PMID- 21062932
OWN - NLM
STAT- MEDLINE
DCOM- 20111017
LR  - 20211020
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 16
IP  - 22
DP  - 2010 Nov 15
TI  - Optimizing the detection of lung cancer patients harboring anaplastic lymphoma 
      kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor 
      treatment.
PG  - 5581-90
LID - 10.1158/1078-0432.CCR-10-0851 [doi]
AB  - PURPOSE: Anaplastic lymphoma kinase (ALK) rearrangements, associated with 
      sensitivity to an experimental ALK/MET inhibitor, occur in 3% to 5% of non-small 
      cell lung cancers. Intratumoral fluorescence in situ hybridization (FISH) 
      heterogeneity has been reported. We explored the heterogeneity basis, the 
      requirements for accurately determining ALK FISH positivity, and the effect of 
      enriching the tested population using clinical and molecular factors. 
      EXPERIMENTAL DESIGN: Lung cancer patients were screened by ALK and MET FISH and 
      for EGFR and KRAS mutations. RESULTS: Thirteen ALK-positive cases were identified 
      from 73 screened patients. Gene copy number increases occurred together with 
      classic rearrangements. All positive cases were adenocarcinomas, 12 were 
      EGFR/KRAS wild-type, and 1 had a coexistent EGFR exon 20 mutation. No association 
      with MET amplification occurred. ALK positivity was associated with <10-pack-year 
      smoking status (P = 0.0004). Among adenocarcinomas, without KRAS or EGFR 
      mutations, with <10-pack-year history, 44.8% of cases were ALK positive. ALK FISH 
      positivity was heterogeneous, but mean values in tumor areas from ALK-positive 
      patients (54% of cells; range, 22-87%) were significantly higher than in adjacent 
      normal tissue or tumor/normal areas from ALK-negative patients (mean, 5-7%). 
      Contiguous sliding field analyses showed diffuse heterogeneity without evidence 
      of focal ALK rearrangements. One hundred percent sensitivity and specificity 
      occurred when four or more fields ( approximately 60 cells) were counted. CONCLUSIONS: 
      Intratumoral ALK FISH heterogeneity reflects technique, not biology. The clinical 
      activity of ALK/MET inhibitors in ALK-positive patients probably reflects ALK, 
      but not MET, activity. Prescreening by histology, EGFR/KRAS mutations, and 
      smoking status dramatically increases the ALK-positive hit rate compared with 
      unselected series.
CI  - (c)2010 AACR.
FAU - Camidge, D Ross
AU  - Camidge DR
AD  - Division of Medical Oncology and Department of Pathology, University of 
      Colorado-Denver, 1665 North Ursula Street, Aurora, CO 80045-0508, USA. 
      ross.camidge@ucdenver.edu
FAU - Kono, Scott A
AU  - Kono SA
FAU - Flacco, Antonella
AU  - Flacco A
FAU - Tan, Aik-Choon
AU  - Tan AC
FAU - Doebele, Robert C
AU  - Doebele RC
FAU - Zhou, Qing
AU  - Zhou Q
FAU - Crino, Lucio
AU  - Crino L
FAU - Franklin, Wilbur A
AU  - Franklin WA
FAU - Varella-Garcia, Marileila
AU  - Varella-Garcia M
LA  - eng
GR  - P50 CA058187/CA/NCI NIH HHS/United States
GR  - P50CA58187/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20101109
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.10.1 (ALK protein, human)
RN  - EC 2.7.10.1 (Anaplastic Lymphoma Kinase)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases)
SB  - IM
MH  - Anaplastic Lymphoma Kinase
MH  - Carcinoma, Non-Small-Cell Lung/diagnosis/*drug therapy/*enzymology/genetics
MH  - ErbB Receptors/biosynthesis/genetics
MH  - Genetic Testing/*methods
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Lung Neoplasms/diagnosis/*drug therapy/*enzymology/genetics
MH  - Mutation
MH  - Pharmacogenetics/methods
MH  - Protein Kinase Inhibitors/pharmacology/*therapeutic use
MH  - Receptor Protein-Tyrosine Kinases/antagonists & inhibitors/*genetics
MH  - Structure-Activity Relationship
PMC - PMC3395226
MID - NIHMS375238
EDAT- 2010/11/11 06:00
MHDA- 2011/10/18 06:00
PMCR- 2012/07/12
CRDT- 2010/11/11 06:00
PHST- 2010/11/11 06:00 [entrez]
PHST- 2010/11/11 06:00 [pubmed]
PHST- 2011/10/18 06:00 [medline]
PHST- 2012/07/12 00:00 [pmc-release]
AID - 1078-0432.CCR-10-0851 [pii]
AID - 10.1158/1078-0432.CCR-10-0851 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2010 Nov 15;16(22):5581-90. doi: 10.1158/1078-0432.CCR-10-0851. 
      Epub 2010 Nov 9.