PURPOSE: Genetic variation in cytochrome P450 2D6 (CYP2D6) and the gene expression ratio of the homeobox 13 (HOXB13) to interleukin-17B receptor (IL17BR) are associated with tamoxifen resistance. We sought to determine the combined effect of inherited (CYP2D6) and somatic (HOXB13/IL17BR) gene variation in tamoxifen-treated breast cancer. EXPERIMENTAL DESIGN: Retrospective analysis of women with node-negative breast cancer randomized to receive 5 years of tamoxifen (North Central Cancer Treatment Group 89-30-52). CYP2D6 metabolism (extensive or decreased) was based on CYP2D6*4 genotype and presence/absence of a CYP2D6 inhibitor. Reverse transcription-PCR profiles for HOXB13 and IL17BR and the cut point separating patients into high- and low-risk categories according to disease-free survival (DFS) were used. A risk factor (CYP2D6:HOXB13/IL17BR) representing the four categories of combining CYP2D6 metabolism (extensive or decreased) and HOXB13/IL17BR (low or high) was created. The association between CYP2D6:HOXB13/IL17BR and DFS and overall survival (OS) was assessed using the log-rank test and proportional hazards modeling. RESULTS:CYP2D6 metabolism and HOXB13/IL17BRgene ratio was available in 110 of 160 (69%) patients. The combined CYP2D6:HOXB13/IL17BR risk factor was significantly associated with DFS (log-rank P = 0.004) and OS (P = 0.009). Relative to women with extensive CYP2D6 metabolism and low HOXB13/IL17BR, those with either decreased metabolism or a high HOXB13/IL17BR ratio had significantly worse OS (adjusted hazard ratio, 2.41; 95% confidence interval, 1.08-5.37; P = 0.031), whereas women with both decreased metabolism and high HOXB13/IL17BR ratio had the shortest survival (adjusted hazard ratio, 3.15; 95% CI, 1.17-8.52; P = 0.024). CONCLUSIONS: An index composed of inherited (CYP2D6) and tumor (HOXB13/IL17BR) gene variation identifies patients with varying degrees of resistance to tamoxifen.
RCT Entities:
PURPOSE: Genetic variation in cytochrome P450 2D6 (CYP2D6) and the gene expression ratio of the homeobox 13 (HOXB13) to interleukin-17B receptor (IL17BR) are associated with tamoxifen resistance. We sought to determine the combined effect of inherited (CYP2D6) and somatic (HOXB13/IL17BR) gene variation in tamoxifen-treated breast cancer. EXPERIMENTAL DESIGN: Retrospective analysis of women with node-negative breast cancer randomized to receive 5 years of tamoxifen (North Central Cancer Treatment Group 89-30-52). CYP2D6 metabolism (extensive or decreased) was based on CYP2D6*4 genotype and presence/absence of a CYP2D6 inhibitor. Reverse transcription-PCR profiles for HOXB13 and IL17BR and the cut point separating patients into high- and low-risk categories according to disease-free survival (DFS) were used. A risk factor (CYP2D6:HOXB13/IL17BR) representing the four categories of combining CYP2D6 metabolism (extensive or decreased) and HOXB13/IL17BR (low or high) was created. The association between CYP2D6:HOXB13/IL17BR and DFS and overall survival (OS) was assessed using the log-rank test and proportional hazards modeling. RESULTS:CYP2D6 metabolism and HOXB13/IL17BR gene ratio was available in 110 of 160 (69%) patients. The combined CYP2D6:HOXB13/IL17BR risk factor was significantly associated with DFS (log-rank P = 0.004) and OS (P = 0.009). Relative to women with extensive CYP2D6 metabolism and low HOXB13/IL17BR, those with either decreased metabolism or a high HOXB13/IL17BR ratio had significantly worse OS (adjusted hazard ratio, 2.41; 95% confidence interval, 1.08-5.37; P = 0.031), whereas women with both decreased metabolism and high HOXB13/IL17BR ratio had the shortest survival (adjusted hazard ratio, 3.15; 95% CI, 1.17-8.52; P = 0.024). CONCLUSIONS: An index composed of inherited (CYP2D6) and tumor (HOXB13/IL17BR) gene variation identifies patients with varying degrees of resistance to tamoxifen.
