WHAT IS TAMOXIFEN RESISTANCE?
Not everybody get the same benefit from cancer treatment. Knowledge of the genetic basis of individual drug response is therefore of major clinical importance. Cytochrome P450 (CYP P450) enzymes are essential for the metabolism of many medications. CYP2D6 is involved in the breakdown of almost 25% of commonly prescribed drugs, including Tamoxifen and antidepressants.
Knowing in advance how the patient’s body is likely to metabolize certain medications could significantly improve the chance of prescribing the right medication at the right dosage. CYP2D6 genotyping is most useful for excluding the use of medications that will not be effective or may cause side effects. The test only assesses some of the genetic variations involved in metabolizing drugs. Between 7-10% of women with breast cancer do not receive the full benefit of tamoxifen treatment due to less functional forms of the CYP2D6 gene, which may prevent the conversion of tamoxifen to its active metabolites. Such reduced effectiveness of tamoxifen due to genetic variation increases the chance of breast cancer recurrence.
Several research studies have confirmed worse clinical outcome in patients with decreased CYP2D6 metabolism. In a 6-year follow-up study it was shown that the presence of 2 functional CYP2D6 alleles was associated with better clinical outcomes and the presence of non-functional or reduced-function alleles with worse clinical outcomes. CYP2D6 allele 4 is also associated with statin-induced side effects in patients with high cholesterol levels. These include muscle pain, myalgia, creatinine kinase elevations without pain with myolysis and myositis (rhapdomyolysis), a potentially fatal side effect. Adverse drug response has an impact on patient compliance and consequently health outcomes; therefore the assessment of risk on an individual level could enhance therapeutic benefit.
Antidepressants cause severe reactions in about 8% of users, and moderately severe reactions in approximately 30% of people who take them, partly due to mutations in genes encoding CYP2D6. CYP2D6 genotyping divides people into four main groups due to the combined effect of gene-drug interaction: 1) Normal metabolizers process certain medications normally and are therefore more likely to benefit from treatment without any serious side effects; 2) Intermediate metabolizers have at least one gene involved in drug metabolism that does not function normally; this may lead to less effective processing of certain medications compared with normal metabolizers; 3) Slow metabolizers process certain drugs more slowly than normal, leading to build up of certain medications with the potential for serious drug side effects; 4) Ultrarapid metabolizers process certain medications so fast that they leave the body before having a chance to work properly. Women with non-functional CYP2D6 alleles taking Tamoxifen for the treatment or prevention of recurrence of breast cancer, who also use antidepressants such as paroxetine and fluoxetine for depression or hot flashes, may not derive the full benefit of anti-cancer treatment due to drug-drug interaction. It has been estimated that 20-30% of patients taking Tamoxifen are using antidepressants.
Pharmacogenetics based drug selection and dose adjustments are an important tool that can be used to individualise drug treatment according to genetic factors. CYP2D6 genotyping provides a way to assess such gene-drug interaction. 1) With introduction of the CYP2D6 genotyping doctors can more accurately predict which medications would be of no benefit to a patient due to impaired metabolic activity. 2) CYP2D6 genotyping provides an indication of which drugs are more likely to be effective based on the patient’s metabolism, but cannot predict how effective a particular drug will be. 3) Poor or slow metabolizers usually require lower doses to achieve the desired effects and to prevent the occurrence of adverse drug reactions at normal dosages. 4) CYP2D6 genotyping may be of value in selecting adjuvant hormonal therapy. In women treated with tamoxifen to reduce the risk of breast cancer development or recurrence, use of aromatase inhibitors is a reasonable alternative in poor drug metabolizers. Raloxifene is metabolized by glucuronide conjugation. 5) CYP inhibitors which include several antidepressants should be avoided in tamoxifen treated women due to drug-drug interaction which may reduce the effectiveness of anti-cancer treatment. 6) It is important to keep in mind that many factors besides the genetic make-up plays a role to determine drug response.
HOW PATIENTS MAY BENEFIT FROM THE
WELLNESS GENESCREEN PROGRAMME
CYP2D6 genotyping is most useful for
excluding the use of medications that may not be effective or cause side
effects. The CYP2D6 allele 4 is associated with statin-induced side effects in
patients with high cholesterol levels. These include muscle pain, myalgia,
creatinine kinase elevations without pain with myolysis and myositis
(rhapdomyolysis), a potentially fatal side effect. Adverse drug response has an
impact on patient compliance and consequently health outcomes; therefore the
assessment of risk on an individual level could enhance therapeutic benefit.
