Impaired tamoxifen metabolism reduces survival in familial breast cancer patients.
OBJECTIVE
Tamoxifen has been the mainstay adjuvant hormonal treatment for breast cancer for many years. Conversion of tamoxifen to its active metabolite, endoxifen, is reduced by low activity of the cytochrome P450 enzyme, CYP2D6. We examined the effect of reduced CYP2D6 activity on the response to tamoxifen in patients with familial early-onset breast cancer.


METHODS
We conducted a case note review and genotyping for the CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*41 alleles in 115 patients (47 BRCA1, 68 BRCA2) with familial breast cancer who had been treated with 20-mg tamoxifen following surgery.


RESULTS
Eight (7%) individuals had genotypes consistent with poor metabolizer status, and 4 (3.5%) individuals took CYP2D6 inhibitor drugs concomitant with their tamoxifen and were also considered poor metabolizer. Time to tumor recurrence, disease-free survival, and overall survival were reduced in the patient group with poor metabolizer CYP2D6 activity. However, a significant effect was confined to patients with BRCA2 mutations with a worse overall survival (median survival, 7 versus 28 years; P = 0.008; adjusted hazard ratio, 9.7).


CONCLUSIONS
Poor metabolizer status for CYP2D6 predicts worse overall survival in patients with familial breast cancer. Therefore, CYP2D6 inhibitor drugs should not be prescribed concomitantly with tamoxifen. Prospective studies should be undertaken to establish the effect of CYP2D6 status on outcome in familial breast cancer patients treated with tamoxifen.
Newman
William G
WG
Department of Medical Genetics, St. Mary's Hospital, University of Manchester, Manchester, United Kingdom. William.newman@manchester.ac.uk
Hadfield
Kristen D
KD
Latif
Ayshe
A
Roberts
Stephen A
SA
Shenton
Andrew
A
McHague
Christopher
C
Lalloo
Fiona
F
Howell
Sacha
S
Evans
D Gareth
DG
D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D004965:Estrogen Antagonists / Q000493:pharmacokinetics* / Q000627:therapeutic use; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D016019:Survival Analysis; D013629:Tamoxifen / Q000493:pharmacokinetics* / Q000627:therapeutic use
D004965:Estrogen Antagonists; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6