![Kaplan–Meier probabilities of relapse-free time (RFT) of breast cancer patients for CYP2D6-metabolizer phenotypes predicted from genotypes. (A), Patients treated with adjuvant tamoxifen (TAM). EMs had a significantly more favorable RFT than patients with impaired phenotypes (PMs or IMs). (B), Patients without TAM showed no differences with respect to a relationship between the CYP2D6- predicted phenotype and RFT [Schroth et al. (79)]. hetEM, heterozygous EM. Originally published in Schroth, W et al.: J Clin Oncol 25 (33), 2007: 5187–93. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.](https://www.researchgate.net/profile/Thomas-Muerdter/publication/26337977/figure/fig2/AS:277159471009792@1443091375029/Kaplan-Meier-probabilities-of-relapse-free-time-RFT-of-breast-cancer-patients-for_Q320.jpg)
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Pharmacogenomics of Tamoxifen Therapy
Hiltrud Brauch,
1,2*
Thomas E. Mu¨ rdter,
1,2
Michel Eichelbaum,
1,2
and Matthias Schwab
1,2,3
BACKGROUND:Tamoxifen is a standard endocrine ther-
apy for the prevention and treatment of steroid hor-
mone receptor–positive breast cancer.
CONTENT:Tamoxifen requires enzymatic activation by
cytochrome P450 (CYP) enzymes for the formation of
active metabolites 4-hydroxytamoxifen and endoxifen.
As compared with the parent drug, both metabolites
have an approximately 100-fold greater affinity for the
estrogen receptor and the ability to inhibit cell prolif-
eration. The polymorphic CYP2D6 is the key enzyme in
this biotransformation, and recent mechanistic, pharma-
cologic, and clinical evidence suggests that genetic vari-
ants and drug interaction by CYP2D6 inhibitors influence
the plasma concentrations of active tamoxifen metabo-
lites and the outcomes of tamoxifen-treated patients. In
particular, nonfunctional (poor metabolizer) and se-
verely impaired (intermediate metabolizer) CYP2D6 al-
leles are associated with higher recurrence rates.
SUMMARY:Accordingly, CYP2D6 (cytochrome P450,
family 2, subfamily D, polypeptide 6) genotyping be-
fore treatment to predict metabolizer status may open
new avenues for individualizing endocrine treatment,
with the maximum benefit being expected for exten-
sive metabolizers. Moreover, strong CYP2D6 inhibi-
tors such as the selective serotonin reuptake inhibitors
paroxetine and fluoxetine, which are used to treat hot
flashes, should be avoided because they severely impair
formation of the active metabolites.
© 2009 American Association for Clinical Chemistry
The pharmacogenomics of drug-metabolizing en-
zymes involved in the biotransformation of tamoxifen
has become a major area of interest, owing to its poten-
tial to predict a breast cancer patient’s treatment out-
come before the initiation of treatment. If the tamox-
ifen pharmacogenomic paradigm were to be borne out
in proof of principle, patients eligible for endocrine
treatment would be able to exploit it by opting for their
personally most powerful medication. Most breast
cancers, particularly those of postmenopausal women,
are hormone receptor positive; therefore, hundreds of
thousands of women worldwide initiate endocrine
treatment each year. On the basis of results of the Early
Breast Cancer Trialist Collaborative Group, the stan-
dard recommendation has been 5 years of therapy with
the selective estrogen receptor (ER)
4
modulator ta-
moxifen (1 ). Tamoxifen is currently prescribed in
⬎120 countries worldwide as a component of standard
adjuvant therapy in early breast cancer and in the met-
astatic setting for patients with steroid hormone
receptor–positive breast tumors. In primary breast
cancer, adjuvant tamoxifen significantly decreases re-
lapse rates and mortality in pre- and postmenopausal
patients, and the therapy benefit from 5 years of adju-
vant tamoxifen is maintained, even ⬎10 years after pri-
mary diagnosis (1 ). In postmenopausal women with
endocrine-responsive disease, tamoxifen is a valid
therapy option, along with aromatase inhibitors (AIs)
(2 ), and is considered the standard care for the preven-
tion of invasive breast cancer in premenopausal
women at high risk, including those who have had duc-
tal carcinoma in situ (3 ), and for the treatment of male
breast cancer (4 ). Tamoxifen is generally well toler-
ated, and menopausal symptoms, including hot
flashes, are the most common side effects. Severe side
effects, such as thromboembolic events or endometrial
carcinoma, are rare (1 ). The clinical benefit of tamox-
ifen has been evident for more than 3 decades; how-
ever, up to 50% of patients who receive adjuvant
tamoxifen relapse or die from tumor-specific resis-
tance or host genome–associated factors.
The field of tamoxifen pharmacogenomics gained
substantial impetus from the elucidation of tamoxifen
metabolism and metabolite pharmacology through
studies that identified major active metabolites formed
by cytochrome P450 (CYP) enzymes, particularly
CYP2D6, which exhibit substantial genetic and pheno-
typic polymorphism. Several clinical studies have re-
ported on the relationship of genotype and/or pheno-
type variants with the clinical outcome of tamoxifen
1
Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Ger-
many;
2
University Tu¨ bingen, Tu¨bingen, Germany;
3
Department of Clinical
Pharmacology, University Hospital Tu¨ bingen, Tu¨bingen, Germany.
* Address correspondence to this author at: Dr. Margarete Fischer-Bosch Institute
of Clinical Pharmacology, Auerbachstrasse 112, 70376 Stuttgart, Germany. Fax
⫹49-(0)711-859295; e-mail hiltrud.brauch@ikp-stuttgart.de.
Received November 28, 2008; accepted June 8, 2009.
Previously published online at DOI: 10.1373/clinchem.2008.121756
4
Nonstandard abbreviations: ER, estrogen receptor; CYP, cytochrome P450; UGT,
UDP-glucuronosyltransferase; SULT, sulfotransferase; EM, extensive metabo-
lizer; PM, poor metabolizer; IM, intermediate metabolizer; UM, ultrarapid
metabolizer; SSRI, serotonin reuptake inhibitor; AI, aromatase inhibitor.
Clinical Chemistry 55:10
1770–1782 (2009) Review
1770
therapy, and international efforts are currently under
way to clarify this relationship.
