CYP2D6 genotyping and use of antidepressants in breast cancer patients: test development for clinical application

Abstract

Approximately 25 % of clinically important drugs and numerous environmental carcinogens are metabolised by CYP2D6. Variation in the CYP2D6 gene and concomitant use of tamoxifen (TAM) with certain antidepressants may increase recurrence risk in breast cancer patients due to reduced enzyme activity. In this study we determined the appropriateness of adding CYP2D6 genotyping to the breast cancer genetic testing options already available in South Africa, which include BRCA mutation screening and transcriptional profiling to assess estrogen receptor (ER) status. A total of 114 South African breast cancer patients, including 52 Caucasian and 62 Coloured (Mixed ancestry), and 63 Caucasian control individuals were genotyped for the most common inactivating allele (CYP2D6*4, rs3892097) previously identified in the CYP2D6 gene. In the initial validation data set consisting of 25 Caucasian and 62 Coloured patients, the CYP2D6*4 allele frequency was significantly higher in Caucasian compared to Coloured patients (24 % vs. 3 %, p < 0.001), similar to previous findings in the general South African population. Extended CYP2D6 genotyping was subsequently performed in an implementation data set of 27 Caucasian breast cancer patients, to determine the prevalence of depression and use of antidepressants in a clinical setting. A medical history of depression and/or use of antidepressants was reported in 37 % (10/27) of these breast cancer patients genotyped for CYP2D6*4. This translational research study has led to increased awareness among clinicians of the potential benefits of CYP2D6 genotyping to facilitate prevention of cumulative risk in a high-risk genetic subgroup of breast cancer patients considered for concomitant treatment of TAM and antidepressants that may reduce enzyme function.

Exome Sequencing in a Family with Luminal-Type Breast Cancer Underpinned by Variation in the Methylation Pathway

“…Due to constantly evolving genetic knowledge, the ideal breast cancer susceptibility test remains elusive as it requires continuous development and refinement as new information on VUS classification and clinical relevance of functional polymorphisms become available in the scientific literature. The identification of actionable functional polymorphisms in important disease pathways covered to a certain extent in the CVD multi-gene assay, which was recently extended to include CYP2D6 pharmacogenetics [ 28 , 31 ], caused a paradigm shift in our understanding of the pieces of the susceptibility puzzle. Implications for genetic counseling remains uncertain and can only be comprehended by incorporating fixed genetic and modifiable environmental risk factors into an existing body of knowledge.…”

“…Only unrelated breast cancer patients with known ER status who signed informed consent for genetic studies were selected for high-throughput genotyping, comprising 60 (37%) Coloured patients of mixed ancestry and 104 (63%) Caucasians, including the index case. Patients with histopathology confirmed breast cancer were recruited at the Tygerberg Hospital Breast Cancer Clinic or referred from private practicing clinicians, as previously described by van der Merwe et al [ 28 ]. Patients referred by clinicians in private practice participated in a chronic disease screen using the CVD multi-gene assay [ 59 ] as the core genetic component, recently extended to include CYP2D6 pharmacogenetics [ 31 ].…”

“…Depression is a major comorbidity in breast cancer survivors and impacts on both the quality of life and treatment decision making. In this context, Van der Merwe et al [ 28 ] recommended CYP2D6 genotyping in breast cancer patients who (1) receive tamoxifen treatment; and (2) are at increased recurrence risk due to a family history of breast cancer/ BRCA -mutation positivity; or (3) are required to take potential competing antidepressants that may inhibit CYP2D6 enzyme function. CYP2D6 genotyping combined with the unique spectrum of BRCA1/2 founder mutations identified in the South African population [ 29 , 30 ], forms part of the pathology-supported pharmacogenetics test developed by van der Merwe [ 31 ] for improved clinical management of patients with breast cancer and associated comorbidities.…”

Serotonin Toxicity and Cytochrome p450 Poor Metaboliser Genotype Patient Case

“…It was demonstrated that homozygote genotype results in a non-functional protein formation [29]. This non-functional allele was described in association with neuroleptic malignant syndrome [30], metoprolol pharmacokinetics/ pharmacodynamics modulation [31], metoclopramide side effect [32], tamoxifen efficacy [33,34], colchicine efficacy [35], with environmental sensitivity-related illnesses [36], enhancing susceptibility to head and neck squamous cell carcinoma and chemotherapeutic response [37], increased incidence of systemic sclerosis [38] the risk of Parkinson's disease [39] and Poor Metaboliser phenotype for several drugs [40]. Patients with the *4/*4 diplotype and depression may require a lower dose of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine or sertraline as compared to patients with the *1/*1 genotype [40].…”

Influence of combinations of drugs that act on the CYP2D6 metabolic pathway in the treatment of major depressive disorder: A population-based study

“…The enzymes of the cytochrome P450 are primarily responsible for the metabolism of drugs. Specifically, the CYP2D6 isoenzyme is responsible for the metabolism of 20–35% of the most commonly used therapeutic drugs [21] and the gene coding for it has over 70 different polymorphisms, including some specific to certain ethnicities or population groups [12,13,32,53]. In vivo studies of AD have shown that drugs such as bupropion, fluoxetine, quinidine, paroxetine, terbinafine and thioridazine inhibit CYP2D6, leading to adverse effects and poor therapeutic response [1,47].…”