Pharmacogenetics based drug selection and dose adjustments are an important
tool that can be used to individualise drug treatment according to genetic
CYP2D6 testing (allele 4) forms part of the Wellness
GeneScreen in patients with breast cancer. This test is an extension of a general health check such as
determination of cholesterol levels, glucose (blood sugar), blood pressure,
body mass index (BMI) etc. to include a DNA test component focused on the
identification of causative factors and genetic risk that may be indicated by
the family history. The genetic test is performed in conjunction with a
questionnaire-based medical, lifestyle and nutrition assessment to identify
genetic risk factors that could help to explain 1) why the disease developed
(in this case breast cancer and any co-morbidities such as obesity or diabetes
that may increase recurrence risk) and 2) develop a risk reduction strategy
guided from the genetic background. The DNA test includes analysis of
genetic variation in the following genes that may be combined with pathology
tests to determine gene expression and response to treatment:
MTHFR - indicates an increased requirement of folate and
other B-vitamins to prevent homocysteine accumulation and DNA damage that may
lead to development of cancer and many other chronic diseases. Biochemical
changes such as folate deficiency, oxidative stress, aberrant DNA methylation
and production of homocysteine thiolactone explains why elevated homocysteine
levels eventually may lead to carcinogenesis. Adequate intake of certain
nutrients was shown to restore enzyme function but careful consideration of the type of
supplements used is advisable as the synthetic form of folate may promote
tumour growth in patients already diagnosed with cancer. Homocysteine is
considered an important tumour marker for monitoring cancer patients during
treatment as levels decline in response to tumour cell death.
Apo E (E2, E4) - associated with elevated cholesterol and triglyceride
levels due to over-absorption or slow removal of fat from the blood. Depending
on the genetic risk factor identified it not only increases the risk of heart
disease but also Alzheimer's disease and dementia or “chemobrain” with use of
chemotherapy to treat cancer.
FV (Leiden), FII (Prothrombin),
PAI-1 - associated with venous
thrombosis, including pulmonary embolus and thrombophilia that may lead to
miscarriage during pregnancy. The risk of thrombosis is also increased with use
of Tamoxifen for treatment of breast cancer. Smoking, obesity, immobility due
to surgery or long-distance travel, use of oral contraceptives and hormone
receptor therapy are also important triggering factors.
HFE – over-absorption of iron from the diet may lead
to chronic fatigue in the early stage of the disease and eventually organ
damage that also increases the risk of various types of cancer, diabetes,
arthritis, etc. This can be prevented by regular blood donation or an
appropriate diet if detected before excessive iron loading occurs with advanced
FTO, ADRB2, FABP2 - Risk of obesity associated with increased risk
of breast cancer, which may partly be mediated through a disturbance in the
methylation pathway and is therefore interpreted in the context of variation in
the MTHFR gene. Obesity is associated with the most aggressive form of breast cancer known as triple-negative breast cancer.
TNFa, PPARg – Inflammation, hypertension, obesity and insulin
resistance that may form part of the features of the metabolic syndrome known
to increase the risk or severity of breast cancer and many other chronic
GSTT1, GSTM1 - Risk of cell damage due to reduced ability of
the body to remove harmful substances e.g. carcinogens in smoke and other
MnSOD, COMT - Risk of breast cancer increases with inadequate
intake of fruits and vegetables, obesity and/or use of hormone replacement
therapy due to oestrogen exposure.
CYP2D6 - By knowing in advance how your body is
likely to metabolise certain medications the efficacy of the medication can be
increased and side effects prevented. Patients who are receiving Tamoxifen and who are at high risk of tumour recurrence due to a family history of breast/ovarian cancer or the presence of a mutation in the BRCA1/2 genes, and patients who are required to take potential competing antidepressants will benefit most from CYP2D6 genotyping.
SOURCE: van der Merwe N, Bouwens CSH, Pienaar R, van der Merwe L,
Yako Y, Geiger DH, Kotze MJ. CYP2D6
genotyping and use of antidepressants in breast cancer patients: Test
development for clinical application. Metab Brain Dis 2012; 27: 319-326.