Pharmacogenetics of anti-estrogen treatment of breast cancer
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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Expression and clinicopathological significance of DNA methyltransferase 1, 3A and 3B in tamoxifen-treated breast cancer patients
2019, GeneCitation Excerpt :The most important therapeutic aims in Estrogen receptor positive (ER+) patients are reduction of estrogen levels and blocking signaling pathway through ER to disrupt tumor growth (Yager and Davidson, 2006; Herynk and Fuqua, 2007). Tamoxifen was approved by the US Food and Drug Administration in 1977 (Del Re et al., 2012) and it has been used as an agent of choice in the treatment of hormone responsive breast tumors for over four decades. Furthermore, this drug is prescribed as a chemo-preventive agent for high-risk women who have a familial history of breast cancer (Mandlekar and Kong, 2001).
Pharmacogenetics of CYP2D6 and tamoxifen therapy: Light at the end of the tunnel?
2016, Pharmacological ResearchCitation Excerpt :Both N-desmethyl-tamoxifen and 4-OH-tamoxifen are secondarily metabolized to 4-OH-N-desmethyl-tamoxifen (endoxifen), by CYP3A4/5 and CYP2D6, respectively. 4-OH-tamoxifen and endoxifen are important active metabolites, exhibiting similar potency [5]. Both N-desmethyl-tamoxifen and 4-OH-tamoxifen are inactivated by UGT and 4-OH-tamoxifen also by SULT1A1.
The genetic variants underlying breast cancer treatment-induced chronic and late toxicities: A systematic review
2014, Cancer Treatment ReviewsCitation Excerpt :Hence, the genetic associations underlying endocrine treatment-induced toxicities such as tamoxifen-induced hot flashes and aromatase inhibitor-associated arthralgia are not included. Nevertheless, it must be noted that the genetics variants associated with these toxicities are extensively described in recent reviews [22,23]. In addition, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was not used in this review.
A miniaturized flow-through cell to evaluate skin permeation of endoxifen
2013, International Journal of PharmaceuticsCitation Excerpt :Breast cancer is the most commonly diagnosed cancer in women worldwide with about 1.38 million newly diagnosed cases each year (Jemal et al., 2011). Nearly 70% of breast cancer patients are hormone-receptor positive (Del Re et al., 2011). For these patients, tamoxifen has been the most widely used adjuvant endocrine therapy (EBCTCG-Secretariat, 2005).
Recent advances in the personalized treatment of estrogen receptor-positive breast cancer with tamoxifen: a focus on pharmacogenomics
2021, Expert Opinion on Drug Metabolism and Toxicology