CYTOCHROME P450 PHARMACOGENETICS AS A PREDICTOR OF TOXICITY AND CLINICAL EFFICAC

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The combination of an anthracycline and cyclophosphamide with or without additional cytotoxic or hormonal therapy represents a common standard approach to therapy in women with invasive breast cancer. Unfortunately, not all women enjoy long term survival with this approach and toxicity is common. A particular concern among women of reproductive age is the permanent loss of fertility secondary to therapy. In addition to the psycho-social impact of premature menopause with regard to reproduction, other associated negative sequelae include hot flashes and possible adverse bone-related consequences. The specific toxicities of doxorubicin include nausea and vomiting, mylosuppression, thrombocytopenia, and cardiac dysfunction (dose-related). While multiple factors influence both the efficacy and the toxicity of therapy, one important variable is the ability of the host to metabolize and clear a compound. Thus, in addition to the agent selected and the total dose administered, polymorphisms of the cytochrome P450 (CYP450) enzymes that alter the metabolism and excretion of chemotherapeutic drugs may have an impact on efficacy and toxicity. A prior retrospective, cohort study identified selected CYP450 enzyme genotypes which predicted for premature ovarian failure in lupus nephritis patients treated with single agent cyclophosphamide. The goal of this study is to delineate the role of genetic variations in premature menopause, hot flashes, and other toxicities in a cohort of premenopausal women with early breast cancer.