Endocrine therapy: is the first generation of targeted drugs the last?

Hormonal therapy for breast cancer is the first targeted therapy used in any type of cancer. It was used successfully without a known target for more than 50 years before Jensen described the oestrogen receptor (ER) in the 1960s. Subsequently, it was found that endocrine therapy was effective only in those patients whose tumours expressed the ER; more recently, it has been recognized that this therapy can also be effective in some patients whose tumours are ERα-negative but ERβ-positive. However, in spite of the ER being present, many tumours develop either primary or secondary resistance to various endocrine approaches. ER-containing tumours may also be classified by molecular markers as luminal A (highly hormone responsive) or luminal B (high degree of proliferation and less hormone responsiveness). Furthermore, the expression of ER, progesterone receptor and human epidermal growth factor receptor 2 (HER2) may change over time as tumours metastasize and progress. The addition of anti-HER2 agents such as trastuzumab and lapatinib to hormonal therapies has improved outcomes but it is unclear whether these approaches are additive or synergistic. Now, mammalian target of rapamycin (mTOR) inhibitors are being successfully used in similar scenarios but once again it is unclear whether the effect of this combination therapy is synergistic; however, mTOR inhibitors produce little response as single agents. In particular, the addition of the mTOR inhibitor everolimus has improved disease-free and overall survival in randomized studies in metastatic disease when added either to an aromatase inhibitor or to tamoxifen. To date, however, no specific biomarkers for the use of everolimus have been reported. Further studies are needed to identify and validate targets of therapy in endocrine-responsive breast cancer.