title: PTCH1 expression at diagnosis predicts imatinib failure in chronic myeloid leukaemia patients in chronic phase.
abstract: The tyrosine kinase inhibitor (TKI) imatinib has revolutionized the management of chronic myeloid leukaemia (CML). However, around 25% of patients fail to sustain an adequate response. We sought to identify gene-expression biomarkers that could be used to predict imatinib response. The expression of 29 genes, previously implicated in CML pathogenesis, were measured by TaqMan Low Density Array in 73 CML patient samples. Patients were divided into low and high expression for each gene and imatinib failure (IF), probability of achieving CCyR, progression free survival and CML related OS were compared by Kaplan-Meier and log-rank. Results were validated in a second cohort of 56 patients, with a further technical validation using custom gene-expression assays in a conventional RT-qPCR in a sub-cohort of 37 patients. Patients with low PTCH1 expression showed a worse clinical response for all variables in all cohorts. PTCH1 was the most significant predictor in the multivariate analysis compared with Sokal, age and EUTOS. PTCH1 expression assay showed the adequate sensitivity, specificity and predictive values to predict for IF. Given the different treatments available for CML, measuring PTCH1 expression at diagnosis may help establish who will benefit best from imatinib and who is better selected for second generation TKI.
authors.affiliation: Centre for Haematology, Department of Medicine, Imperial College London, London, United Kingdom.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Alonso-Dominguez
authors.forename: Jacob
authors.initials: J
authors.lastname: Grinfeld
authors.forename: Mary
authors.initials: M
authors.lastname: Alikian
authors.forename: David
authors.initials: D
authors.lastname: Marin
authors.forename: Alistair
authors.initials: A
authors.lastname: Reid
authors.forename: Mustafa
authors.initials: M
authors.lastname: Daghistani
authors.forename: Corinne
authors.initials: C
authors.lastname: Hedgley
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Brien
authors.forename: Richard E
authors.initials: RE
authors.lastname: Clark
authors.forename: Jane
authors.initials: J
authors.lastname: Apperley
authors.forename: Letizia
authors.initials: L
authors.lastname: Foroni
authors.forename: Gareth
authors.initials: G
authors.lastname: Gerrard
mesh_terms: D001549:Benzamides / Q000627:therapeutic use*; D015331:Cohort Studies; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D000068877:Imatinib Mesylate; D053208:Kaplan-Meier Estimate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D015466:Leukemia, Myeloid, Chronic-Phase / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D008875:Middle Aged; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010865:Pilot Projects; D010879:Piperazines / Q000627:therapeutic use*; D011237:Predictive Value of Tests; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000235:genetics*; D012680:Sensitivity and Specificity; D059467:Transcriptome; D017211:Treatment Failure
chemical_list: D001549:Benzamides; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011956:Receptors, Cell Surface; D000068877:Imatinib Mesylate