Breast Cancer Research and Treatment

, Volume 93, Supplement 1, pp 3–10 | Cite as

Endocrine therapy – current benefits and limitations

Article
First Online:

Summary

Endocrine therapy is a valuable option for the treatment of postmenopausal women with estrogen receptor (ER)-positive breast cancer due to its demonstrated efficacy and favorable safety profile. Although tamoxifen has been the established treatment for more than 20 years its long-term use is associated with several tolerability concerns and may lead to increased risk of endometrial cancer and thromboembolic complications. In addition, many patients who initially respond to treatment with endocrine agents such as tamoxifen eventually relapse with resistant disease. Sequential use of endocrine therapies is often used in patients as resistance to individual agents develops. Several endocrine approaches have been developed that deprive the tumor of estrogen stimulation, either by directly modulating the ER-signaling pathway or by lowering serum or tumor concentrations of estrogen. In the classic pathway of estrogen signal transduction, the steroid hormone binds to its intracellular ER, triggering a cascade of events that ultimately leads to altered gene transcription. More recently, it has become apparent that ER activation can also occur via estrogen-independent receptor activation or by non-nuclear action through cell surface receptors. Consequently, molecular cross-talk exists between the ER and growth factor signaling cascades, which is a key factor in de novo and acquired resistance to endocrine therapy. Inappropriate activation of growth factor signaling can readily promote endocrine therapy failure in breast cancer cells, either by overriding the growth-inhibitory properties of antiestrogenic drugs or by establishment of a new self-propagating autocrine loop that efficiently drives resistant cell growth. Fulvestrant is a new type of ER antagonist with no agonist effects that binds, blocks and causes degradation of the ER. As multiple signaling pathways are involved in the activation of ER, the use of agents such as fulvestrant that directly target the ER and lead to both degradation of the receptor and abrogation of ER signaling may prevent or delay the development of absolute endocrine resistance. In addition, combining antiestrogenic drugs with inhibitors of cell signaling molecules to target both the ER and growth factor signaling pathways is likely to provide a means of delaying endocrine therapy resistance, leading the way to more effective breast cancer treatment.

Keywords

breast cancer estrogen receptor fulvestrant long-term estrogen deprivation optimal endocrine sequence postmenopausal 
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Notes

Acknowledgement

We thank Dr Tracey Spurway from Complete Medical Communications Ltd., who provided medical writing support on behalf of AstraZeneca.

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Copyright information

© Springer 2005

Authors and Affiliations

  1. 1.Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff UniversityCardiffUK
  2. 2.Royal Marsden Hospital NHS Trust and Institute of Cancer ResearchLondonUK

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