Cytochrome P450 2D6 and homeobox 13/interleukin-17B receptor: combining inherited and tumor gene markers for prediction of tamoxifen resistance.
OBJECTIVE
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.


METHODS
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.
Goetz
Matthew P
MP
Department of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota 55905, USA. goetz.matthew@mayo.edu
Suman
Vera J
VJ
Couch
Fergus J
FJ
Ames
Matthew M
MM
Rae
James M
JM
Erlander
Mark G
MG
Ma
Xiao-Jun
XJ
Sgroi
Dennis C
DC
Reynolds
Carol A
CA
Lingle
Wilma L
WL
Weinshilboum
Richard M
RM
Flockhart
David A
DA
Desta
Zeruesenay
Z
Perez
Edith A
EA
Ingle
James N
JN
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D005819:Genetic Markers; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008875:Middle Aged; D018123:Receptors, Interleukin / Q000235:genetics* / Q000378:metabolism; D053722:Receptors, Interleukin-17; D012189:Retrospective Studies; D012307:Risk Factors; D013629:Tamoxifen / Q000627:therapeutic use
D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D005819:Genetic Markers; C484414:HOXB13 protein, human; D018398:Homeodomain Proteins; C408922:IL17RB protein, human; D018123:Receptors, Interleukin; D053722:Receptors, Interleukin-17; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6
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