Concordance of anaplastic lymphoma kinase (ALK) gene rearrangements between circulating tumor cells and tumor in non-small cell lung cancer.

Chye Ling Tan,Alvin Soon-Tiong Lim,Tse Hui Lim,Tony Kh Lim,Yong Wei Chua,Mei Kim Ang,Chwee Teck Lim,Wan-Teck Lim,Daniel Shao-Weng Tan,Angela Takano,Man Chun Leong,Brendan Pang

doi:10.18632/oncotarget.8136

Abstract

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.

Highlights

Lung cancer accounts for about 13% of all cancer diagnoses and remains the leading cause of death by cancer in the world [1], with almost 70% of patients diagnosed with locally advanced or metastatic disease at presentation [1, 2]
This discovery resulted in the accelerated development and approval by the U.S Food and Drug Administration (FDA) of the anaplastic lymphoma kinase (ALK)-targeting tyrosine kinase inhibitors (TKIs) crizotinib (Xalkori®, Pfizer, New York, USA) in 2011, and ceritinib (ZykadiaTM, Novartis, Basel, Switzerland) in 2014 to treat patients with metastatic Non-small cell lung cancer (NSCLC) who express the abnormal ALK gene [10, 11]
We further explored the potential use of circulating tumor cells (CTC) in lung cancer, as a surrogate for molecular testing of the primary tumor for ALK gene rearrangement

Summary

Introduction

Lung cancer accounts for about 13% of all cancer diagnoses and remains the leading cause of death by cancer in the world [1], with almost 70% of patients diagnosed with locally advanced or metastatic disease at presentation [1, 2]. The overall incidence of ALK gene rearrangement in NSCLC ranges between 0.4% and 13.4%, and is similar in both Asian and Western populations [9]. This discovery resulted in the accelerated development and approval by the U.S Food and Drug Administration (FDA) of the ALK-targeting tyrosine kinase inhibitors (TKIs) crizotinib (Xalkori®, Pfizer, New York, USA) in 2011, and ceritinib (ZykadiaTM, Novartis, Basel, Switzerland) in 2014 to treat patients with metastatic NSCLC who express the abnormal ALK gene [10, 11]

Methods

Results

Conclusion