Authors: Matthew P Goetz; James M Rae; Vera J Suman; Stephanie L Safgren; Matthew M Ames; Daniel W Visscher; Carol Reynolds; Fergus J Couch; Wilma L Lingle; David A Flockhart; Zeruesenay Desta; Edith A Perez; James N Ingle Journal: J Clin Oncol Date: 2005-12-20 Impact factor: 44.544
Authors: Soonmyung Paik; Steven Shak; Gong Tang; Chungyeul Kim; Joffre Baker; Maureen Cronin; Frederick L Baehner; Michael G Walker; Drew Watson; Taesung Park; William Hiller; Edwin R Fisher; D Lawrence Wickerham; John Bryant; Norman Wolmark Journal: N Engl J Med Date: 2004-12-10 Impact factor: 91.245
Authors: Yixin Wang; Jan G M Klijn; Yi Zhang; Anieta M Sieuwerts; Maxime P Look; Fei Yang; Dmitri Talantov; Mieke Timmermans; Marion E Meijer-van Gelder; Jack Yu; Tim Jatkoe; Els M J J Berns; David Atkins; John A Foekens Journal: Lancet Date: 2005 Feb 19-25 Impact factor: 79.321
Authors: Daniel S Oh; Melissa A Troester; Jerry Usary; Zhiyuan Hu; Xiaping He; Cheng Fan; Junyuan Wu; Lisa A Carey; Charles M Perou Journal: J Clin Oncol Date: 2006-02-27 Impact factor: 44.544
Authors: Matthew P Goetz; Vera J Suman; James N Ingle; Andrea M Nibbe; Dan W Visscher; Carol A Reynolds; Wilma L Lingle; Mark Erlander; Xiao-Jun Ma; Dennis C Sgroi; Edith A Perez; Fergus J Couch Journal: Clin Cancer Res Date: 2006-04-01 Impact factor: 12.531
Authors: A Howell; J Cuzick; M Baum; A Buzdar; M Dowsett; J F Forbes; G Hoctin-Boes; J Houghton; G Y Locker; J S Tobias Journal: Lancet Date: 2005 Jan 1-7 Impact factor: 79.321
Authors: James N Ingle; Vera J Suman; James A Mailliard; John W Kugler; James E Krook; John C Michalak; Thomas M Pisansky; Lester E Wold; John H Donohue; Matthew P Goetz; Edith A Perez Journal: Breast Cancer Res Treat Date: 2006-03-15 Impact factor: 4.872
Authors: William J Irvin; Christine M Walko; Karen E Weck; Joseph G Ibrahim; Wing K Chiu; E Claire Dees; Susan G Moore; Oludamilola A Olajide; Mark L Graham; Sean T Canale; Rachel E Raab; Steven W Corso; Jeffrey M Peppercorn; Steven M Anderson; Kenneth J Friedman; Evan T Ogburn; Zeruesenay Desta; David A Flockhart; Howard L McLeod; James P Evans; Lisa A Carey Journal: J Clin Oncol Date: 2011-07-18 Impact factor: 44.544
Authors: Barbara K Dunn; Mark H Greene; Jenny M Kelley; Joseph P Costantino; Robert J Clifford; Ying Hu; Gong Tang; Neely Kazerouni; Philip S Rosenberg; Daoud M Meerzaman; Kenneth H Buetow Journal: Int J Mol Epidemiol Genet Date: 2010-09-05
Authors: Michael R Mallmann; Andrea Staratschek-Jox; Christian Rudlowski; Michael Braun; Andrea Gaarz; Matthias Wolfgarten; Walther Kuhn; Joachim L Schultze Journal: EPMA J Date: 2010-08-20 Impact factor: 6.543