Personalized Health Care (PHC) in Cancer - Genomic Biomarkers for Pharmaceutical Development - page 34

CYP2D6 AND HORMONE THERAPY IN BREAST CANCER
Breast cancers expressing the ER are dependent on estrogen for growth. Selective ER
modulators inhibit estrogen binding to ERs, reducing the proliferation of ER+ tumors.
Tamoxifen, a selective ER modulator, is the most widely used anti-estrogen therapy for pre-
menopausal and postmenopausal women with metastatic breast cancer, for adjuvant treat-
ment of primary breast cancer, and as a chemopreventative agent for women with a high
risk of developing breast cancer [6,11] . Tamoxifen needs to be converted to the metabolite
endoxifen for biological activity, and this conversion is catalyzed by the enzyme cytochrome
P450 2D6 (CYP2D6). Polymorphisms in this gene can significantly affect enzymatic activ-
ity ( Table 2.4 ), and more than 75 CYP2D6 variant alleles have been reported [82] . Among
healthy Europeans, 6-10% are deficient in CYP2D6 metabolism [83] . These individuals con-
vert tamoxifen to endoxifen poorly - a 15-fold lower rate of conversion is observed in vitro -
and therefore may not derive full therapeutic benefit from tamoxifen therapy. Interestingly,
12 women with breast cancer taking adjuvant tamoxifen were given CYP2D6 inhibitors to
assess the role of this enzyme on the levels of endoxifen. Results indicated that the plasma
concentrations of endoxifen decreased approximately two-fold after four weeks of exposure
to CYP2D6 inhibitors, confirming the role of CYP2D6 in tamoxifen metabolism [84] .
A comparison of 1,325 patients after nine years of follow-up revealed that following
tamoxifen treatment, patients with the low metabolism genotype (low CYP2D6 activity)
have a two-fold increased risk of recurrence compared to those with the high metabolism
genotype [85] . Additionally, in a German study of women diagnosed with ER+ primary
invasive breast cancer who either received adjuvant tamoxifen monotherapy or did not
receive therapy, the tamoxifen-treated patients with intermediate or poor CYP2D6 activity
had shorter relapse-free times and event-free survival than patients with normal CYP2D6
metabolism. In patients not treated with tamoxifen, CYP2D6 activity did not affect survival,
suggesting that CYP2D6 activity predicts response to tamoxifen, but is not a general prog-
nostic marker for BC patients [86] . Alternatively, other retrospective analyses have not sup-
ported a role for CYP2D6 in the metabolism of tamoxifen, showing no association between
CYP2D6 genotype and recurrence-free survival in women with ER+ breast cancer treated
with tamoxifen [87-89] . Unfortunately, there is a large degree of heterogeneity between the
relevant clinical studies, making it difficult to compare them directly to get a better under-
standing of the discrepancies. What is known, though, is that the studies that did not report
an association between CYP2D6 genotype and tamoxifen metabolism also did not measure

TABLE 2.4 The Effect of multiple CYP2d6 Alleles and their Effect on Enzyme Activity

CYP2D6 Alleles Allele Designation Enzyme Activity

*1, *2, *33, *35 Normal or Wild Type Normal

*3, *4, *5-*8, *11-*16, *18-*21, *36, *38, *40, *42, *44,
*56, *62

Null No protein, inactive or negligible

*9, *10, *17, *29, *41, *59 Reduced Activity Decreased

*22, *28, *30-*32, *34, *37, *39, *43, *45-*55 Unknown Activity Unknown

(Adapted from Hoskins et al. [85] .)