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

D. Ross Camidge, Scott A. Kono, Antonella Flacco, Aik-Choon Tan, Robert C. Doebele, Qing Zhou, Lucio Crino, Wilbur A. Franklin, Marileila Varella-Garcia

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)5581-5590
Number of pages10
JournalClinical Cancer Research
Volume16
Issue number22
DOIs
Publication statusPublished - 2010 Nov 15
Externally publishedYes

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Gene Rearrangement
Lung Neoplasms
Fluorescence In Situ Hybridization
Therapeutics
Mutation
anaplastic lymphoma kinase
Adenocarcinoma
Smoking
Gene Dosage
Non-Small Cell Lung Carcinoma

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment. / Camidge, D. Ross; Kono, Scott A.; Flacco, Antonella; Tan, Aik-Choon; Doebele, Robert C.; Zhou, Qing; Crino, Lucio; Franklin, Wilbur A.; Varella-Garcia, Marileila.

In: Clinical Cancer Research, Vol. 16, No. 22, 15.11.2010, p. 5581-5590.

Research output: Contribution to journalArticle

Camidge, DR, Kono, SA, Flacco, A, Tan, A-C, Doebele, RC, Zhou, Q, Crino, L, Franklin, WA & Varella-Garcia, M 2010, 'Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment', Clinical Cancer Research, vol. 16, no. 22, pp. 5581-5590. https://doi.org/10.1158/1078-0432.CCR-10-0851
Camidge, D. Ross ; Kono, Scott A. ; Flacco, Antonella ; Tan, Aik-Choon ; Doebele, Robert C. ; Zhou, Qing ; Crino, Lucio ; Franklin, Wilbur A. ; Varella-Garcia, Marileila. / Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment. In: Clinical Cancer Research. 2010 ; Vol. 16, No. 22. pp. 5581-5590.
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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.",
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T1 - Optimizing the detection of lung cancer patients harboring anaplastic lymphoma kinase (ALK) gene rearrangements potentially suitable for ALK inhibitor treatment

AU - Camidge, D. Ross

AU - Kono, Scott A.

AU - Flacco, Antonella

AU - Tan, Aik-Choon

AU - Doebele, Robert C.

AU - Zhou, Qing

AU - Crino, Lucio

AU - Franklin, Wilbur A.

AU - Varella-Garcia, Marileila

PY - 2010/11/15

Y1 - 2010/11/15

N2 - 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.

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 (∼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.

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