Cancer - Breast & Ovarian

The role of genetic variability in drug metabolism pathways in breast cancer prognosis.

Choi, J-YN et al., 2006. Pharmacogenomics 7(4):613-624.

Abstract:

Among patients receiving adjuvant therapy for breast cancer, there is variability in treatment outcomes, and it is unclear which patients will receive the most benefit from treatment and which will have better disease-free survival. To date, most studies of breast cancer prognosis have focused on tumor characteristics, but it is likely that pharmacogenetics, genetic variability in the metabolism of therapeutic agents, also plays a role in the prediction of survival. In this paper, we briefly discuss the metabolic pathways of drugs commonly used for the treatment of breast cancer (cyclophosphamide, doxorubicin, taxanes, tamoxifen and aromatase inhibitors) and describe the known genetic variants that may impact those pathways. Studies that have evaluated potential effects of these genetic variants on treatment outcomes are also discussed. It is likely that the application of pharmacogenetics, particularly in the setting of randomized clinical trials, will contribute to findings that may result in individualized therapeutic dosing.

Journal Link  |  PMID

High-throughput genomic technology in research and clinical management of breast cancer - Plasma-based proteomics in early detection and therapy

Davis, M & Hanash, S, 2006. Breast Canc. Res. 8(6):217-220

Abstract:

Protein-based breast cancer biomarkers are a promising resource for breast cancer detection at the earliest and most treatable stages of the disease. Plasma is well suited to proteomic-based methods of biomarker discovery because it is easily obtained, is routinely used in the diagnosis of many diseases, and has a rich proteome. However, due to the vast dynamic range in protein concentration and the often uncertain tissue and cellular origin of plasma proteins, proteomic analysis of plasma requires special consideration compared with tissue and cultured cells. This review briefly touches on the search for plasma-based protein biomarkers for the early detection and treatment of breast cancer.

Journal Link| PMID

Comment

A brief overview of the clinical use of proteomic assays of blood proteins in the diagnosis and staging of breast cancer.   A good beginning site for novices and a quick review for the experienced, whether a basic scientist or a clinician.

Functional analysis of the breast cancer genome

Ellis, MJ, 2006. J. Clin. Oncology 10;24(11):1649-50 (editorial)

Introduction

Clinicians have long recognized that a diagnosis of breast cancer encompasses different tumor types with very different clinical outcomes. The first critical step toward a biomarker-based sub-classification schema to aid disease management occurred with the widespread introduction of tumor estrogen-receptor (ER) measurement three decades ago. It is worth revisiting the literature of the time, because the introduction of ER testing was very controversial. In particular, investigators worried that a benefit from endocrine therapy in ER–disease could not be excluded. It took the weight of a meta-analysis to resolve this issue, but even today we worry about excluding a patient from appropriate endocrine therapy because of false-negative ER results. The single-sample prediction problem continues to be central to the current debate regarding new and more complex biomarker approaches. Apparently robust group predictions typical of these analyses does not necessarily require great measurement accuracy. Prospective clinical testing, on the other hand, needs to be highly precise to avoid the potentially tragic consequences of tumor misclassification.

Journal Link | PMID

Comment

This brief editorial is a succinct description of the rationale by which differences in gene expression can lead to development of new and novel drugs for treatment of cancer.

CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment.

Jin et al., 2005. J. Natl. Cancer Inst. 97(1):30-39.

Background: The efficacy of tamoxifen therapy for the treatment of breast cancer varies widely among individuals. Plasma concentrations of the active tamoxifen metabolite endoxifen are associated with the cytochrome P450 (CYP) 2D6 genotype. We examined the effects of concomitant use of selective serotonin reuptake inhibitor antidepressants, which are CYP2D6 enzyme inhibitors commonly prescribed to treat hot flashes in women who take tamoxifen, and genotypes for genes that encode tamoxifen-metabolizing enzymes on plasma concentrations of tamoxifen and its metabolites. Methods: Eighty patients with newly diagnosed with breast cancer who were beginning tamoxifen therapy (20 mg/day orally), 24 of whom were taking CYP2D6 inhibitors, were genotyped for common alleles of the CYP2D6, CYP2C9, CYP3A5, and sulfotransferase (SULT) 1A1 genes. Plasma concentrations of tamoxifen and its metabolites were measured after 1 and 4 months of tamoxifen therapy. Differences in plasma concentrations of tamoxifen and its metabolites between genotype groups were analyzed by the Wilcoxon rank sum test. All statistical tests were two-sided. Results: Among all women, plasma endoxifen concentrations after 4 months of tamoxifen therapy were statistically significantly lower in subjects with a CYP2D6 homozygous variant genotype (20.0 nM, 95% confidence interval [CI] = 11.1 to 28.9 nM) or a heterozygous genotype (43.1 nM, 95% CI = 33.3 to 52.9 nM) than in those with a homozygous wild-type genotype (78.0 nM, 95%CI = 65.9 to 90.1 nM) (both P = .003). Among subjects who carried a homozygous wild-type genotype, the mean plasma endoxifen concentration for those who were using CYP2D6 inhibitors was 58% lower than that for those who were not (38.6 nM versus 91.4 nM, difference = -52.8 nM, 95% CI = -86.1 to -19.5 nM, P = .0025). The plasma endoxifen concentration was slightly reduced in women taking venlafaxine, a weak inhibitor of CYP2D6, whereas the plasma endoxifen concentration was reduced substantially in subjects who took paroxetine (a potent inhibitor of CYP2D6). Genetic variations of CYP2C9, CYP3A5, or SULT1A1 had no statistically significant associations with plasma concentrations of tamoxifen or its metabolites. Conclusion: Interactions between CYP2D6 polymorphisms and coadministered antidepressants and other drugs that are CYP2D6 inhibitors may be associated with altered tamoxifen activity.

Journal Link | PMID

Comment

This study highlights the significant relationship between a patient's genome, her chemotherapy for breast cancer and associated psychotherapies for the depression that may accompany breast cancer and its treatment.  The focus is on cytochrome P450 enzymes that metabolize tamoxifen and SSRI antidepressants that also inhibitor them.