In light of the potential for a future translation of
tamoxifen pharmacogenomics into clinical practice,
this review seeks to impart the underlying pharmaco-
logic, genetic, and phenotypic principles for a mecha-
nistic explanation of tamoxifen efficacy. It highlights
the biotransformation of tamoxifen into primary and
secondary metabolites with an emphasis on the clini-
cally active metabolites 4-hydroxytamoxifen and
4-hydroxy-N-desmethyltamoxifen (endoxifen). Ow-
ing to the key role of CYP2D6, this review focuses on
the relationships between the CYP2D6
5
(cytochrome
P450, family 2, subfamily D, polypeptide 6) genotype
and phenotype. This discussion also includes the phe-
nocopying effect of CYP2D6 inhibitors, which are fre-
quently coadministered to alleviate hot flashes in post-
menopausal women treated with tamoxifen. These
basic research findings provide the scientific back-
ground for a thorough discussion of the currently
available literature on tamoxifen pharmacogenetic
studies. Finally, there is a possibility that other drug-
metabolizing enzymes and even nonmetabolic factors
can influence tamoxifen efficacy. In considering these
topics, this review provides an overview of the princi-
ples of the emerging practice of personalized medicine
for the improvement of the outcomes of endocrine
drug treatment in breast cancer.
Tamoxifen Metabolism and Active Metabolites
trans-Tamoxifen {(Z)-2-[4-(1,2-diphenylbut-1-enyl)-
phenoxy]-N,N-dimethyl-ethanamine} undergoes ex-
tensive phase I and phase II metabolism in the hu-
man liver (Fig. 1). The bioconversion of tamoxifen
involves N-oxidation, N-demethylation, and hy-
droxylation. Formation of the major metabolite
N-desmethyltamoxifen is primarily catalyzed by
CYP3A4 and 3A5, with minor contributions by
CYP2D6, 1A1, 1A2, 2C19, and 2B6 (5–7 ). The steady-
state plasma concentration of N-desmethyltamoxifen
after 20 mg tamoxifen is administered daily for at least
3 months is approximately twice as high as that of the
parent drug (100 –290
g/L vs 72–160
g/L) (8 –14 ).
This fact is of utmost clinical importance because
N-desmethyltamoxifen is subject to hydroxylation,
predominantly at the para position, to produce the ma-
jor clinically active metabolite endoxifen. Importantly,
the conversion of N-desmethyltamoxifen into endox-
ifen is catalyzed almost exclusively by CYP2D6
(15, 16). Plasma concentrations of endoxifen have
been observed to range from a mean of 8.1
g/L (n ⫽51)
for patients with 2 variant CYP2D6 alleles to 20.7
g/L
(n ⫽55) for patients with 2 wild-type alleles (17 ). In ad-
dition, N-desmethyltamoxifen can also be desmethylated
by CYP3A4 to form N,N-didesmethyltamoxifen.
Another clinically active metabolite is 4-
hydroxytamoxifen, which is formed by 4-hydroxylation,
also at the para position of the phenyl ring of the parent
drug. This conversion is catalyzed by a number of CYPs,
including CYP2D6, 3A4, 2C9, 2B6, and 2C19 (7, 18–
21 ). Compared with endoxifen, the steady-state con-
centrations of 4-hydroxytamoxifen are lower, ranging
from 1.15
g/L to 6.4
g/L (11, 14, 22 ). With the ex-
ception of endoxifen and 4-hydroxytamoxifen, no
other highly active metabolites have been described
thus far.
Further hydroxylation also occurs at the 4⬘posi-
tion of the other phenyl ring system, leading to 4⬘-
hydroxytamoxifen, which is mainly mediated by
CYP2B6 and 2D6 (7 ), and to 4⬘-hydroxy-N-
desmethyltamoxifen. Another hydroxylated metabo-
lite,
␣
-hydroxytamoxifen, is produced mainly by
CYP3A4 (5, 6, 23, 24 ).
4-Hydroxylated metabolites undergo in vitro
chemical isomerization into the respective E or cis iso-
mers (25 ), which are weak ER antagonists. In addition,
isomerization of 4-hydroxytamoxifen is catalyzed by
CYP1B1, 2B6, and 2C19 (7 ). Of note, an accumulation
of cis-4-hydroxytamoxifen was observed in tumor tis-
sues of patients whose tumors showed resistance to ta-
moxifen treatment (26 ); however, because data on the
plasma concentrations of cis isomers are sparse, this
observation may be regarded as preliminary. Addi-
tional hydroxylation of 4-hydroxytamoxifen by
CYP3A4 and 2D6 at the phenyl moiety leads to 3,4-
dihydroxytamoxifen (27 ), a compound that is capable
of binding covalently to protein and to DNA, thereby
contributing to the reported toxic and carcinogenic ef-
fects associated with tamoxifen treatment (28, 29).
Another route of tamoxifen metabolism is the for-
mation of tamoxifen-N-oxide by flavin-containing
monooxygenases 1 and 3, with a chance for tamoxifen-
N-oxide to be reduced back to tamoxifen by a number
of different CYPs, including CYP2A6, 1A1, 3A4, and
others (30, 31). From an analytical point of view, how-
ever, this metabolite cannot be ignored because of the
likelihood of chemical reduction of the N-oxide during
5
Human genes:
CYP2D6
, cytochrome P450, family 2, subfamily D, polypeptide 6;
CYP2D7P1
, cytochrome P450, family 2, subfamily D, polypeptide 7 pseudogene
1;
CYP2D7P2
, cytochrome P450, family 2, subfamily D, polypeptide 7 pseudo-
gene 2;
CYP2D8P1
, cytochrome P450, family 2, subfamily D, polypeptide 8
pseudogene 1;
CYP2D8P2
, cytochrome P450, family 2, subfamily D, polypeptide
8 pseudogene 2;
CYP2C9
, cytochrome P450, family 2, subfamily C, polypeptide
9;
CYP2C19
, cytochrome P450, family 2, subfamily C, polypeptide 19;
CYP2B6
,
cytochrome P450, family 2, subfamily B, polypeptide 6;
CYP3A4
, cytochrome
P450, family 2, subfamily A, polypeptide 4;
CYP3A5
, cytochrome P450, family
2, subfamily A, polypeptide 5;
SULT1A1
, sulfotransferase family, cytosolic, 1A,
phenol-preferring, member 1;
BRCA1
, breast cancer 1, early onset;
BRCA2
,
breast cancer 2, early onset.
