title: A 2-gene classifier for predicting response to the farnesyltransferase inhibitor tipifarnib in acute myeloid leukemia.
abstract: At present, there is no method available to predict response to farnesyltransferase inhibitors (FTIs). We analyzed gene expression profiles from the bone marrow of patients from a phase 2 study of the FTI tipifarnib in older adults with previously untreated acute myeloid leukemia (AML). The RASGRP1/APTX gene expression ratio was found to predict response to tipifarnib with the greatest accuracy using a "leave one out" cross validation (LOOCV; 96%). RASGRP1 is a guanine nucleotide exchange factor that activates RAS, while APTX (aprataxin) is involved in DNA excision repair. The utility of this classifier for predicting response to tipifarnib was validated in an independent set of 58 samples from relapsed or refractory AML, with a negative predictive value (NPV) and positive predictive value (PPV) of 92% and 28%, respectively (odds ratio of 4.4). The classifier also predicted for improved overall survival (154 vs 56 days; P < .001), which was independent of other covariates, including a previously described prognostic gene expression classifier. Therefore, these data indicate that a 2-gene expression assay may have utility in categorizing a population of patients with AML who are more likely to respond to tipifarnib.
authors.affiliation: Veridex, 3210 Merryfield Row, La Jolla, CA 92121, USA. mraponi1@ocdus.jnj.com
authors.forename: Mitch
authors.initials: M
authors.lastname: Raponi
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Lancet
authors.forename: Hongtao
authors.initials: H
authors.lastname: Fan
authors.forename: Lesley
authors.initials: L
authors.lastname: Dossey
authors.forename: Grace
authors.initials: G
authors.lastname: Lee
authors.forename: Ivana
authors.initials: I
authors.lastname: Gojo
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Feldman
authors.forename: Jason
authors.initials: J
authors.lastname: Gotlib
authors.forename: Lawrence E
authors.initials: LE
authors.lastname: Morris
authors.forename: Peter L
authors.initials: PL
authors.lastname: Greenberg
authors.forename: John J
authors.initials: JJ
authors.lastname: Wright
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Harousseau
authors.forename: Bob
authors.initials: B
authors.lastname: Löwenberg
authors.forename: Richard M
authors.initials: RM
authors.lastname: Stone
authors.forename: Peter
authors.initials: P
authors.lastname: De Porre
authors.forename: Yixin
authors.initials: Y
authors.lastname: Wang
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors*; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics* / Q000517:prevention & control; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D016016:Proportional Hazards Models; D015363:Quinolones / Q000494:pharmacology* / Q000627:therapeutic use*; D012008:Recurrence; D015203:Reproducibility of Results; D016019:Survival Analysis
chemical_list: C438188:APTX protein, human; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D009687:Nuclear Proteins; D015363:Quinolones; C491790:RASGRP1 protein, human; D051231:Farnesyltranstransferase; C402769:tipifarnib