Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients.
BACKGROUND
Tamoxifen is widely used as endocrine therapy for oestrogen-receptor-positive breast cancer. However, many of these patients experience recurrence despite tamoxifen therapy by incompletely understood mechanisms. In the present report we propose that tamoxifen resistance may be due to differences in activity of metabolic enzymes as a result of genetic polymorphism. Cytochrome P450 2D6 (CYP2D6) and sulfotransferase 1A1 (SULT1A1) are polymorphic and are involved in the metabolism of tamoxifen. The CYP2D6*4 and SULT1A1*2 genotypes result in decreased enzyme activity. We therefore investigated the genotypes of CYP2D6 and SULT1A1 in 226 breast cancer patients participating in a trial of adjuvant tamoxifen treatment in order to validate the benefit from the therapy.


METHODS
The patients were genotyped using PCR followed by cleavage with restriction enzymes.


RESULTS
Carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen (relative risk = 0.28, 95% confidence interval = 0.11-0.74, P = 0.0089). A similar pattern was seen among the SULT1A1*1 homozygotes (relative risk = 0.48, 95% confidence interval = 0.21-1.12, P = 0.074). The combination of CYP2D6*4 and/or SULT1A1*1/*1 genotypes comprised 60% of the patients and showed a 62% decreased risk of distant recurrence with tamoxifen (relative risk = 0.38, 95% confidence interval = 0.19-0.74, P = 0.0041).


CONCLUSIONS
The present study suggests that genotype of metabolic enzymes might be useful as a guide for adjuvant endocrine treatment of postmenopausal breast cancer patients. However, results are in contradiction to prior hypotheses and the present sample size is relatively small. Findings therefore need to be confirmed in a larger cohort.
Department of Biomedicine and Surgery, Division of Cellbiology, Faculty of Health Sciences, Linköping, Sweden. piapa@ibk.liu.se
Pia
P
Wegman
Linda
L
Vainikka
Olle
O
Stål
Bo
B
Nordenskjöld
Lambert
L
Skoog
Lars-Erik
LE
Rutqvist
Sten
S
Wingren
D000328:Adult; D000368:Aged; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology* / Q000627:therapeutic use; D015239:Arylsulfotransferase / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D017024:Chemotherapy, Adjuvant; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D009362:Neoplasm Metastasis; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D017698:Postmenopause; D012008:Recurrence; D012307:Risk Factors; D018401:Sample Size; D013629:Tamoxifen / Q000494:pharmacology* / Q000627:therapeutic use; D016896:Treatment Outcome
D018931:Antineoplastic Agents, Hormonal; D013629:Tamoxifen; D019389:Cytochrome P-450 CYP2D6; D015239:Arylsulfotransferase; C117544:SULT1A1 protein, human