Tamoxifen Pharmacogenomics Review
Clinical Chemistry 55:10 (2009) 1771
Fig. 1. Metabolic transformation of tamoxifen in humans.
Major metabolic pathways are highlighted with bold arrows. Enzymes preferentially catalyzing a distinct metabolic step are
indicated in bold. Hb, hemoglobin; FMO1, flavin-containing monooxygenase 1.
Review
1772 Clinical Chemistry 55:10 (2009)
sample preparation, a reason why the quantification of
tamoxifen-N-oxide may be regarded as a problem in
the analysis of tamoxifen metabolites. Thus far, few
data on this issue are available, suggesting that the
N-oxide in a patient’s plasma accounts for ⬍15% of
tamoxifen (32 ).
At the level of phase II tamoxifen metabolism, sul-
fation and glucuronidation are major mechanisms.
O-glucuronidation of 4-hydroxytamoxifen is mainly
mediated by UDP-glucuronosyltransferases (UGTs)
UGT1A4, 2B15, 2B7, 1A8, and various others to produce
4-hydroxytamoxifen-O-glucuronide (33–35 ). Endox-
ifen is predominantly glucuronidated by UGT1A10 and
1A8 to the corresponding O-glucuronide. Of note is
that in addition to hydroxylated metabolites that un-
dergo phase II metabolism at the hydroxyl moiety,
tamoxifen itself is conjugated by UGT1A4 to the cor-
responding N
⫹
-glucuronide (36, 37). In contrast to
endoxifen, which does not form any N
⫹
-glucuronide,
4-hydroxytamoxifen is glucuronidated by UGT1A4 at
the amino group to produce 4-hydroxytamoxifen-
N
⫹
-glucuronide (34, 37). The formation of sulfates
of 4-hydroxytamoxifen and endoxifen is catalyzed
by sulfotransferases (SULTs) SULT1E1, 1A1, and 2A1
(32, 38). E isomers of both 4-hydroxytamoxifen and
endoxifen are also substrates for these conjugation
reactions but seem to have different affinities for differ-
ent isoenzymes (33 ).
␣
-Hydroxytamoxifen is sulfatized
by SULT2A1 (39 ); the resulting
␣
-hydroxytamoxifen
sulfate is suspected to exert carcinogenic effects after
covalently binding to DNA (40, 41).
Although the number of tamoxifen metabolites
that have been identified in vitro is large (Fig. 1), in
vivo analytical measurements of plasma samples
from tamoxifen-treated patients have quantified few
metabolites, including N-desmethyltamoxifen, endox-
ifen, 4-hydroxytamoxifen, N,N-didesmethyltamoxifen,
␣
-hydroxytamoxifen, and tamoxifen-N-oxide (Table 1).
Therefore, there may be other, yet-unidentified tamox-
ifen metabolites present at relevant concentrations in pa-
tients’ plasma.
CYP2D6 Biochemistry and Genetics
CYP2D6 is a member of CYP enzyme family 2, which in
humans constitutes one third of all CYPs and is one of the
largest and best studied of isoenzyme families. Human
CYPs are heme-containing monooxygenases, and the hu-
man genome contains 57 CYP genes and about the same
number of pseudogenes grouped into 18 families and
44 subfamilies according to sequence similarities (http://
drnelson.utmem.edu/CytochromeP450.html). CYP2D6
is involved in the metabolism of many clinically im-
portant drugs, including

-blockers, antiarrhythmics,
antihypertensives, antipsychotics, antidepressants,
opioids, and others. A recent analysis of the routes of
Table 1. Tamoxifen and metabolites.
Compounds
Mean plasma
concentrations,
nmol/LaEffect on ER/affinity for ER
(estradiol ⴝ100%)
Involvement of
CYP2D6
Tamoxifen 190–420 Weak antagonist/2%
b
N
-Desmethyltamoxifen 280–800 Weak antagonist/1%
b
Minor
N
,
N
-Didesmethyltamoxifen 90–120 Weak antagonist No
Endoxifen 14–130 Strong antagonist/equal to 4-hydroxytamoxifen Almost exclusively
4-Hydroxytamoxifen 3–17
c
Strong antagonist/188%
b
Among others
␣
-Hydroxytamoxifen 1 None No
3,4-Dihydroxytamoxifen No data available Weak antagonist/high affinity Together with CYP3A4
Tamoxifen-
N
-oxide 15–24 Weak antagonist
d
No
4-Hydroxytamoxifen-
O
-glucuronide No data available No antagonist
e
See 4-hydroxy-tamoxifen
4-Hydroxytamoxifen-
N
⫹
-glucuronide No data available No antagonist
e
See 4-hydroxy-tamoxifen
Endoxifen-
O
-glucuronide No data available No antagonist
e
See endoxifen
␣
-Hydroxytamoxifen sulfate No data available No data available No
a
Range of mean plasma concentrations according to different investigators [Dowsett et al.
(9)
, Hutson et al.
(10)
, Jin et al.
(11)
, Lee et al.
(12)
, Sheth et al.
(14)
,
Lim et al.
(17)
, Stearns et al.
(22)
, Gjerde et al.
(32)
, Langan-Fahey et al.
(108)
].
b
According to Wakeling and Slater
(109)
.
c
MacCallum et al.
(13)
reported much higher concentrations (67 nmol/L).
d
Might be due to reduction to tamoxifen.
e
According to Lazarus et al.
(110)
.
Tamoxifen Pharmacogenomics Review
Clinical Chemistry 55:10 (2009) 1773
elimination for the “top 200 drugs” in the US (http://
www.rxlist.com; most frequently prescribed 200 drugs,
April 2008) showed that 15% were drugs that are
CYP2D6 substrates, compared with subfamilies
CYP3A (37%) and CYP2C (33%) (42 ).
