Introduction 1 2 3 4 5 6 7 10 ® Endocrine therapy resistance 11 12 13 12 13 13 14 15 16 14 19 15 19 Growth factor pathways 20 21 22 15 23 25 4 4 7 4 4 26 27 4 28 Combination therapy 1 29 30 HER2 31 32 18 33 34 35 Fig. 1 thick black arrow gray arrows Stars  AI  SERD  MoAb  TKI  FTI  CCI  28  36 37 38 4 39 39 37 40 41 41 41 42 43 43 44 45 44 46 47 48 3 49 1 52 3 39 53 18 46 54 4 35 50 55 56 Table 1 Summary of letrozole in combination with growth factor signaling inhibitors in preclinical models Target for growth factor inhibitor Combination regimen Summary of key findings References EGFR/HER2 Letrozole + AEE78 Combination enhanced antiproliferative effects in MCF-7 (ER+ HER2−), ZR75.1 (ER+ HER2+), and BT474 (ER+ HER2+) cell lines 42 Partial restoration of growth inhibitory effects of letrozole in refractory cell lines (LTLT-Ca; long-term letrozole treated) 43 mTOR Letrozole + RAD001 (everolimus) Letrozole + RAD001 significantly increased apoptosis compared with either agent alone 50 Co-treatment increased sensitivity to letrozole in resistant MCF-7 cells with constitutively active Akt 48 RAD001 increased antiproliferative effects of letrozole in MCF-7 Arom 1 cell line 47 IGFBP Letrozole + rhIGFBP-3 rhIGFBP-3 Enhanced letrozole activity in MCF-7-Ca cells in vitro and in vivo 51 rhIGFBP recombinant human insulin-like growth factor binding protein 57 58 12 1 Clinical trials of letrozole in combination with inhibitors of growth factor signaling pathways 2 Table 2 Clinical studies of letrozole and inhibitors of growth factor signaling pathways Target for growth factor inhibitor Combination regimen Study type and patient population Summary of key findings References HER2 Letrozole + trastuzumab  n ORR 26%; median TTP 5.8 months 59 EGFR/HER2 Letrozole + lapatinib  n Letrozole + lapatinib safely combined at recommended single agent doses 60  n Ongoing trial; primary end point TTP 61 mTOR Letrozole + RAD-001 (everolimus)  n RAD001 pharmacokinetics not altered by letrozole 62  n Ongoing trial of efficacy and biomarkers 63 Letrozole + CCI-779 (temsirolimus)  n No difference in ORR, but trend to longer PFS with letrozole + temsirolimus (30 mg) 64  n Terminated 65 Farnesyl transferase Letrozole + tipifarnib   n ORR 38% for letrozole and 26% for letrozole + tipifarnib (NS) 66  n No longer recruiting 67 VEGF Letrozole + bevacizumab (anti-VEGF monoclonal antibody)  n Letrozole + bevacizumab is well-tolerated 54 Endocrine therapy (tamoxifen or aromatase inhibitor) + bevacizumab  n Planned trial 54 Bcr-abl Letrozole + imatinib  n Letrozole + imatinib is feasible 68 BC  ORR  TTP  PFS  AI  TBC  69 54 70 54 71 71 2 54 Fig. 2 Planned CALGB trial of first-line endocrine therapy (tamoxifen or aromatase inhibitor) with or without bevacizumab  59 59 60 61 3 63 Fig. 3 Letrozole and lapatinib phase III trial design. Target recruitment: 1,280 patients  72 Microarray/gene profiling studies and optimization of treatment with letrozole 73 74 75 77 78 79 80 80 81 82 83 84 85 84 86 87 N N 87 88 89 89 90 89 91 92 93 Conclusions Hormone-sensitive breast cancer can be regarded as a chronic disease with a persistent risk of escape from effective endocrine control. Activation of growth factor signaling pathways has been implicated in progression of HR+ breast cancer to an estrogen-independent phenotype and the development of resistance to endocrine therapy, particularly tamoxifen. It has been hypothesized that combining endocrine therapy with targeted signal transduction inhibitors may circumvent hormone-independent signaling pathways, so that patients may experience prolonged disease control. HER2 Gene expression profiling has been validated as a useful new tool to predict risk of relapse in patients treated with hormone therapy and chemotherapy. This approach will help physicians to identify which patient will likely benefit from specific therapies, such as letrozole. Tailoring therapy to individual patient profiles (clinical, histologic, pathologic, and genetic) will become more sophisticated in the future, helping to maximize the benefits of endocrine therapy throughout the breast cancer continuum; letrozole will undoubtedly become an integral part of the next generation of tailored combination regimens for the treatment of breast cancer.