material from 52 EGFR TKI-treated patients was studied: 29 responders and 23 nonresponders. Adenocarcinoma subtypes and morphologic features were defined in histologic and cytologic material. EGFR mutations were detected by sequencing, copy number by chromogenic in situ hybridization, and expression by immunohistochemistry. Results.-Tumors from TKI responders tended to be better-differentiated adenocarcinomas with bronchioloalveolar carcinoma components. Nonresponders showed more heterogeneous morphology, higher grade, and more subtypes, and were more likely to show solid growth. In nonresponders, the only pure bronchioloalveolar carcinoma was mucinous, a subtype known to be negative for EGFR mutations. Using World Health Organization criteria, all tumors in both groups other than pure bronchioloalveolar carcinomas would be classified as adenocarcinomas, mixed subtype, thereby obscuring some of these distinctions. EGFR mutations were significantly more common in responders (22/29 vs 0/23; P .001). Immunohistochemistry and chromogenic in situ hybridization results were not significantly correlated with EGFR mutations or response to TKIs in this study. Conclusions.-Overall, histologic differences exist between tumors that respond to TKIs and those that do not, although sampling affects classification, and there is significant histologic overlap between the 2 groups. Response is strongly associated with EGFR mutations.
Original Article Morphologic Features of Adenocarcinoma of the Lung Predictive of Response to the Epidermal Growth Factor Receptor Kinase Inhibitors Erlotinib and Geﬁtinib Maureen F. Zakowski, MD; Sanaa Hussain, MD; William Pao, MD, PhD; Marc Ladanyi, MD; Michelle S. Ginsberg, MD; Robert Heelan, MD; Vincent A. Miller, MD; Valerie W. Rusch, MD; Mark G. Kris, MD ● Context.—A subset of lung adenocarcinomas appears heterogeneous morphology, higher grade, and more sub- preferentially sensitive to epidermal growth factor receptor types, and were more likely to show solid growth. In non- (EGFR) tyrosine kinase inhibitors (TKIs). EGFR-activating responders, the only pure bronchioloalveolar carcinoma mutations and never smoking are associated with response was mucinous, a subtype known to be negative for EGFR to TKIs. mutations. Using World Health Organization criteria, all Objectives.—To describe the morphology of adenocar- tumors in both groups other than pure bronchioloalveolar cinomas responsive to TKIs, compare it to tumors in nonre- carcinomas would be classiﬁed as adenocarcinomas, mixed sponding patients, and correlate ﬁndings with EGFR mu- subtype, thereby obscuring some of these distinctions. tations, gene copy number, and protein expression. EGFR mutations were signiﬁcantly more common in re- Design.—Material from 52 EGFR TKI-treated patients sponders (22/29 vs 0/23; P .001). Immunohistochemis- was studied: 29 responders and 23 nonresponders. Ade- try and chromogenic in situ hybridization results were not nocarcinoma subtypes and morphologic features were de- signiﬁcantly correlated with EGFR mutations or response ﬁned in histologic and cytologic material. EGFR mutations to TKIs in this study. were detected by sequencing, copy number by chromo- Conclusions.—Overall, histologic differences exist be- genic in situ hybridization, and expression by immunohis- tween tumors that respond to TKIs and those that do not, tochemistry. although sampling affects classiﬁcation, and there is sig- Results.—Tumors from TKI responders tended to be bet- niﬁcant histologic overlap between the 2 groups. Response ter-differentiated adenocarcinomas with bronchioloalveo- is strongly associated with EGFR mutations. lar carcinoma components. Nonresponders showed more (Arch Pathol Lab Med. 2009;133:470–477) L ung cancer remains the leading cause of cancer death in the United States and worldwide in both men and women.1 The treatment of non–small cell lung cancer appear preferentially susceptible to the effects of the TKI geﬁtinib (Iressa, AstraZeneca, Wilmington, Del). A similar agent, erlotinib (Tarceva, Genentech, South San Francisco, (NSCLC) has recently expanded beyond surgery and con- Calif), has also been used with success against the same ventional chemotherapy with the identiﬁcation of tumors spectrum of lung carcinomas. Adenocarcinoma with BAC responsive to tyrosine kinase inhibitors (TKIs). Histopa- features corresponds to the World Health Organization thology, along with careful clinical/molecular correlation, (WHO) classiﬁcation of adenocarcinoma, mixed subtype plays a critical role in the selection of patients most likely with a BAC component. to respond to these new small molecule agents. The epidermal growth factor receptor (EGFR) is a mem- We have previously shown2 that among NSCLCs, ade- ber of a family of transmembrane glycoproteins that in- nocarcinoma, and, interestingly, the subtype adenocarci- cludes HER-2, HER-3, and HER-4 that functions as a re- noma with bronchioloalveolar carcinoma (BAC) features, ceptor tyrosine kinase and is present on and is commonly overexpressed in most NSCLCs. Overexpression in NSCLC ranges from about 40% to 90%. Differences in ex- Accepted for publication July 29, 2008. pression may relate to differences in assessment tech- From the Departments of Pathology (Drs Zakowski, Hussain, and Ladanyi), Medicine (Drs Pao, Miller, and Kris), Radiology (Drs Gins- niques, deﬁnition of level of overexpression, and differ- berg and Heelan), and Surgery (Dr Rusch), Memorial Sloan-Ketter- ences in the study populations.3 Agents that interfere with ing Cancer Center, New York, NY. Dr Hussain is currently afﬁliated phosphorylation of critical tyrosine residues can block sig- with the Department of Pathology, S. E. D. Medical Laboratories, nal transduction through EGFR. Geﬁtinib and erlotinib Albuquerque, NM. are such agents. The US Food and Drug Administration Dr Miller has received honoraria from Genentech (South San Fran- approved geﬁtinib in 2003 as targeted monotherapy for cisco, Calif) and OSI Pharmaceuticals (Melville, NY), which comarket the treatment of patients with locally advanced or meta- and manufacture erlotinib. The other authors have no relevant ﬁnancial interest in the products or companies described in this article. static NSCLC. Use of this drug was subsequently restrict- Reprints: Maureen F. Zakowski, MD, Department of Pathology, Me- ed when a trial in unsel
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