The human CYP2D6 locus on chromosome 22 in-
cludes the CYP2D6 gene and pseudogenes CYP2D7P1
(cytochrome P450, family 2, subfamily D, polypep-
tide 7 pseudogene 1), CYP2D7P2 (cytochrome P450,
family 2, subfamily D, polypeptide 7 pseudogene 2),
CYP2D8P1 (cytochrome P450, family 2, subfamily D,
polypeptide 8 pseudogene 1), and CYP2D8P2 (cyto-
chrome P450, family 2, subfamily D, polypeptide 8
pseudogene 2) originally described as pseudogenes
CYP2D7 and CYP2D8 (43 ). The CYP2D6 gene consists
of 9 exons and 8 introns, and the sequence is highly
polymorphic. By way of clinical observation (i.e., ad-
ministration of the antiarrhythmic and oxocytic drug
sparteine (44 ) and the antihypertensive agent debriso-
quine (45 )), the first CYP2D6 phenotypic variant
(sparteine/debrisoquine polymorphism) distinct from
an extensive metabolizer (EM) phenotype was identi-
fied more than 30 years ago and was termed a “poor
metabolizer” (PM) phenotype. Currently, 4 CYP2D6
phenotypes are commonly observed in Caucasian pop-
ulations on the basis of their drug-oxidation capacities:
EM, intermediate metabolizer (IM), PM, and ultra-
rapid metabolizer (UM) (46–48). Among Caucasians,
about 7%–10% of individuals are PMs, 10%–15% are
IMs, and, at the opposite end of the activity spectrum,
up to 10%–15% are UMs.
The PM status can be deduced with ⬎99% cer-
tainty from the presence of 2 nonfunctional alleles,
with ⬎20 null alleles having been identified (43 ).
Therefore, it is possible to exactly predict the CYP2D6
PM phenotype (i.e., lack of catalytic function of the
enzyme) by genotyping the patient’s DNA without the
need to phenotype (42, 46, 48, 49 ). The EM phenotype
is due to the presence of 1 or 2 allelic variants with
wild-type function, such as *1 or *2. This phenotype
can be separated by genotype into homozygous or
heterozygous EMs, depending on whether they carry
1 or 2 functional alleles. Because heterozygous EMs
who carry one *1 or *2 allele in combination with an
IM or PM allele have somewhat impaired enzyme
production and function, they have been classified as
IMs, assuming a gene-dosage effect such that het-
erozygous EMs would have only 50% of the enzyme
amount and catalytic activity of homozygous EMs.
This assumption is not correct, however, and there is
substantial overlap between homozygous and het-
erozygous EMs in both enzyme content and activity.
Consequently, the genotype has a rather poor pre-
dictive value. Of note is that the IM has a phenotype
and genotype distinct from the heterozygous EM
(47, 50 –52 ) that involves impaired gene expression
and enzyme function (these variants include *9, *10,
and *41) and/or nonfunctional variants (47, 52 ).
Within the German population, 2%–3% are carriers
of a duplicated/multiplied CYP2D6 gene and there-
fore have very high enzyme activity (UM). These dif-
ferences in enzyme activity can have profound con-
sequences on the plasma concentrations of drug
metabolites, as has been observed for the tricyclic
antidepressant nortriptyline. A ⬎30-fold difference
between PMs and UMs in steady-state plasma con-
centrations of nortriptyline was observed when nor-
triptyline was prescribed as a standard daily dose of
100–150 mg (53, 54). With respect to UM pheno-
type, however, only 20%–30% of UM phenotypes
observed in the Caucasian population are identifi-
able through genotyping (46, 48, 55 ).
Thus far, systematic genetic analyses of large
numbers of individuals have led to the discovery of
⬎100 different alleles [http://www.cypalleles.ki.se,
(56 )]. At least 15 of these alleles encode nonfunc-
tional gene products caused by aberrant splicing,
nonsense codons, mutations of single base pairs,
small insertions/deletions, larger chromosomal de-
letions of the entire CYP2D6 gene, CYP2D6/CYP2D7
hybrid genes, or mutations that cause lack of heme
incorporation or otherwise produce nonfunctional
full-length proteins.
There are significant ethnic differences with re-
spect to PM, IM, and UM frequencies, heralding the
possibility that different ethnic groups vary with re-
spect to the clinical outcomes of drug therapy with
CYP2D6 substrates. Within this context it is important
to appreciate that the frequency of gene duplication is
much higher in northeastern African populations
[e.g., 29% in Ethiopia (57 )] and in Saudi Arabia
[21% (58 )] compared with populations of European
descent (59, 60 ). In Asian populations, however, the
CYP2D6*10-associated IM is prevalent (61 ), with
the frequency in Han Chinese being 57% and the PM
playing a minor role (59 ).
Overall, an awareness of the CYP2D6 genotype–
phenotype relationship may influence treatment deci-
sions, particularly in cases for which an effective alter-
native drug is available. As in the case of orally
administered codeine, which in the 10% of Caucasians
who are PMs is not metabolized efficiently to mor-
phine and therefore provides little analgesic effect,
there is a chance that women with a CYP2D6 PM or IM
genotype/phenotype also will not benefit from the an-
tiestrogenic effects of tamoxifen, owing to insufficient
production of active metabolites. With respect to UMs,
who in cases of codeine treatment develop severe opi-
oid side effects due to rapid morphine formation
(62, 63), it is important to note that such women pa-
Review
1774 Clinical Chemistry 55:10 (2009)
tients may be more susceptible to hot flashes during
tamoxifen therapy.
CYP2C9,2C19,2B6,3A4, and 3A5 Genetics
Other important CYP isoenzymes of subfamily 2 that
are involved in the bioactivation of tamoxifen are
CYP2C9, 2C19, and 2B6 (15, 18); these enzymes are
also polymorphic. Of the ⬎30 variant alleles of
CYP2C9 (cytochrome P450, family 2, subfamily C,
polypeptide 9), the *2 and *3 alleles have been thor-
oughly investigated and found to be associated with
significant but highly variable reductions in intrinsic
clearance, depending on the substrate (64 ). The *3 al-
lele is more strongly affected than *2, with a reduction
in enzyme activity of up to 90% for some specific drugs
(65 ). Both alleles are present in approximately 35% of
Caucasians but are less prevalent in black and Asian
populations (42, 66). About 2% and 24% of individu-
als in the Caucasian population are homozygous and
heterozygous for the variants, respectively (67 ). Nu-
merous clinical studies have demonstrated the clinical
significance of CYP2C9 genetics with respect to an as-
sociation with higher incidences of adverse drug reac-
tions. The most prominent example is warfarin, an an-
ticoagulant, and several retrospective and prospective
studies have confirmed that CYP2C9 genetics is clini-
cally useful for adjusting warfarin dosage to reduce se-
rious warfarin-related bleeding events (68, 69). The
anticoagulant response also depends on the genetics of
vitamin K epoxide reductase (68 ). Moreover, gastroin-
testinal bleeding from nonsteroidal antiinflammatory
drugs (70 ) and such side effects as hypoglycemia
caused by sulfonylureas (71 ) have also been attributed
to CYP2C9 polymorphisms.
