Tamoxifen had its origins as a failed morning-after contraceptive that became the first successful targeted treatment in cancer.^1-3 Tamoxifen dominated the antiestrogenic treatment of metastatic breast cancer (MBC) for 30 years and went forward as the only candidate for long-term adjuvant antiestrogen treatment.^2,3 As a result of decades of clinical testing, tamoxifen was the only candidate in the pioneering of breast cancer chemoprevention.⁴ There was a reason for this. Try as they may, medicinal chemists in the pharmaceutical industry could not improve on tamoxifen for the treatment of MBC. The list of nonsteroidal antiestrogens evaluated to treat MBC is long: nafoxidine, trioxifene, keoxifene (reinvented and renamed raloxifene to treat osteoporosis⁵), toremifene, droloxifene, and arzoxifene.^6,7 As a result, an alternative strategy for antiestrogen therapy was advanced. Specific inhibitors of CYP19, the aromatase enzyme, were investigated. In the 1970s, Dr Angela Brodie, the mother of aromatase inhibitors (AIs), used translational research to show that a clinically useful drug was possible.⁸ The pharmaceutical industry again struggled for a decade to find suitable oral candidates to compete with tamoxifen. Today, there are three established agents that dominate breast cancer treatment and prevention for postmenopausal women: anastrozole, exemestane, and letrozole. So it comes as some surprise that a phase I study of endoxifen, a tamoxifen metabolite, was successfully completed in patients with endocrine refractory breast cancer.

中文翻译：

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Endoxifen：是终点，还是我们开始？

他莫昔芬的起源是失败的早晨避孕药，后来成为避孕药中第一个成功的靶向治疗方法。^1-3他莫昔芬在转移性乳腺癌（MBC）的抗雌激素治疗中占主导地位，并持续了30年，成为长期辅助抗雌激素治疗的唯一候选药物。^2,3经过数十年的临床测试，他莫昔芬是乳腺癌化学预防领域的唯一候选人。⁴这是有原因的。尽可能尝试，制药行业的药物化学家无法改善他莫昔芬在MBC治疗中的作用。评估用于治疗MBC的非甾体类抗雌激素的清单很长：萘丁胺，三氧芬，酮咯芬（已重新发明并更名为雷洛昔芬，用于治疗骨质疏松症⁵），托瑞米芬，屈洛昔芬和阿佐昔芬。^6,7结果，抗雌激素治疗的替代策略得到了发展。研究了CYP19（芳香酶）的特异性抑制剂。在1970年代，芳香酶抑制剂（AIs）的母亲安吉拉·布罗迪（Angela Brodie）博士通过转化研究表明，临床上有用的药物是可能的。⁸制药行业再次奋斗了十年，以寻找合适的口服候选药物与他莫昔芬竞争。如今，在绝经后妇女的乳腺癌治疗和预防中占主导地位的三种药物是：阿那曲唑，依西美坦和来曲唑。因此，令人惊讶的是，对内分泌难治性乳腺癌患者成功完成了他莫昔芬代谢物endoxifen的I期研究。