Morphologic Features of Adenocarcinoma of the Lung Predictive of Response to the Epidermal Growth Factor Receptor Kinase Inhibitors Erlotinib and Gefitinib by ProQuest


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									                                                             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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