title: The sum of gains and losses of genes encoding the protein tyrosine kinase targets predicts response to multi-kinase inhibitor treatment: Characterization, validation, and prognostic value.
abstract: Validated predictive biomarkers for multi-tyrosine kinase inhibitors (MTKI) efficacy are lacking. We hypothesized that interindividual response variability is partially dependent on somatic DNA copy number alterations (SCNAs), particularly those of genes encoding the protein tyrosines targeted by MTKI (called target genes). Genomic alterations were investigated in MTKI responsive and non responsive patients with different histological subtypes included in the ProfiLER protocol (NCT 01774409). From March 2013 to August 2014, 58 patients with advanced cancer treated with one of 7 MTKIs were included in the ProfiLER trial and split into one discovery cohort (n = 13), and 2 validation cohorts (n = 12 and 33). An analysis of the copy number alterations of kinase-coding genes for each of 7 MTKIs was conducted. A prediction algorithm (SUMSCAN) based on the presence of specific gene gains (Tumor Target Charge, TTC) and losses (Tumor Target Losses, TTL) was conceived and validated in 2 independent validation cohorts. MTKI sensitive tumors present a characteristic SCNA profile including a global gain profile, and specific gains for target genes while MTKI resistant tumors present the opposite. SUMSCAN favorable patients achieved longer progression-free and overall survival. This work shows that the copy number sum of kinase-coding genes enables the prediction of response of cancer patients to MTKI, opening a novel paradigm for the treatment selection of these patients.
authors: Department of Translational Research, Centre Leon Berard, 69008 Lyon France.
authors: Xiaojun
authors: X
authors: Jiang
authors: Department of Translational Research, Centre Leon Berard, 69008 Lyon France.
authors: Daniel
authors: D
authors: Pissaloux
authors: Department of Medical Oncology, Centre Leon Berard, 69008 Lyon France.
authors: Christelle
authors: C
authors: De La Fouchardiere
authors: Department of Medical Oncology, Centre Leon Berard, 69008 Lyon France.
authors: Françoise
authors: F
authors: Desseigne
authors: Department of Translational Research, Centre Leon Berard, 69008 Lyon France.
authors: Qing
authors: Q
authors: Wang
authors: Department of Translational Research, Centre Leon Berard, 69008 Lyon France.
authors: Valery
authors: V
authors: Attignon
authors: Department of Pathobiology, Centre Leon Berard, 69008 Lyon France.
authors: Marie-Eve
authors: ME
authors: Fondrevelle
authors: Department of Pathobiology, Centre Leon Berard, 69008 Lyon France.
authors: Arnaud
authors: A
authors: De La Fouchardiere
authors: Department of Medical Oncology, Centre Leon Berard, 69008 Lyon France.
authors: Maurice
authors: M
authors: Perol
authors: Department of Medical Oncology, Centre Leon Berard, 69008 Lyon France.
authors: Philippe
authors: P
authors: Cassier
authors: Department of Clinical Research, Centre Leon Berard, 69008 Lyon France.
authors: Christelle
authors: C
authors: Seigne
authors: Department of Clinical Research, Centre Leon Berard, 69008 Lyon France.
authors: David
authors: D
authors: Perol
authors: Department of Medical Oncology, Centre Leon Berard, 69008 Lyon France.
authors: Isabelle
authors: I
authors: Ray-Coquard
authors: Department of Surgery, Centre Leon Berard, 69008 Lyon France.
authors: Pierre
authors: P
authors: Meeus
authors: Department of Medical Oncology, Centre Leon Berard, 69008 Lyon France.
authors: Jerome
authors: J
authors: Fayette
authors: Department of Medical Oncology, Centre Leon Berard, 69008 Lyon France.
authors: Aude
authors: A
authors: Flechon
authors: Department of Medical Oncology, Gustave Roussy, 94805, Villejuif France.
authors: Axel
authors: A
authors: Le Cesne
authors: Department of Medical Oncology, Centre Oscar Lambret, 59020 Lille France.
authors: Nicolas
authors: N
authors: Penel
authors: Department of Medical Oncology, Centre Leon Berard, 69008 Lyon France.
authors: Olivier
authors: O
authors: Tredan
authors: Department of Translational Research, Centre Leon Berard, 69008 Lyon France.|Department of Medical Oncology, Centre Leon Berard, 69008 Lyon France.
authors: Jean-Yves
authors: JY
authors: Blay
mesh_terms: D000328:Adult; D000368:Aged; D000465:Algorithms; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D056915:DNA Copy Number Variations; D003661:Decision Support Techniques; D018572:Disease-Free Survival; D005260:Female; D005784:Gene Amplification; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005820:Genetic Testing / Q000379:methods; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000401:mortality / Q000473:pathology; D018579:Patient Selection; D057285:Precision Medicine; D011237:Predictive Value of Tests; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D012307:Risk Factors; D015398:Signal Transduction; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases
keywords: biomarker; chromosomal instability; multi-kinase inhibitor; regorafenib