Breast Cancer Clinical Trial
Official title:
Genetic Study of CYP2D6 Enzyme and Therapeutic Drug Monitoring of Tamoxifen in Premenopausal Women With Breast Cancer
Aim of work:
1. To estimate the frequency of Cyp2D6*1 and *4 alleles in Egyptian patients maintained on
tamoxifen (20 mg/day) for management of ER +ve breast cancer.
2. To measure levels of tamoxifen, 4-hydroxy tamoxifen, N-desmethyl-tamoxifen and 4-
hydroxyl-N-desmethyl-tamoxifen (endoxifen) in the serum of these patients.
3. To correlate between the levels of tamoxifen/active metabolite enoxifen ratio and
CYP2D6*1,*4 genotyping.
4. To investigate which is more valuable investigatory tool for prediction of the clinical
outcome (response and/or toxicity) in these patients; either the measurements related to
pharmacokinetics: tamoxifen/endoxifen levels or the pharmacogenetic analysis of CYP2D6
*1,*4.
Breast cancer is considered to be the most common cancer among women worldwide. The majority
of breast cancer cases (almost 80%) are classified as hormone-dependent cancer, since
estrogen, acting via estrogen receptor alpha (ER-α) or estrogen receptor beta (ER-β), is the
major inducer of the development and growth of the tumor. These are also called ER-positive
breast cancers. The remaining cases are not induced by estrogen and are classified as
hormone-independent, or ER-negative, cancers. Since the growth of hormone-dependent cancer
cells can be down-regulated by the oppositely active hormones, several endocrine therapies
that limit the actions of estrogen (through blocking its production or its receptors) have
been developed over the past years. These endocrine therapies have played an important part
in treating and improving the outcomes of women with all stages of the disease . Selective
estrogen receptor modulators (SERMs) have also been studied for their anti-cancer activity.
Selective estrogen receptor modulators (SERMs) are a class of drugs that act on the estrogen
receptor (ER); a characteristic that distinguishes these substances from pure ER agonists and
antagonists as their action is different in various tissues, thereby granting the possibility
to selectively inhibit or stimulate estrogen-like action in various tissues .
Tamoxifen, which is a SERM, is important for the treatment and prevention of estrogen
receptor (ER) positive breast cancer commonly in premenopausal women. It has been shown to
decrease disease recurrence and mortality rates by as much as 50% and 30% respectively. It
has been also used as a prophylactic treatment for patients who are at high risk of
developing breast cancer. Post-menopausal breast cancer patients are commonly treated
nowadays with aromatase inhibitors (AIs) for 5 years, alone or combined with tamoxifen for a
3-5 year period. Tamoxifen monotherapy in postmenopausal women with breast cancer may be used
for 10 years if the side effects from AIs are too bothersome .
Besides acting as SERMs, it has recently been found that some of tamoxifen's metabolites (as
norendoxifen) also act as aromatase inhibitors in vitro. Aromatase converts steroids (e.g.,
testosterone to estradiol), the inhibition of which severely decreases the amount of
available estrogen in the body .
The most common side effects of Tamoxifen:
- Hot flashes, the most common side effect of tamoxifen, affect up to 80% of women.
- Increased risk of endometrial hyperplasia and polyps
- Increased risk for cataract.
- Increased risk for thromboembolic events as well as clinical depression .
Pharmacokinetics of tamoxifen and its clinical implications:
Tamoxifen is a prodrug that is metabolized by several cytochrome P450 enzymes. It is a
relatively weak antiestrogen in comparison to its active metabolites, particularly endoxifen.
Two parallel pathways bioactivate tamoxifen to endoxifen (4-OH-N-desmethyltamoxifen) through
several overlapping cytochrome P450 (CYP) enzymes; primarily CYP3A4/5 and CYP2D6.
For many years, 4-hydroxy-tamoxifen has believed to be primarily responsible for the clinical
activity; however, the CYP2D6 metabolites 4-hydroxy-tamoxifen and endoxifen
(4-OH-N-desmethyl-tamoxifen) have equal affinity for the estrogen receptor. Because serum
concentrations of endoxifen are 6 to 12 times higher than 4-hydroxy-tamoxifen in patients
receiving long-term tamoxifen therapy, many think endoxifen is the most significant tamoxifen
metabolite.
The rate limiting step in tamoxifen metabolism is catalyzed by the highly polymorphic CYP2D6
enzyme so that CYP2D6 genotype can be translated into predicted metabolic activity
phenotypes: poor metabolizer (PM), intermediate metabolizer (IM), extensive metabolizer (EM),
ultrarapid metabolizer (UM), which are strongly predictive of endoxifen concentration during
tamoxifen treatment.
There is substantial variation in CYP2D6 genotypes among different populations. CYP2D6*1 is
the wild-type allele and is associated with normal enzyme activity and the normal "extensive
metabolizer" phenotype. The CYP2D6 alleles *2, *33, and *35 are also considered to have
near-normal activity. Other alleles include variants that produce a non-functioning enzyme
(e.g., *3, *4, *5, and *6) or an enzyme with reduced activity (e.g., *10, *17, and *41).
There are large inter-ethnic differences in the frequency of these alleles, with *3, *4, *5,
*6, and *41 being more common in the Caucasian population, *17 more common in Africans, and
*10 more common in Asians. Also it was found that *1 and *4 alleles are more common in
Egyptians.
Patients with low-activity CYP2D6 phenotypes have substantially lower endoxifen steady-state
concentrations . It is unclear whether patients with genotypes that confer low CYP2D6
activity have inferior efficacy from tamoxifen treatment, but if so, preemptive genotyping to
guide tamoxifen dose selection could be a viable strategy to improve treatment effectiveness.
Despite the proven efficacy of tamoxifen, some women experience cancer recurrence during or
after treatment. Therapeutic failure may be caused by tumor resistance to antiestrogen
therapy or inadequate bioactivation of tamoxifen to its active metabolite, endoxifen.
Some studies have reported that patients with low endoxifen concentrations (below 5.9 ng/ml)
have increased the risk of inferior tamoxifen efficacy with consequent cancer recurrence
compared with its concentration in intermediate and rapid or ultra-rapid metabolizers taking
the same dose. This can open the way for application of therapeutic drug monitoring of
tamoxifen and its metabolite endoxifen for possible dose escalation especially a fixed dose
of the drug is usually used which is 20 mg/day.
The issue of relying on genotyping profile of CYP2D6 and its variants or use of TDM of
tamoxifen and its metabolite endoxifen or the combination of both parameters to correlate
with clinical response, adverse effect and dose modification of tamoxifen is still under
investigation.
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