Impact of Metabolizing Enzymes on Drug Response of Endocrine Therapy in Breast Cancer

Pilar H Saladores; Jana C Precht; Werner Schroth; Hiltrud Brauch; Matthias Schwab

Disclosures

Expert Rev Mol Diagn. 2013;13(4):349-65. 

In This Article

Abstract and Introduction

Abstract

Estrogen-receptor positive breast cancer accounts for 75% of diagnosed breast cancers worldwide. There are currently two major options for adjuvant treatment: tamoxifen and aromatase inhibitors. Variability in metabolizing enzymes determines their pharmacokinetic profile, possibly affecting treatment response. Therefore, prediction of therapy outcome based on genotypes would enable a more personalized medicine approach, providing optimal therapy for each patient. In this review, the authors will discuss the current evidence on the most important metabolizing enzymes in endocrine therapy, with a special focus on CYP2D6 and its role in tamoxifen metabolism.

Introduction

Breast cancer has the highest incidence of cancer in women worldwide. According to statistics reported by the WHO, over 1.38 million women are affected with breast cancer and of those, 458,000 die each year.[201] A majority of these women are found to have hormone receptor-positive breast cancer, specifically classified with estrogen receptor (ER)- or progesterone receptor-positive status or both. Approximately 75% of diagnosed breast cancers occur in postmenopausal women and within that group, more than two-thirds are characterized as having ER-positive status. These affected women are considered candidates for endocrine therapies, which include either tamoxifen or aromatase inhibitors (AIs) as standard adjuvant therapy for early breast cancer.

Tamoxifen was first approved in 1977 by the US FDA in the adjuvant setting and thereafter was approved in the chemopreventive setting.[202] Adjuvant tamoxifen is considered the gold standard of care in antiestrogenic treatment of ER-positive breast cancer in premenopausal women and remains a major option of treatment in postmenopausal women. Tamoxifen therapy for 5 years substantially lowers the yearly relapse rates and mortality in primary breast cancer,[1] and this clinical benefit is further maintained when tamoxifen is continued for 10 years rather than stopping at 5 years, as shown by the ATLAS trial.[2] Notably, 10 years of tamoxifen can halve breast cancer mortality during the second decade after diagnosis. Pharmacologically, tamoxifen is a competitive partial agonist inhibitor of ER and belongs to a class of drugs known as selective ER modulators, which exhibit either agonistic or antagonistic effects at the ER depending on the location of action in the body.[3] For instance, tamoxifen acts antagonistically in mammary tissue by blocking the ER from its endogenous ligand, estradiol, but acts agonistically in the bone.[3] Thus, the drug provides a further benefit by increasing bone density and preventing osteoporosis in breast cancer patients.

Since the 1990s, direct hormone suppression has been another option for antihormonal therapy to prevent growth of estrogen-dependent breast cancer cells. As the enzyme aromatase (CYP19A1) catalyzes the crucial last step of estradiol biosynthesis, it is an efficient target to lower estrogen levels by inhibition with AIs. Indeed, the currently used third generation AIs provide efficient reduction of estradiol levels and have been proven to be effective in the adjuvant endocrine treatment of postmenopausal breast cancer. Clinical studies have shown that AIs are superior to tamoxifen with regard to disease-free survival[4–7] and are deemed to be the preferred treatment for postmenopausal ER-positive breast cancer, either as up-front monotherapy or sequential to tamoxifen.[8] In contrast to earlier generation AIs, the nonsteroidal compounds anastrozole and letrozole, as well as the steroidal exemestane, provide the highest target specificity and inhibitory potential.[9–11] Although they are proven to be safe, a substantial proportion of patients suffers from severe side effects including arthralgia, myalgia and loss of bone density.[12,13]

This review addresses the role of drug metabolizing enzymes (DMEs) that potentially influence pharmacokinetics and drug efficiency of both tamoxifen and AIs. Importantly, both drug classes target estrogen-mediated growth of breast cancer cells. Therefore, metabolizing enzymes controlling the supply of circulating estrogens are probably relevant for drug efficiency; however, with the exception of CYP19A1, other enzymes' contribution or confounding impact is beyond the scope of this review.

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