Elsevier

Cancer Treatment Reviews

Volume 38, Issue 5, August 2012, Pages 442-450
Cancer Treatment Reviews

Pharmacogenetics of anti-estrogen treatment of breast cancer

https://doi.org/10.1016/j.ctrv.2011.08.003Get rights and content

Abstract

A major effort is underway to select genetic polymorphisms potentially relevant to the clinical efficacy and safety of endocrine treatment of breast cancer. Genetic factors of the host that affect the metabolism of tamoxifen, a widely used drug for the adjuvant treatment of breast cancer, have received particular attention. Cytochrome P450 isoform 2D6 (CYP2D6) is a key step in the metabolism of tamoxifen to its active moiety endoxifen. Women with functionally deficient genetic variants of CYP2D6 who are given drugs that inhibit CYP2D6 are exposed to low endoxifen plasma levels and may enjoy reduced benefits from tamoxifen treatment. Therefore, CYP2D6 status may be an important predictor of the benefits of tamoxifen to an individual; unfortunately, the data are not uniformly concordant, and definitive evidence that would suggest the routine analysis of CYP2D6 before commencing tamoxifen treatment is not yet available. Recent research has focused on the role UDP-glucuronosyltransferases, a family of metabolizing enzymes that play an important role in the metabolic clearance of tamoxifen and of the aromatase inhibitors as well, and how interindividual differences in these enzymes may play a role in the clinical outcome upon administration of anti-estrogen treatment. In conclusion, whether a pharmacogenetic profile should be obtained prior to initiating tamoxifen therapy is currently a matter of debate, although summing up all the scientific evidence available on this issue it appears that the genetic screening would be an useful support for clinical decision making in selected patients.

Introduction

Breast cancer is the most common malignancy of women in the Western world and it is associated with an enormous amount of morbidity and mortality worldwide. According to estimates by the World Health Organization International Agency for Research on Cancer, approximately 1.29 million women were diagnosed and over 400,000 women died with breast cancer in 2008.40

The first major classification of breast cancer is the identification of the estrogen (ER) and progesterone (PR) receptor status. More than two thirds of breast cancers are positive on immunohistochemical staining to the estrogen receptor (ER), so hormonal therapies are the backbone of treatment for the large majority of patients with breast cancer. Both estrogen synthesis and activity through the ER have been targeted by therapies to control endocrine-dependent breast cancer; however, not all women whose tumors express ER derive benefit from hormonal therapies. Differentiating breast cancers, just on the basis of ER and PR status vastly improves treatment efficacy26; the ER-positive (ER+) tumors are dependent on estrogen signaling for their growth and replication and they can be treated by antiestrogen therapy with either tamoxifen or an aromatase inhibitor (AIs). The ER-negative (ER−) tumors, instead, are not estrogen-dependent and will not respond to antiestrogen therapy but are more responsive to first line chemotherapeutic combinations such as paclitaxel, 5-FU, doxorubicin and cyclophosphamide (T/FAC).62 Expression of the PR is highly correlated with ER expression but the effect of PR status on treatment seems to be less important than that of ER.18 Tamoxifen is the gold standard treatment for early and advanced disease and its activity on ER+ cancers is considered the first form of molecular targeted therapy. Recently, the introduction of aromatase inhibitors either in metastatic or in adjuvant setting has added a novel and more active tool in the breast cancer treatment.66 Another well characterized tumor marker is the human epidermal growth factor receptor 2 (HER2/neu). HER2 has been identified as a marker of poor prognosis and increased cancer aggressiveness59 and treatment of HER2+ tumors has changed significantly with the use of trastuzumab, a monoclonal antibody specific for the HER2/neu protein.

Despite these important clinical advances, however, not all patients respond to endocrine therapy and a substantial number of patients who respond will develop subsequent disease progression or recurrence while on therapy. Pharmacogenetics may account in part for the interpatient variability in treatment response to endocrine therapies than that is commonly observed. Variations in genes that encode for enzymes associated with drug metabolism or elimination, or a drug target, can lead to individual differences in drug distribution, metabolism, activity, and toxicity.22, 86 SNPs are often found in the promoter region or in the coding region of the gene and they can cause, respectively, an altered expression of the enzyme or amino acid substitution in the translated protein (non-synonymous SNP), resulting in a variant protein that have increased or decreased activity relative to the wild-type protein. It has also been demonstrated that a SNP in a coding region that does not change the amino acid sequence (synonymous SNP) can impact protein folding kinetics and create an improperly folded and functionally variant protein.47 The identification of SNPs that considerably alter the function or expression of proteins involved in the pharmacokinetics or pharmacodynamics of drugs and their ultimate effect on efficacy and safety is the aim of pharmacogenetics, with the purpose of an individualized and personalized therapy. Treatment for breast cancer is constantly evolving as new technologies, therapies, and strategies are discovered and the individualization of breast cancer treatment promises to increase effectiveness and decrease drug-related toxicities while reducing health care costs.

Section snippets

Aromatase (CYP19A1)

When ovarian estrogen synthesis ceases at the menopause, estrogens continue to be synthesized in different tissue compartments from circulating androgens. The key pathway is aromatization of androstenedione into estrone, probably accounting for as much as 90% of the total estrogens synthesized in a postmenopausal woman (Fig. 1). Aromatase, also called estrogen synthetase, is a cytochrome P450-dependent enzyme symbolized as CYP19A1 and catalyzes three consecutive hydroxylation reactions

Endocrine treatment of breast cancer: Tamoxifen

Tamoxifen is the most commonly used agent for the treatment of ER+ breast cancer and belongs to the class of selective estrogen receptor modulators (SERMs). The drug was approved by the US Food and Drug Administration in 1977 for the treatment of metastatic breast cancer and subsequently approved for use in the adjuvant setting; in addition, the Early Breast Cancer Trialists’ Collaborative Group demonstrated that five years of therapy with tamoxifen reduced the annual risk of breast cancer

Endocrine treatment of breast cancer: Aromatase inhibitors

In post-menopausal women, the major source of estrogen is the peripheral synthesis of estrone and estradiol by aromatase, which is the target of specific inhibitors. Aromatase inhibitors including anastrozole, exemestane and letrozole, exert their activity by inhibiting estrogens production. They proved to be active in advanced and early breast cancers in postmenopausal hormone receptor–positive patients30, 31 and have demonstrated improved activity compared to tamoxifen in various clinical

Conclusions and perspectives

Hormonal treatment of receptor positive breast cancer is of paramount importance for the survival of patients with breast cancer. However, despite the large number of data that, at least indirectly, provide evidence of the potential clinical importance of many factors of variability that affects the metabolism and target interaction of anti-estrogen drugs, little use is made in the clinic of the available testing to assess such variability.

Due to the lack of convincing data arising from

Conflict of interest statement

The authors certify that there is no conflict of interest with any financial organization regarding the material discussed in the manuscript that could inappropriately influence the work presented herein.

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