Prevalent breast cancer patients with a homozygous mutant status for CYP2D6*4: response and biomarkers in tamoxifen users.
Retrospective studies suggest that single nucleotide polymorphisms in the cytochrome P450 2D6 (CYP2D6) gene predict reduced tamoxifen metabolism, better tolerance and worse treatment outcome. We hypothesized that women with this genotype lack tamoxifen-induced endometrial and biochemical changes in follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG). We identified 56 breast cancer patients attending the follow-up clinic with a homozygous mutant (HM) status for the CYP2D6*4 null variant. Here, we report a detailed assessment of tamoxifen activity in 19 CYP2D6 HM women, while they were using tamoxifen either for metastatic (n = 5) or for early disease (n = 14). We assessed response to tamoxifen in metastatic disease. Endometrial appearances and serum levels of FSH and SHBG were assessed from retrospective and prospective testing. Our findings do suggest that the presence of two CYP2D6*4 alleles does not exclude a durable response of tamoxifen in metastatic breast cancer. The transvaginal ultrasonographic appearance of the endometrium in CYP2D6*4/*4 patients on tamoxifen is similar as seen in the normal population of tamoxifen users. The endometrium is increased in thickness with subepithelial cysts and endometrial polyps. Serum levels of FSH and SHBG in CYP2D6*4 HM tamoxifen users were in the range of what would be expected during tamoxifen treatment in the general population. Our findings do show CYP2D6*4/*4 carriers to have activity of tamoxifen on breast cancer, endometrium and serum levels of FSH and SHBG. They support clinical trials prospectively testing the effect of CYP2D6 genetic variability in response to tamoxifen before denying this drug to breast cancer patients only based on their CYP2D6*4 status.
Dieudonné
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AS
Department of Obstetrics and Gynecology, University Hospital Leuven, Herestraat 49, 3000, Leuven, Belgium.
Lambrechts
D
D
Claes
B
B
Vandorpe
T
T
Wildiers
H
H
Timmerman
D
D
Billen
J
J
Leunen
K
K
Amant
F
F
Berteloot
P
P
Smeets
A
A
Paridaens
R
R
Weltens
C
C
Van Limbergen
E
E
Van den Bogaert
W
W
Vergote
I
I
Van Huffel
S
S
Christiaens
M R
MR
Neven
P
P
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics*; D018567:Breast Neoplasms, Male / Q000188:drug therapy / Q000235:genetics; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004717:Endometrium / Q000187:drug effects; D005260:Female; D005640:Follicle Stimulating Hormone / Q000097:blood; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D012738:Sex Hormone-Binding Globulin / Q000032:analysis / Q000187:drug effects; D013629:Tamoxifen / Q000627:therapeutic use*
D014408:Biomarkers, Tumor; D020845:Selective Estrogen Receptor Modulators; D012738:Sex Hormone-Binding Globulin; D013629:Tamoxifen; D005640:Follicle Stimulating Hormone; D019389:Cytochrome P-450 CYP2D6