For the CYP2C19 gene (cytochrome P450, family
2, subfamily C, polypeptide 19), the known null alleles
(CYP2C19*2,*3,*4,*5,*6,*7, and *8) have no
CYP2C19 enzyme activity (PM); the *2 allele is preva-
lent in Caucasians. These null alleles are due to a splice
defect (*2), a premature stop codon (*3), or an alter-
ation in CYP2C19 structure and/or stability (72 )
(http://www.cypalleles.ki.se/). Recently, several new
CYP2C19 alleles have been identified (*9–*25) in indi-
viduals from different racial groups; however, whether
these mutations produce significant alterations in en-
zyme activity in vivo is not clear. CYP2C19*2 and *3
are the most frequent variants. According to geno-
typing and phenotyping results and in analogy to
CYP2D6, the distribution of PMs shows wide inter-
ethnic differences. In Caucasian Europeans, the mean
frequency of PM individuals is 3%, whereas PM fre-
quencies as high as 23% have been identified in Asian/
Oceanian populations (72, 73). Carriers of heterozy-
gous variants constitute 32% of Caucasians, however
(74 ). A promoter variant of CYP2C19*17 has recently
been identified and shown to be associated with in-
creased CYP2C19 activity in vivo (UM) with the
CYP2C19 substrate omeprazole [a proton pump in-
hibitor (75 )] and the antidepressant escitalopram
(76 ). Differences in CYP2C19*17 allele frequency have
been reported: 18% in both a Swedish and an Ethiopian
population (75 ), 25% in a German population (77 ),
and 27% in a Polish population (78 ). A lower fre-
quency (4%) has been reported for Chinese individuals
(75 ). Given these genotype/phenotype relationships,
there is a possibility that the CYP2C19 UM may play a
role in tamoxifen metabolism and clinical outcome, as
we have reported for our breast cancer tamoxifen phar-
macogenetic study (79 ).
With respect to CYP2B6 (cytochrome P450, family
2, subfamily B, polypeptide 6), the most common vari-
ant allele, *6, occurs at frequencies of 15%– 60% across
different populations (80 ). Genotyping of CYP2B6*6
predicted increased plasma concentrations of efavirenz
and nevirapine and efavirenz-related neurotoxicity in
HIV-infected individuals (81, 82), and the results sug-
gested reducing the dose by 35% in African patients
who were homozygous for CYP2B6*6 (83 ). These find-
ings are in agreement with the lower activities of
CYP2B6*6 isoenzyme, which may be substrate depen-
dent, however. At present, any contribution of CYP2B6
variants to tamoxifen outcome is unknown.
The most important CYP isoenzyme subfamilies
involved in human drug metabolism are CYP3A4 and
3A5, which participate in the metabolism of 40% of the
drugs that are most frequently prescribed (42 ). There is
little evidence for a relevant contribution of CYP3A4
(cytochrome P450, family 2, subfamily A, polypeptide
4) gene expression and enzyme function, although de-
fective CYP3A4 mutants may account for toxicity in
very rare cases (84 ). In contrast, genetic polymor-
phisms define much of the variation in CYP3A5 (cyto-
chrome P450, family 2, subfamily A, polypeptide 5)
expression. The higher incidence of the inactive
CYP3A5*3 variant in Caucasians (85%–95%) vs Afri-
can Americans (30%–50%) causes the lower CYP3A5
protein level seen in Caucasians compared with African
Americans (⬎30% vs 50%). CYP3A5*6 and *7 lack any
functional activity and occur solely in individuals of
African origin. Apart from a clear effect on the immu-
nosuppressant tacrolimus (85 ), the contribution of the
polymorphic CYP3A5 enzyme to CYP3A-mediated
metabolism remains controversial. It is difficult to de-
lineate the relative contributions of CYP3A4 and
CYP3A5 because their protein structures, functions,
and substrates are so similar. In fact, one of these en-
zymes may functionally compensate for the lack of the
other. Whether CYP3A4 and/or CYP3A5 variants con-
tribute to tamoxifen outcome is unknown.
Tamoxifen Pharmacogenomics Review
Clinical Chemistry 55:10 (2009) 1775
Tamoxifen Pharmacogenomics
The rationale underlying the tamoxifen pharmaco-
genomic principle is that variant DNA sequences of
drug-metabolizing enzymes that encode proteins
with reduced or absent enzyme function may be as-
sociated with lower plasma concentrations of active
tamoxifen metabolites, which could have an impact
on the efficacy of tamoxifen treatment. About 30
years ago, Jordan et al. characterized the first potent
antiestrogen metabolite, 4-hydroxytamoxifen, and
reported a 100-fold greater affinity for the ER than
the parent drug (86 ). This metabolite was later
shown to be 30- to 100-fold more potent than ta-
moxifen in suppressing estrogen-dependent cell
proliferation (86 – 89 ). Despite its potency as an an-
tiestrogen, the contribution of this metabolite to the
overall clinical effect of tamoxifen has remained un-
clear, because its plasma concentrations are rela-
tively low compared with those of tamoxifen and
other metabolites (86 ). Our knowledge of the link
between tamoxifen metabolism and treatment re-
sponse rapidly expanded after the characterization
of endoxifen (16, 22 ), which, although it had been
identified in the late 1980s, initially remained ob-
scure with respect to its biological activity. Finally, a
series of laboratory studies for the characterization
of its pharmacology established that endoxifen has a
potency equivalent to 4-hydroxytamoxifen in terms
of its binding affinity for ERs (16 ), suppression of
estrogen-dependent proliferation of breast cancer
cells (16, 89, 90 ), and modulation of estrogen-
mediated global gene expression (91 ). A detailed in
vitro analysis showed that endoxifen is formed
mainly by 4-hydroxylation of the primary metabo-
lite N-desmethyltamoxifen, with the CYP2D6 en-
zyme catalyzing this rate-limiting step (15 ). Owing to
the dominant role of CYP2D6 in the formation of en-
doxifen, variation in the CYP2D6 genotype and pheno-
type is at the heart of tamoxifen pharmacogenetics. The
currently available evidence for this notion is based on
findings obtained at 2 levels of clinical investigations,
which addressed (a) the association between the con-
centrations of active tamoxifen metabolites either with
CYP2D6 genotype or by clinical outcome, and (b) the
association between CYP2D6 genotype and clinical
outcome. The latter approach has shown that patients
with 2 functional CYP2D6 alleles benefited the most
from tamoxifen treatment. Further elucidation of the
relationship between plasma concentrations of en-
doxifen in vivo and clinical outcomes will require
additional detailed investigations with large patient
cohorts.
