TY - JOUR
T1 - Rearranged EML4-ALK fusion transcripts sequester in circulating blood platelets and enable blood-based crizotinib response monitoring in non-small-cell lung cancer
AU - Nilsson, R Jonas A
AU - Karachaliou, Niki
AU - Berenguer, Jordi
AU - Gimenez-Capitan, Ana
AU - Schellen, Pepijn
AU - Teixido, Cristina
AU - Tannous, Jihane
AU - Kuiper, Justine L
AU - Drees, Esther
AU - Grabowska, Magda
AU - van Keulen, Marte
AU - Heideman, Danielle A M
AU - Thunnissen, Erik
AU - Dingemans, Anne-Marie C
AU - Viteri, Santiago
AU - Tannous, Bakhos A
AU - Drozdowskyj, Ana
AU - Rosell, Rafael
AU - Smit, Egbert F
AU - Wurdinger, Thomas
PY - 2016/1/5
Y1 - 2016/1/5
N2 - PURPOSE: Non-small-cell lung cancers harboring EML4-ALK rearrangements are sensitive to crizotinib. However, despite initial response, most patients will eventually relapse, and monitoring EML4-ALK rearrangements over the course of treatment may help identify these patients. However, challenges associated with serial tumor biopsies have highlighted the need for blood-based assays for the monitoring of biomarkers. Platelets can sequester RNA released by tumor cells and are thus an attractive source for the non-invasive assessment of biomarkers.METHODS: EML4-ALK rearrangements were analyzed by RT-PCR in platelets and plasma isolated from blood obtained from 77 patients with non-small-cell lung cancer, 38 of whom had EML4-ALK-rearranged tumors. In a subset of 29 patients with EML4-ALK-rearranged tumors who were treated with crizotinib, EML4-ALK rearrangements in platelets were correlated with progression-free and overall survival.RESULTS: RT-PCR demonstrated 65% sensitivity and 100% specificity for the detection of EML4-ALK rearrangements in platelets. In the subset of 29 patients treated with crizotinib, progression-free survival was 3.7 months for patients with EML4-ALK+ platelets and 16 months for those with EML4-ALK- platelets (hazard ratio, 3.5; P = 0.02). Monitoring of EML4-ALK rearrangements in the platelets of one patient over a period of 30 months revealed crizotinib resistance two months prior to radiographic disease progression.CONCLUSIONS: Platelets are a valuable source for the non-invasive detection of EML4-ALK rearrangements and may prove useful for predicting and monitoring outcome to crizotinib, thereby improving clinical decisions based on radiographic imaging alone.
AB - PURPOSE: Non-small-cell lung cancers harboring EML4-ALK rearrangements are sensitive to crizotinib. However, despite initial response, most patients will eventually relapse, and monitoring EML4-ALK rearrangements over the course of treatment may help identify these patients. However, challenges associated with serial tumor biopsies have highlighted the need for blood-based assays for the monitoring of biomarkers. Platelets can sequester RNA released by tumor cells and are thus an attractive source for the non-invasive assessment of biomarkers.METHODS: EML4-ALK rearrangements were analyzed by RT-PCR in platelets and plasma isolated from blood obtained from 77 patients with non-small-cell lung cancer, 38 of whom had EML4-ALK-rearranged tumors. In a subset of 29 patients with EML4-ALK-rearranged tumors who were treated with crizotinib, EML4-ALK rearrangements in platelets were correlated with progression-free and overall survival.RESULTS: RT-PCR demonstrated 65% sensitivity and 100% specificity for the detection of EML4-ALK rearrangements in platelets. In the subset of 29 patients treated with crizotinib, progression-free survival was 3.7 months for patients with EML4-ALK+ platelets and 16 months for those with EML4-ALK- platelets (hazard ratio, 3.5; P = 0.02). Monitoring of EML4-ALK rearrangements in the platelets of one patient over a period of 30 months revealed crizotinib resistance two months prior to radiographic disease progression.CONCLUSIONS: Platelets are a valuable source for the non-invasive detection of EML4-ALK rearrangements and may prove useful for predicting and monitoring outcome to crizotinib, thereby improving clinical decisions based on radiographic imaging alone.
KW - Adult
KW - Aged
KW - Aged, 80 and over
KW - Blood Platelets/metabolism
KW - Carcinoma, Non-Small-Cell Lung/blood
KW - Crizotinib
KW - Drug Monitoring/methods
KW - Female
KW - Humans
KW - In Situ Hybridization, Fluorescence
KW - Kaplan-Meier Estimate
KW - Lung Neoplasms/blood
KW - Male
KW - Middle Aged
KW - Oncogene Proteins, Fusion/blood
KW - Outcome Assessment (Health Care)/methods
KW - Prognosis
KW - Proportional Hazards Models
KW - Protein Kinase Inhibitors/therapeutic use
KW - Pyrazoles/therapeutic use
KW - Pyridines/therapeutic use
KW - Reproducibility of Results
KW - Reverse Transcriptase Polymerase Chain Reaction
U2 - https://doi.org/10.18632/oncotarget.6279
DO - https://doi.org/10.18632/oncotarget.6279
M3 - Article
C2 - 26544515
SN - 1949-2553
VL - 7
SP - 1066
EP - 1075
JO - Oncotarget
JF - Oncotarget
IS - 1
ER -