Pharmacokinetics and pharmacogenomics in breast cancer chemotherapy☆
Introduction
Breast cancer incidence is predicted to occur in over 180,000 women per year in the United States (http://www.cancer.org/) and over 45,000 women per year in the UK (http://info.cancerresearchuk.org/cancerstats/types/breast/). It is one of the most common causes of cancer death in the developed world. Five-year survival rates are ~ 80% in both the US and the UK.
There are multiple treatment options for breast cancer. Pre- or post-therapy surgical resection is commonly used. Radiation therapy typically follows surgery for early stage disease and shows a reduction of local recurrence by 26% after 3 years of follow-up. Partial breast irradiation via intraoperative radiotherapy (radiotherapy administered during surgery), brachytherapy (radiation delivered via a catheter), or three dimensional conformal radiotherapy, is being assessed in clinical trials [1].
In postmenopausal women, estrogen receptor and/or progesterone receptor positive breast cancers (approximately 70% of all postmenopausal breast cancers) are typically treated with anti-estrogen therapy. Tamoxifen has been the mainstay of endocrine therapy; this is a direct inhibitor of the estrogen receptor. Recently aromatase inhibitors have been developed, for example letrozole, exemestane and anastrozole. These block estrogen synthesis by inhibiting aromatase (CYP19A1). Aromatase inhibitors are reported to improve efficacy and have a preferential toxicity profile compared to tamoxifen. In addition, the utility of long term use of tamoxifen to prevent recurrence is unclear and patients who have received 5 years of tamoxifen therapy are typically transferred to an aromatase inhibitor [2], [3], [4].
Targeted therapy, including monoclonal antibodies, is a growing field. Trastuzumab (Herceptin) has been used since 1998 in patients who have been identified with HER2 over-expression via immunohistochemistry, or ERBB2 (the gene that encodes HER2) gene amplification using fluorescence in situ hybridization (FISH). HER2 over-expression/ERBB2 amplification typically occurs in approximately 30% of breast tumors and trastuzumab is given to these patients usually in combination with chemotherapy regimens [5], [6], [7]. Bevacizumab (Avastin) was recently approved (2008) for use in combination with paclitaxel to treat HER2 negative metastatic breast cancer. This antibody targets the vascular endothelial growth factor (VEGF) and inhibits tumor angiogenesis [7].
Locally advanced or metastatic disease is treated with cytotoxic chemotherapy (Table 1). Treatment strategies for breast cancer based on chemotherapy are the focus of this review.
Section snippets
Anti-mitotics
During cell division tubulin dimers form microtubules. During anaphase microtubules have the ability to grow and shorten at either end (known as treadmilling). Taxanes stabilize the microtubules by binding to sites on tubulin dimers, blocking treadmilling and preventing the continuation of cell division. Conversely, vinca alkaloids function by disrupting microtubules, consequently inhibiting mitosis.
Cyclophosphamide
Cyclophosphamide is an alkylating agent, which has commonly been used in combination therapy to treat breast cancer for the past three decades. Cyclophosphamide undergoes metabolism to form phosphoramide mustard and acrolein. Phosphoramide mustard is the active DNA cross-linking metabolite.
Antimetabolites
Antimetabolites affect DNA synthesis by blocking purine or pyrimidine biosynthesis pathways. 5-fluorouracil inhibits the conversion of dUMP to dTMP by forming a stable ternary complex with thymidylate synthase and the methylenetetrahydrofolate co-factor, leading to a depletion of thymidine in the cell. Capecitabine is an oral 5-fluorouracil prodrug, which ultimately has the same mechanism of action. Methotrexate is an anti-folate, and gemcitabine is a purine analogue.
Anthracyclines
Anthracyclines are DNA intercalating agents that act as Topoisomerase II poisons. Doxorubicin and epirubicin are commonly used cytotoxics in combination with other chemotherapy agents for the treatment of postmenopausal breast cancer. Common toxicity includes cardiotoxicity, consequently work on improving tolerance to anthracyclines by means of novel carrier systems such as pegylated liposomal doxorubicin are being assessed to help reduce toxic events [50].
Platinums
Platinum drugs, such as cisplatin and carboplatin, act in similar ways to alkylating agents. They cause DNS cross-links leading to mitotic arrest. Carboplatin has a significantly reduced toxicity profile compared to its parent drug, cisplatin, particularly nephrotoxicity and neurotoxicity, but has similar efficacy. Previously untreated breast cancer patients derive more benefit from platinum therapy than previously treated patients [62].
Combination therapy
Chemotherapy for breast cancer is usually given in combination (Table 1). However, although the majority of pharmacogenomics studies are performed on samples from patients who have received combination therapy, the polymorphisms assessed are usually deemed specific to one of the drugs used in the combination. In addition, in vitro studies to determine novel genome regions involved in chemosensitivity [65], [66] or to assess the functional role of genetic polymorphisms typically use monotherapy.
Conclusions
Significant interindividual variability in pharmacokinetic parameters exists for the majority of chemotherapy agents used to treat breast cancer. Pharmacogenomics has the potential to identify markers predicting pharmacokinetics in addition to predicting outcome and toxicity profiles. To date the evidence for the utility of pharmacogenomics in selecting breast cancer chemotherapy is minimal. However, some interesting recent findings warrant validation in large, prospective studies to determine
Acknowledgements
SM is funded by Genome Quebec, and GL holds the Alan B Brown Chair in Molecular Genomics.
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This review is part of the Advanced Drug Delivery Reviews theme issue on “Recent advances in Cancer Chemotherapy: Current Strategies, Pharmacokinetics, and Pharmacogenomics”.