Effects of Tamoxifen Metabolite Concentrations
Prospective cohort studies of adjuvant tamoxifen treat-
ment have shown wide interindividual variation in the
formation of tamoxifen metabolites and substantial re-
ductions in the steady-state plasma concentrations of
endoxifen during tamoxifen treatment in women car-
rying CYP2D6 gene variants (8, 11, 22 ). Moreover,
convincing evidence have shown that selective seroto-
nin reuptake inhibitors (SSRIs) such as paroxetine and
fluoxetine, which are known to be strong CYP2D6 in-
hibitors, reduce plasma endoxifen concentrations. In
particular, the phenocopy of a significant reduction in
endoxifen plasma concentrations induced by SSRIs
was observed in breast cancer patients homozygous for
the wild-type CYP2D6 genotype, whereas the concen-
trations of other metabolites remained unaffected by
the CYP2D6 genotype/phenotype. Although the rela-
tionship between CYP2D6 variants and plasma endox-
ifen concentrations was first shown for patients with
the PM CYP2D6*4 genotype (11 ), a quantitative ap-
proach that included PM, IM, and UM genotypes sub-
stantiated this relationship (8 ); however, endoxifen
concentrations overlap across genotypes. It follows
that other factors may modify plasma endoxifen
concentrations.
A relationship between CYP2D6 variants and
higher concentrations of N-desmethyltamoxifen (i.e.,
the endoxifen precursor) has been reported at the level
of chemoprevention. Significantly higher plasma con-
centrations of N-desmethyltamoxifen were reported
for mutation carriers after 1 year of tamoxifen therapy,
indicating that the conversion to clinically active en-
doxifen may be impaired (92 ).
A more recent study addressed the relationship be-
tween CYP2D6 and SULT1A1 (sulfotransferase family,
cytosolic, 1A, phenol-preferring, member 1) geno-
types, including the effect of SULT1A1 copy number
on the pharmacokinetics of tamoxifen during steady-
state treatment (32 ). Whereas both CYP2D6 and
SULT1A1 genotypes influenced the pharmacokinet-
ics of tamoxifen metabolites, SULT1A1 copy num-
ber did not. Lower metabolic ratios with respect to
the formation of endoxifen and 4-hydroxytamoxifen
but higher metabolic ratios for the formation of
N-desmethyltamoxifen (endoxifen precursor) were
observed in carriers of CYP2D6 variant genotypes, a
result consistent with a gene-dosage effect. In contrast,
patients carrying CYP2D6 alleles with high predicted
enzymatic activity showed higher metabolic ratios for
both active metabolites. Whether such metabolic ratios
are of clinical relevance remains to be determined.
Similarly, a study of a prospective cohort of Ko-
rean patients with early or metastatic breast cancer
found an association between the IM CYP2D6*10 ho-
Review
1776 Clinical Chemistry 55:10 (2009)
mozygous variant and lower steady-state plasma con-
centrations of 4-hydroxytamoxifen and endoxifen
(17 ), and a Chinese study found that patients homozy-
gous for CYP2D6*10 had lower serum concentrations
of 4-hydroxytamoxifen (93 ). The high prevalence of
the CYP2D6*10 allele in East Asia, together with the IM
association of impaired formation of an active metabolite,
confirms the CYP2D6 PM findings in Caucasians.
Clinical Outcome of Tamoxifen Therapy and
Prediction
The first evidence linking CYP2D6 variants with treat-
ment response was obtained from a prospective ran-
domized phase III trial of postmenopausal women
with ER-positive breast cancer (North Central Cancer
Treatment Group adjuvant breast cancer trial) for the
investigation of the effect of adding the androgen flu-
oxymesterone for 1 year to the standard regimen of 5
years of adjuvant tamoxifen. The pharmacogenetic in-
vestigation of patients from the tamoxifen-only arm
showed that after a median follow-up of 11.4 years, the
CYP2D6*4 variant allele was an independent predictor
of a higher risk of relapse and a lower incidence of hot
flashes (94 ). A follow-up study found that in addition
to CYP2D6 genetics, the phenocopying due to the
coprescription of CYP2D6 inhibitors (SSRIs) was an
independent predictor of breast cancer outcome in
postmenopausal women taking tamoxifen (95 ). Re-
cently, a robust association between CYP2D6 genotype
and treatment outcome was obtained from a nonran-
domized retrospective cohort of ER-positive post-
menopausal breast cancer patients undergoing adju-
vant tamoxifen therapy (79 ). At a median follow-up of
71 months, carriers of PM and IM genotypes (i.e., car-
riers of CYP2D6*4,*5,*10, and *41 alleles) had signif-
icantly more breast cancer recurrences, shorter relapse-
free times, and worse event-free survival than carriers
of functional alleles (Fig. 2). This association was not
observed in postmenopausal ER-positive patients not
treated with tamoxifen. Interestingly, the UM
CYP2C19*17 variant also had a favorable effect on ta-
moxifen treatment outcome. Patients with the ho-
mozygous *17 genotype had significantly fewer breast
cancer recurrences, longer relapse-free times, and bet-
ter event-free survival than non-*17 carriers. Overall,
this study suggested that genotyping for CYP2D6*4,*5,
*10, and *41 could identify patients who would derive
little benefit from adjuvant tamoxifen therapy. Al-
though the CYP2D6 EM phenotype will identify the
patients likely to benefit from tamoxifen, accounting
for about 50% of all patients, the benefit will be maxi-
mal for individuals with the combination of fully func-
tional CYP2D6 alleles and the CYP2C19 UM. The lat-
ter will apply to one third of all patients, indicating that
the tamoxifen pharmacogenetics issue will be relevant
Fig. 2. Kaplan–Meier probabilities of relapse-free time (RFT) of breast cancer patients for CYP2D6-metabolizer
phenotypes predicted from genotypes.
