Endocrine therapy and acquired endocrine resistance in advanced breast cancer:

      First-line treatment of metastatic estrogen receptor (ER) positive breast cancer with
      endocrine therapy such as Tamoxifen or aromatase inhibitors (AI) is efficacious, but
      development of secondary resistance is inevitable with median progression free survival of 9
      months.1 Acquired resistance can be contributed by molecular cross-talk between estrogen
      receptors and other key survival and proliferative pathways. In particular, the PI3K/Akt/MAP
      kinase signaling pathway is upregulated with prolonged estrogen deprivation and is an
      important feature of progressive disease biology.2

      The BOLERO-2 study showed an improvement in response rates and progression free survival with
      the addition of Everolimus, an mTOR-inhibitor to Exemestane in metastatic ER-positive breast
      cancer after failure on a non-steroidal AI.3 Synergy was also seen in a Phase 2 clinical
      trial with the combination of Fulvestrant and Everolimus in the second line setting.4
      However, the clinical experience with Everolimus has been poor, with frequent adverse effects
      rendering the combination with endocrine therapy highly toxic. More recently, the PALOMA-1/3
      studies have showed that targeting the CDK4/CDK6/E2F axis with Palbociclib is a feasible
      strategy with marked improvements in clinical endpoints when combined with Letrozole in the
      first line, and Fulvestrant after AI-failure.5,6 While the therapy was reasonably
      well-tolerated, Palbociclib remains prohibitively expensive, and is not widely used in
      countries where healthcare systems do not cover the cost of this novel combination.

      Potential of Metformin and Simvastatin as anti-cancer agents:

      It has been widely recognized that Metformin and Simvastatin, both commonly used medications
      in diabetes mellitus and dyslipidemia, have anti-cancer properties. Years of experience in
      the real world have shown that at standard doses, these 2 drugs can be used in combination
      with little toxicities. Metformin, a biguanide, results in activation of AMPK which
      consequently inhibits mTOR through phosphorylation of TSC2, as well as anti-proliferative
      effects through reduction in insulin receptor mediated mitogenesis and inhibition of cyclin
      dependent kinases.7,8 Pre-clinical studies in mouse xenograft models showed that at an
      equivalent dose of at least 1500mg per day, Metformin reduced the effective dosage of
      standard chemotherapeutic agents, and had preferential effects on tumor cells.9 Studies of
      Metformin in MCF7, an ER-positive breast cancer cell line, also showed that it resulted in
      significant reduction in protein synthesis as well as inhibition of the mTOR pathway.10
      Simvastatin, a lipophilic HMGCoA reductase inhibitor, has been shown to interrupt oncogenic
      signaling by prenylation-dependent proteins including the RAS oncogene family, and attenuate
      PI3K signaling. In a recent window-of-opportunity study by the inverstigators' group, the
      investigators showed that at the usual prescribed dose of Simvastatin (20mg), a short course
      of therapy resulted in evident apoptosis and de-activation of the PI3K/Akt/mTOR and MAPK/ERK
      pathways in both clinical specimens as well as breast cancer cell lines.12

      The investigators believe that there is untapped potential in the usage of Metformin and
      Simvastatin in targeting the PI3K/Akt/mTOR pathway which is upregulated in metastatic
      ER-positive breast cancer after progression on first-line endocrine therapy, and that this
      inexpensive and non-toxic combination will show synergy with Fulvestrant in the second-line
      (and beyond) setting.