The use of selective estrogen receptor modulators and selective estrogen receptor down-regulators in breast cancer

Best Pract Res Clin Endocrinol Metab. 2004 Mar;18(1):47-66. doi: 10.1016/j.beem.2003.08.002.


Tamoxifen is one of the most effective treatments for breast cancer through its ability to antagonize estrogen-dependent growth by binding estrogen receptors (ERs) and inhibiting proliferation of breast epithelial cells. However, tamoxifen has estrogenic agonist effects in other tissues such as bone and endometrium due to liganded ER activating target genes in these different types of cell. Several novel anti-estrogen compounds have been developed which have a reduced agonist profile on breast and gynaecological tissues. These compounds offer the potential for enhanced efficacy and reduced toxicity compared with tamoxifen. In advanced breast cancer clinical data exist for two groups of agents: the selective estrogen receptor modulators (SERMs), further divided into "tamoxifen-like" (e.g. toremifene, droloxifene and idoxifene) and "fixed ring" compounds (e.g. raloxifene, arzoxifene and EM-800), and the selective estrogen receptor down-regulators (SERDs; e.g. fulvestrant (ICI 182780), SR 16234 and ZK 191703) also termed "pure anti-estrogens". In phase II trials in tamoxifen-resistant metastatic breast cancer the SERMs show low objective response rates (range 0-15%), suggesting cross resistance with tamoxifen. Randomized phase III trials for toremifene and idoxifene in over 1500 patients showed no significant difference compared with tamoxifen. Fewer clinical data exist for the "fixed ring" SERMs and it remains unclear whether any clinical advantage exists for the "fixed ring" SERMs over tamoxifen as first-line therapy. The main advantage for SERMs such as tamoxifen and raloxifene probably remains in early-stage disease (adjuvant therapy or prevention). Fulvestrant and the other SERDs have a high affinity for the estrogen receptor (ER) compared to tamoxifen, but none of its agonist activities. Of the SERDs, only fulvestrant has entered the clinic and this new agent is showing promising clinical activity in the treatment of advanced breast cancer. Recently published phase III studies have shown fulvestrant to be at least as effective as the third-generation aromatase inhibitor anastrozole in patients whose disease has relapsed or progressed on prior endocrine therapy. Surprisingly, however, in a phase III trial versus tamoxifen for the first-line therapy of advanced breast cancer fulvestrant did not attain the requirements for equivalence to tamoxifen, and in terms of time-to-treatment failure was inferior (5.9 versus 7.8 months for fulvestrant and tamoxifen, respectively; P=0.029). Future clinical studies will evaluate fulvestrant in the neoadjuvant setting together with its optimal sequencing in relation to tamoxifen and other endocrine therapies in advanced disease.

Publication types

  • Review

MeSH terms

  • Antineoplastic Agents, Hormonal / adverse effects
  • Antineoplastic Agents, Hormonal / therapeutic use*
  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • Clinical Trials, Phase II as Topic
  • Down-Regulation / drug effects
  • Estrogen Antagonists / adverse effects
  • Estrogen Antagonists / therapeutic use*
  • Estrogens / metabolism
  • Evidence-Based Medicine / methods
  • Female
  • Humans
  • Neoplasms, Hormone-Dependent / drug therapy*
  • Neoplasms, Hormone-Dependent / metabolism
  • Receptors, Estrogen / metabolism
  • Selective Estrogen Receptor Modulators / adverse effects
  • Selective Estrogen Receptor Modulators / therapeutic use*


  • Antineoplastic Agents, Hormonal
  • Estrogen Antagonists
  • Estrogens
  • Receptors, Estrogen
  • Selective Estrogen Receptor Modulators