(A), Patients treated with adjuvant tamoxifen (TAM). EMs had a significantly more favorable RFT than patients with impaired
phenotypes (PMs or IMs). (B), Patients without TAM showed no differences with respect to a relationship between the
CYP2D6
-
predicted phenotype and RFT [Schroth et al.
(79)
]. hetEM, heterozygous EM. Originally published in Schroth, W et al.: J Clin Oncol 25
(33), 2007: 5187–93. Reprinted with permission. © 2008 American Society of Clinical Oncology. All rights reserved.
Tamoxifen Pharmacogenomics Review
Clinical Chemistry 55:10 (2009) 1777
for a substantial fraction of breast cancer patients re-
ceiving endocrine treatment.
Clinical studies from Korea, China, and Japan also
have linked poor clinical outcome with CYP2D6 genet-
ics. As expected for populations with a high prevalence
of the IM CYP2D6*10 allele, the *10 homozygote geno-
type was associated with a poor clinical outcome in a
Korean cohort of metastatic breast cancer patients,
whereas the *10 heterozygote and wild-type homozy-
gote genotypes were not (17 ). Likewise, patients from
China who were homozygous for the CYP2D6*10 allele
(93 ) showed an association with unfavorable disease-
free survival. The latter result was substantiated
through comparison with a control patient group
without tamoxifen treatment, in which no association
between clinical outcome and the CYP2D6*10 variant
was observed. Moreover, patients homozygous for
CYP2D6*10 from a Japanese breast cancer cohort that
underwent adjuvant tamoxifen monotherapy showed
a significantly higher incidence of recurrence within 10
years of follow-up, compared with patients with wild-
type CYP2D6 (96 ). Although some of the sample sizes
were low in the Asian studies demonstrating the geno-
type– efficacy correlation, the findings of the clinical
implications of CYP2D6 genotypes predictive for ta-
moxifen efficacy are in line with the findings of others.
On the other hand, a study from the US reported
no association between CYP2D6 genetics and tamox-
ifen outcome (97 ), and contradictory results for this
relationship were reported in a study from Sweden,
which found the CYP2D6*4 variant to be associated
with a better clinical outcome in tamoxifen-treated pa-
tients (98 ). An extended study showed favorable
disease-free survival in CYP2D6*4 carriers compared
with patients homozygous or heterozygous for the
functional CYP2D6 allele (99 ).
The issue of the role of CYP2D6 in tamoxifen ther-
apy for breast cancer has also been addressed within the
context of breast cancer prevention. For example, data
from the Italian Tamoxifen Trial suggest that women
with a CYP2D6*4/*4 genotype may be less likely to ben-
efit from tamoxifen as a chemopreventive agent. This
finding supports the notion of CYP2D6 playing an im-
portant role in tamoxifen’s metabolic activation and
efficacy (100 ). Moreover, the “a priori” hypothesis that
hot flashes may be an independent predictor of tamox-
ifen efficacy has been addressed in the Women’s
Healthy Eating and Living randomized trial (101 ).Of
the 864 patients taking tamoxifen, 674 (78%) reported
hot flashes, and 12.9% of these patients had experi-
enced recurrent breast cancer after 7.3 years of follow-
up, whereas 21% of the patients who did not have hot
flashes had recurrent breast cancer during this period.
Because hot flashes were a stronger predictor of a breast
cancer–specific outcome than age, hormone receptor
status, or tumor stage at diagnosis, the authors sug-
gested an association between side effects, tamoxifen
metabolism, and efficacy. Finally, a small study of fa-
milial breast cancer patients who were carriers of either
BRCA1 (breast cancer 1, early onset) or BRCA2 (breast
cancer 2, early onset) mutations and treated with ta-
moxifen suggested a relationship between CYP2D6 PM
status and a worse survival in familial breast cancer
(102 ); however, because of the small numbers of pa-
tients as well as the inclusion of ER-positive and ER-
negative patients in this investigation, clarification
provided by further studies will be needed to distin-
guish a pharmacogenetic effect from a poor prognostic
effect in carriers of these BRCA mutations.
Given the current treatment practice of long-term
estrogen deprivation in ER-positive postmenopausal
breast cancer patients with the use of AIs as a valid
option, the question of the impact of pharmacogenetic
variation on the optimal choice for adjuvant endocrine
therapy has been addressed in a modeling analysis
(103 ). A Markov model was created to examine
whether the optimal treatment strategy for patients
with the wild-type CYP2D6 gene differs from that for
carriers of the CYP2D6*4 mutation. The study used
patients from the BIG1–98 trial, information from this
trial on relapse risk, and the corresponding genotype
data of Goetz et al. (94 ). Under the assumption that AI
metabolism is independent from CYP2D6, the model
suggests that the 5-year benefit of adjuvant tamoxifen
therapy may exceed even that of up-front AI treatment
in postmenopausal CYP2D6 EM patients.
Conclusion: Clinical Relevance of CYP2D6 in Breast
Cancer
Strong mechanistic, pharmacologic, and clinical evi-
dence, as well as modeling data, now indicate that ta-
moxifen efficacy and clinical outcome depend on
CYP2D6 metabolism controlled by CYP2D6 enzyme
polymorphisms and on pharmacologic interactions.
Data from international studies have consistently dem-
onstrated that plasma concentrations of active tamox-
ifen metabolites are linked with genetically determined
CYP2D6 metabolizer status, phenocopying by strong
CYP2D6 inhibitors, and clinical outcome. The few
conflicting data may be explained by variation in the
studies with respect to patient-inclusion criteria, ta-
moxifen doses, length of treatment, additional chemo-
therapy regimens, or a lack of consistent ER testing.
Importantly, most authors agree that CYP2D6 gene
variants, as well as inhibition of CYP2D6 by prescribed
comedications such as SSRIs, may decrease tamoxifen
metabolism and thus negatively affect tamoxifen effi-
cacy and treatment outcome.
