Concordance of anaplastic lymphoma kinase (ALK) gene rearrangements between circulating tumor cells and tumor in non-small cell lung cancer
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Chye Ling Tan1,*, Tse Hui Lim1,*, Tony KH Lim1, Daniel Shao-Weng Tan2, Yong Wei Chua1, Mei Kim Ang2, Brendan Pang3, Chwee Teck Lim4,5, Angela Takano1, Alvin Soon-Tiong Lim1, Man Chun Leong6 and Wan-Teck Lim2,7
1 Department of Pathology, Singapore General Hospital, Singapore
2 Department of Medical Oncology, National Cancer Center Singapore, Singapore
3 Department of Molecular Oncology, National University Health System Singapore, Singapore
4 Faculty of Engineering, Department of Biomedical Engineering, National University of Singapore, Singapore
5 Mechanobiology Institute, National University of Singapore, Singapore
6 Clearbridge Biomedics Pte Ltd, Singapore
7 Institute of Molecular and Cell Biology, Singapore
* These authors have contributed equally to this work
Wan-Teck Lim, email:
Keywords: ALK-gene rearrangement, circulating tumor cells, fluorescent in-situ hybridization, lung cancer, molecular diagnosis
Received: November 14, 2015 Accepted: February 28, 2016 Published: March 16, 2016
Anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC) is routinely evaluated by fluorescent in-situ hybridization (FISH) testing on biopsy tissues. Testing can be challenging however, when suitable tissue samples are unavailable. We examined the relevance of circulating tumor cells (CTC) as a surrogate for biopsy-based FISH testing. We assessed paired tumor and CTC samples from patients with ALK rearranged lung cancer (n = 14), ALK-negative lung cancer (n = 12), and healthy controls (n = 5) to derive discriminant CTC counts, and to compare ALK rearrangement patterns. Blood samples were enriched for CTCs to be used for ALK FISH testing. ALK-positive CTCs counts were higher in ALK-positive NSCLC patients (3–15 cells/1.88 mL of blood) compared with ALK-negative NSCLC patients and healthy donors (0–2 cells/1.88 mL of blood). The latter range was validated as the ‘false positive’ cutoff for ALK FISH testing of CTCs. ALK FISH signal patterns observed on tumor biopsies were recapitulated in CTCs in all cases. Sequential CTC counts in an index case of lung cancer with no evaluable tumor tissue treated with crizotinib showed six, three and eleven ALK-positive CTCs per 1.88 mL blood at baseline, partial response and post-progression time points, respectively. Furthermore, ALK FISH rearrangement suggestive of gene copy number increase was observed in CTCs following progression. Recapitulation of ALK rearrangement patterns in the tumor on CTCs, suggested that CTCs might be used to complement tissue-based ALK testing in NSCLC to guide ALK-targeted therapy when suitable tissue biopsy samples are unavailable for testing.
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