Molecularly Targeted Endocrine Therapies for Breast Cancer

The identification of the estrogen receptor (ER) provided the first target for antiestrogenic therapeutic agents. Endocrine therapies, either by blocking or downregulating the receptor or by suppressing the estrogen production, inhibit the proliferative effect of estradiol on ER. While the activity on ER is considered a real target-mediated therapy, the effect on enzymatic activity involved in estrogen production (mainly inhibition of aromatase by aromatase inhibitors, AIs, and ovarian ablation) could be considered an "indirect" targeted strategy. In addiction to the direct ligand-ER signal, the complexity of endocrine and non endocrine pathways has led to combination therapies against different targets. Tamoxifen is the widely investigated, most used and representative of drugs blocking the ER and has been introduced in the advanced disease, in neoadjuvant and adjuvant setting and for chemo-prevention of high risk women. Its role has been challenged in the last years by the introduction of third generation aromatase inhibitors that have proven a higher activity than tamoxifen and different toxicity. Several other SERMs (selective estrogen receptor modulators) have been investigated, but none of them was clearly superior to tamoxifen. SERDs (selective estrogen receptor downregulators) act as pure estrogen antagonist. They are used in the treatment of advanced breast cancers and their role in other settings still needs further investigation. Here we discuss the well established data with SERMs, SERDs and AIs, mechanisms underlying resistance and rationale for recycling endocrine compounds and for simultaneously targeting different pathways.