Tamoxifen Pharmacokinetics Beyond the Genotyping Era

Abstract

Breast cancer is the most commonly diagnosed malignancy in women in almost all countries worldwide and is the primary cause of cancer death among women. Approximately 1.7 million new cases of breast cancer and about 522,000 deaths from breast cancer occurred around the world in 2012. Changes in the understanding of the biology of the disease have contributed to improvement in therapy. Breast cancer is not a single disease, but is composed of distinct subtypes associated with diverse clinical outcomes. This finding has contributed to the ending of one-size-fits-all therapies for breast cancer. The personalization (or individualization) of breast cancer treatment is based on a patient’s unique biologic profile that should guide therapy. The ultimate goal is increased efficacy, ideally with less drugrelated toxicity. The expression of estrogen and/or progesterone receptors was one of the first identified tumor characteristics that may predict response to therapy. About twothirds of breast cancers express estrogen receptors (ERs) and are dependent on estrogen for growth. Selective estrogen receptor modulators and aromatase inhibitors are effective therapies for hormone receptor-positive breast cancers as they deprive breast cancer cells of estrogens or estrogenic growth stimuli. Tamoxifen (approved by the FDA in 1977) is a selective estrogen receptor modulator which acts by blocking the action of estrogen in breast tissue by competing with estrogen for binding to the ER. For almost forty years, tamoxifen has been widely used as endocrine therapy for estrogen receptor-positive breast cancer, both in the adjuvant setting and for metastatic disease. Five years of tamoxifen is currently the standard of care for premenopausal women with early breast cancer. In postmenopausal women tamoxifen is used in sequence with aromatase inhibitors or for women with contraindications to aromatase inhibitors. Tamoxifen for 5 years has been shown to be highly effective in the adjuvant treatment of ER-positive breast cancer, reducing breast cancer recurrence by nearly forty percent and cancer-specific mortality by approximately a third during the first 15 years. Further reductions in breast cancer recurrence and mortality have been observed by continuing tamoxifen therapy for 10 years. In metastatic disease, tamoxifen has been associated with prolonged remission and survival.