EXE prolongs survival time, time to tumor progression, and time to treatment failure compared with MA and offers a well-tolerated treatment option for postmenopausal women with progressive advanced breast cancer who experienced failure of tamoxifen.

Human prostatic steroid 5alpha-reductase, encoded by the SRD5A2 gene on chromosome band 2p23, catalyses the irreversible conversion of testosterone to dihydrotestosterone (DHT), the most active androgen in the prostate, with NADPH as its cofactor. This enzyme has never been purified but a number of competitive inhibitors have been developed for this enzyme since increased steroid 5alpha-reductase activity may cause benign prostatic hypertrophy and prostate cancer. We report here the detailed biochemical and pharmacogenetic dissection of the human enzyme by analysing 10 missense substitutions and three double mutants which are all naturally found in humans. Nine of these 13 mutants reduce activity (measured as Vmax) by 20% or more, three increase steroid 5alpha-reductase by more than 15% and one results in essentially unaltered kinetic properties suggesting that it is a truly neutral ('polymorphic') amino acid substitution. Substantial pharmacogenetic variation among the mutants was also observed when three competitive inhibitors, finasteride, GG745 (dutasteride) and PNU157706, were investigated. Our studies not only define the substrate and cofactor binding sites of human steroid 5alpha-reductase, but also have significant consequences for the pharmacological usage of steroid 5alpha-reductase inhibitors in human patients treated for prostatic conditions.

Exemestane 25 mg once daily seems to be an attractive alternative to chemotherapy for the treatment of patients with metastatic breast cancer after multiple hormonal therapies have failed.

Disclosure: W.R.M. discloses that this article discusses letrozole (Novartis), anastrozole (AstraZeneca), and exemestane (Pfizer) for validation of mechanism of action. He has also been on the advisory board for Pfizer and received speaker's honoraria. J.B. has received honoraria and research funding from Pfizer (exemestane). A.M.H.B. has received honoraria and research support from AstraZeneca (anastrozole research). R.W.B. discloses that this article discusses exemestane (Pfizer), anastrozole (AstraZeneca), and letrozole (Novartis) for use in breast cancer therapy. He also received an honorarium for participating in an expert panel meeting from Pfizer/CC Ford Healthcare. E.d.S. is an employee and has stock options in Pfizer (exemestane). P.E.L. has received speaker's honoraria from Novartis, AstraZeneca, and Pfizer. A.L. discloses no conflict of interest. N.M. discloses that the article discusses exemestane (Pfizer), anastrozole (AstraZeneca), and letrozole (Novartis) for breast cancer treatment, and he has been on an advisory board and received honoraria from Pfizer (exemestane). T.M. has research funding from Novartis (letrozole) and has received a consulting fee from Pfizer (exemestane). H.S. has research funding and has received an honorarium from Pfizer (exemestane). P.E.G. discloses that this article discusses letrozole (Novartis), anastrozole (AstraZeneca), and exemestane (Pfizer) for validation of mechanism of action. He also discloses that the article discusses aromatase inhibitors for prevention (Novartis, AstraZeneca, Pfizer), and that he has received speaker's honoraria from Novartis, AstraZeneca, and Pfizer. The content of this manuscript has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from any commercial bias; they have disclosed no financial relationships relevant to this content.

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