Endocrine therapy is the cornerstone of treatment for patients with hormone receptor
      (HR)-positive advanced breast cancer. The selection of endocrine agents takes account of the
      menopausal status, the type of previous adjuvant endocrine treatment, the disease free
      interval and past medical history1.

      The goal of endocrine treatment is to block or interfere with the function of estrogen or
      progesterone. The major source of estrogen in premenopausal women is the ovaries. In
      premenopausal women with HR-positive advanced breast cancer, tamoxifen, ovarian function
      suppression or a combination of those have been used. Unfortunately, not all patients have a
      response to first-line endocrine therapy, and even patients who have a response will
      eventually become resistant. Patients experiencing disease progression with a first-line
      endocrine therapy may benefit from other endocrine agents, such as aromatase inhibitors
      (steroidal or nonsteroidal) and the estrogen receptor (ER) antagonist2-5. Aromatase
      inhibitors combined with luteinizing hormone-releasing hormone (LHRH) analogs or ovarian
      ablation are also a feasible treatment modality for premenopausal patients with HR-positive
      advanced breast cancer6.

      An emerging mechanism of endocrine resistance in aberrant signaling through the
      phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) signaling
      pathway7-9. Growing evidence supports a close interaction between the mTOR pathway and ER
      signaling. A substrate of mTOR complex 1 (mTORC1), called S6 kinase 1, phosphorylates the
      activation function domain 1 of ER, which is responsible for ligand-independent receptor
      activation10. Everolimus is a sirolimus derivative that inhibits mTOR through allosteric
      binding to mTORC111. In preclinical models, the use of everolimus in combination with
      aromatase inhibitors results in synergistic inhibition of the proliferation and induction of
      apoptosis12. In a randomized, phase 2 study comparing neoadjuvant everolimus plus letrozole
      with letrozole alone in patients with newly diagnosed ER-positive breast cancer, the response
      rate for the combination was higher than that for letrozole alone13. Recently, the Breast
      Cancer Trials of Oral Everolimus-2 (BOLERO-2) study showed that the addition of everolimus to
      exemestane significantly improved progression-free survival, with observed medians of 6.9 and
      2.8 months, corresponding to a 57% reduction in the hazard ratio14.

      Based on this rationale, the investigators introduced randomized trial to evaluate the
      efficacy of addition of everolimus to letrozole with LHRH agonist in premenopausal metastatic
      breast cancer patients who failed to tamoxifen treatment.