Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment

Clin Cancer Res. 2010 Nov 15;16(22):5581-90. doi: 10.1158/1078-0432.CCR-10-0851. Epub 2010 Nov 9.

Abstract

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 (∼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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anaplastic Lymphoma Kinase
  • Carcinoma, Non-Small-Cell Lung / diagnosis
  • Carcinoma, Non-Small-Cell Lung / drug therapy*
  • Carcinoma, Non-Small-Cell Lung / enzymology*
  • Carcinoma, Non-Small-Cell Lung / genetics
  • ErbB Receptors / biosynthesis
  • ErbB Receptors / genetics
  • Genetic Testing / methods*
  • Humans
  • In Situ Hybridization, Fluorescence
  • Lung Neoplasms / diagnosis
  • Lung Neoplasms / drug therapy*
  • Lung Neoplasms / enzymology*
  • Lung Neoplasms / genetics
  • Mutation
  • Pharmacogenetics / methods
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use*
  • Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
  • Receptor Protein-Tyrosine Kinases / genetics*
  • Structure-Activity Relationship

Substances

  • Protein Kinase Inhibitors
  • ALK protein, human
  • Anaplastic Lymphoma Kinase
  • ErbB Receptors
  • Receptor Protein-Tyrosine Kinases