Review
1778 Clinical Chemistry 55:10 (2009)
There are a number of potential clinical conse-
quences from these emerging data on CYP2D6 and the
outcomes of tamoxifen treatment. First, potent SSRIs
such as paroxetine or fluoxetine should not be used to
relieve hot flashes in breast cancer patients receiving ta-
moxifen. Although SSRIs are one of the few evidence-
based therapy options for menopausal vasomotor symp-
toms (104 ), convincing data now indicate that these
drugs may compromise tamoxifen efficacy via a pheno-
copying effect due to interference with CYP2D6-
dependent tamoxifen metabolism. Yet, differences in the
plasma concentrations of tamoxifen metabolites have
been observed, depending on the strength of the CYP2D6
inhibitor (11, 105 ). If treatment of hot flashes is indicated,
an SSRI such as citalopram or escitalopram or a selective
norepinephrine reuptake inhibitor such as venlafaxine
should be used, because these compounds have shown no
appreciable inhibition of CYP2D6.
Second, the relationship between CYP2D6 geno-
type, phenotype, and treatment outcome points to a
possible benefit of up-front CYP2D6 genotyping prior
to a decision on an adjuvant endocrine treatment. A
comprehensive robust, standardized, and quality-
controlled CYP2D6-genotyping assay will have to test
for genetic variants that could affect tamoxifen metab-
olism. According to the data of Goetz et al. (94 ) and
Schroth et al. (79 ), such assays should include testing
for common PM alleles (CYP2D6*3,*4, and *5) and for
IM alleles, depending on the individual’s ethnic origin.
Of note, *41 is the most frequent IM allele in Europe-
ans, *17 is the principal IM allele in Africans, and *10
dominates in Asians (*9 should also be considered)
(59 ). Other areas of interest with respect to clinical
application are the measurement of plasma endoxifen
concentrations as a surrogate of CYP2D6 phenotype.
Given alternative treatment options (i.e., tamox-
ifen vs AI), and considering the available scientific and
clinical evidence, an individualized approach for en-
docrine treatment of postmenopausal breast cancer
patients is desirable. One may speculate that tamoxi-
fen alone is adequate for CYP2D6 EMs and EM carri-
ers, whereas postmenopausal patients with variant
CYP2D6 alleles may fare better with up-front AI ther-
apy. Although this approach may be regarded as
straightforward for PM patients, the best treatment
may be less clear for IM patients. IM is a common phe-
notype among many ethnic groups, including Cauca-
sians, African Americans, and Asians, so data on link-
ing IM genotypes with therapeutic threshold and
efficacy are in demand to adequately address the clini-
cally important question of tamoxifen dose adjust-
ment. Similarly, any impact of UM phenotypes on
metabolite concentrations, treatment efficacy, and tox-
icity that have potential implications for dosing re-
quires further investigations. Formal recommenda-
tions on the integration of CYP2D6 genotypes into
treatment decisions still must await validation of these
genotypes in larger retrospective studies, as is being
attempted by the International Tamoxifen Pharmaco-
genetics Consortium (http://www.pharmgkb.org/do/
serve?objId⫽63&objCls⫽Project), or prospective
clinical trials. Thus far, no study has addressed the
question of whether genetically predisposed differ-
ences in 4-hydroxytamoxifen and endoxifen concen-
trations are associated with treatment response or dis-
ease progression and with side effects such as hot
flashes, including phenocopying effects; therefore,
therapeutic drug monitoring as a useful surrogate is
currently not available in the case of tamoxifen.
Whether determination of the CYP2D6 genotype will
become a diagnostic tool for selecting the appropriate
adjuvant endocrine therapy for ER-positive postmeno-
pausal breast cancer patients awaits validation in pro-
spective clinical trials that randomize tamoxifen vs AI
treatment according to CYP2D6 genotypes. Such pro-
spective clinical trials are currently being planned.
Other open questions may address the clinical rel-
evance of other drug-metabolizing enzymes and muta-
tions, as well as ethnic variation, in the prevalence of
their treatment outcome–relevant genotypes. Finally,
there is the possibility that pharmacokinetic genes will
only partly explain the pharmacogenomics of tamox-
ifen. It will therefore be important to also explore the
contribution of pharmacodynamic genes in evaluating
antiestrogen resistance as a feature of the tumor cell
and in addressing the role of genes associated with
estrogen-mediated cell proliferation. Within this con-
text, it will be interesting to learn whether genes encod-
ing the ER, its coactivators, or its corepressors (106 ),as
well as antiestrogen resistance genes (107 ) and their
variants, will affect the response to tamoxifen. Such
results may increase the overall potential of tamoxifen
pharmacogenomics.
To this end, it is important to appreciate that most
cancer therapies in current use have been established
empirically. The recent progress in our understanding
of the pharmacology and pharmacogenetics of tamox-
ifen, however, holds promise for the improvement of
treatments through personalized medicine. Because
the genome-based approach uses CYP2D6 genotyping
to predict a patient’s metabolizer phenotype, ethical
issues need to be sufficiently addressed. In the light of
acceptable alternatives, an informed choice about ad-
juvant endocrine treatment and, most importantly,
avoiding a therapy that may lack efficacy must be of
prime interest. It will therefore be important to make
patients and their caregivers aware of these issues and
to initiate discussions with regulatory authorities.
Tamoxifen Pharmacogenomics Review
Clinical Chemistry 55:10 (2009) 1779
Author Contributions: All authors confirmed they have contributed to
the intellectual content of this paper and have met the following 3 re-
quirements: (a) significant contributions to the conception and design,
acquisition of data, or analysis and interpretation of data; (b) drafting
or revising the article for intellectual content; and (c) final approval of
the published article.
Authors’ Disclosures of Potential Conflicts of Interest: Upon
manuscript submission, all authors completed the Disclosures of Poten-
tial Conflict of Interest form. Potential conflicts of interest:
Employment or Leadership: None declared.
Consultant or Advisory Role: None declared.
Stock Ownership: None declared.
Honoraria: None declared.
Research Funding: Robert Bosch Foundation, Stuttgart, Germany,
and Bundesministerium fu¨ r Bildung und Forschung Grant No.
01ZP0502.
Expert Testimony: None declared.
Role of Sponsor: The funding organizations played no role in the
design of study, choice of enrolled patients, review and interpretation
of data, or preparation or approval of manuscript.
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Review
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