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Novel Strategies in Hormone Receptor-Positive Advanced Breast Cancer: Overcoming Endocrine Resistance

  • Systemic Therapies (M Liu and T Haddad, Section Editors)
  • Published:
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Abstract

Resistance to standard endocrine therapies in hormone receptor-positive advanced breast cancer represents a significant clinical challenge. Different intracellular signaling pathways mediate independent activation of the estrogen receptor (ER), promoting tumor cell proliferation despite anti-hormonal treatment. Recently, the inhibition of cell cycle regulators, CDK4 and CDK6, has demonstrated to significantly enhance the effectiveness of endocrine therapy by overcoming or delaying resistance to estrogen blockade. Strategies such as inhibition of the PI3K/mTOR pathway or epigenetic modulation of ER-related gene expression are closely following the trail of CDK inhibitors. Here, we seek to review the most recent efforts to improve outcomes in these patients, in an attempt to extend endocrine treatment and defer the need for cytotoxic regimens. We also discuss future directions to be considered in the treatment of ER-positive disease, as mechanisms of resistance to these new agents arise.

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References

Papers of particular interest, published recently, have been highlighted: • Of importance

  1. Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA et al. US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. 2014;106(5). doi:10.1093/jnci/dju055.

  2. NCCN Clinical Practice Guidelines in Oncology. Breast Cancer (version 2.2016). National Comprehensive Cancer Network. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed August 5, 2016.

  3. Partridge AH, Rumble RB, Carey LA, et al. Chemotherapy and targeted therapy for women with human epidermal growth factor receptor 2-negative (or unknown) advanced breast cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2014;32(29):3307–29. doi:10.1200/JCO.2014.56.7479.

    Article  PubMed  Google Scholar 

  4. Schiff R, Massarweh S, Shou J, Osborne CK. Breast cancer endocrine resistance: how growth factor signaling and estrogen receptor coregulators modulate response. Clin Cancer Res. 2003;9(1 Pt 2):447S–54.

    CAS  PubMed  Google Scholar 

  5. Jeselsohn R, Buchwalter G, De Angelis C, Brown M, Schiff R. ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol. 2015;12(10):573–83. doi:10.1038/nrclinonc.2015.117.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Alves CL, Elias D, Lyng MB, et al. High CDK6 protects cells from fulvestrant-mediated apoptosis and is a predictor of resistance to fulvestrant in estrogen receptor-positive metastatic breast cancer. Clin Cancer Res. 2016. doi:10.1158/1078-0432.CCR-15-1984.

    PubMed  Google Scholar 

  7. Sabnis GJ, Goloubeva OG, Kazi AA, Shah P, Brodie AH. HDAC inhibitor entinostat restores responsiveness of letrozole-resistant MCF-7Ca xenografts to aromatase inhibitors through modulation of Her-2. Mol Cancer Ther. 2013;12(12):2804–16. doi:10.1158/1535-7163.MCT-13-0345.

    Article  CAS  PubMed  Google Scholar 

  8. Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77. doi:10.1186/bcr2419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Boulay A, Rudloff J, Ye J, et al. Dual inhibition of mTOR and estrogen receptor signaling in vitro induces cell death in models of breast cancer. Clin Cancer Res. 2005;11(14):5319–28. doi:10.1158/1078-0432.CCR-04-2402.

    Article  CAS  PubMed  Google Scholar 

  10. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–9. doi:10.1056/NEJMoa1109653.

    Article  CAS  PubMed  Google Scholar 

  11. Yardley DA, Noguchi S, Pritchard KI, et al. Everolimus plus exemestane in postmenopausal patients with HR(+) breast cancer: BOLERO-2 final progression-free survival analysis. Adv Ther. 2013;30(10):870–84. doi:10.1007/s12325-013-0060-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yardley DA, Ismail-Khan RR, Melichar B, et al. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromatase inhibitor. J Clin Oncol. 2013;31(17):2128–35. doi:10.1200/JCO.2012.43.7251. This is the phase II study that demonstrated improvement in survival with the addition of entinostat to exemestane after resistance to non-steroidal aromatase inhibitors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. 2015;16(1):25–35. doi:10.1016/s1470-2045(14)71159-3.

    Article  CAS  PubMed  Google Scholar 

  14. Finn RS, Martin M, Rugo HS, Jones S, Im S-A, Gelmon KA et al., editors. PALOMA-2: primary results from a phase 3 trial of palbociclib plus letrozole compared with placebo plus letrozole in postmenopausal women with ER+/HER2− advanced breast cancer. 2016 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3–7, 2016; Chicago, IL (USA): J Clin Oncol. 2016;34(suppl; abstr 507). This is the phase III study that confirms PFS benefit with palbociclib and letrozole in the first-line setting of ER-positive advanced breast cancer .

  15. Walker AJ, Wedam S, Amiri-Kordestani L, et al. FDA approval of palbociclib in combination with fulvestrant for the treatment of hormone receptor-positive, HER2-negative metastatic breast cancer. Clin Cancer Res. 2016. doi:10.1158/1078-0432.CCR-16-0493.

    Google Scholar 

  16. Turner NC, Ro J, Andre F, et al. Palbociclib in hormone-receptor-positive advanced breast cancer. N Engl J Med. 2015;373(3):209–19. doi:10.1056/NEJMoa1505270.

    Article  CAS  PubMed  Google Scholar 

  17. Spring L, Bardia A, Modi S. Targeting the cyclin D-cyclin-dependent kinase (CDK) 4/6-retinoblastoma pathway with selective CDK 4/6 inhibitors in hormone receptor-positive breast cancer: rationale, current status, and future directions. Discov Med. 2016;21(113):65–74.

    PubMed  Google Scholar 

  18. Finn RS, Aleshin A, Slamon DJ. Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers. Breast Cancer Res. 2016;18(1):17. doi:10.1186/s13058-015-0661-5.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Cancer Genome Atlas N. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70. doi:10.1038/nature11412.

    Article  CAS  Google Scholar 

  20. O’Brien N, Di Tomaso E, Ayala R, Tong L, Issakhanian S, Linnartz R et al., editors. In vivo efficacy of combined targeting of CDK 4/6, ER and PI3K signaling in ER+ breast cancer. Proceedings from the 105th Annual Meeting of the American Association for Cancer Research; April 5–9, 2014; San Diego, CA (USA): (abstr 4756).

  21. VanArsdale T, Boshoff C, Arndt KT, Abraham RT. Molecular pathways: targeting the cyclin D-CDK4/6 axis for cancer treatment. Clin Cancer Res. 2015;21(13):2905–10. doi:10.1158/1078-0432.CCR-14-0816.

    Article  CAS  PubMed  Google Scholar 

  22. O’Leary B, Finn RS, Turner NC. Treating cancer with selective CDK4/6 inhibitors. Nat Rev Clin Oncol. 2016;13(7):417–30. doi:10.1038/nrclinonc.2016.26.

    Article  CAS  PubMed  Google Scholar 

  23. Flaherty KT, Lorusso PM, Demichele A, et al. Phase I, dose-escalation trial of the oral cyclin-dependent kinase 4/6 inhibitor PD 0332991, administered using a 21-day schedule in patients with advanced cancer. Clin Cancer Res. 2012;18(2):568–76. doi:10.1158/1078-0432.CCR-11-0509.

    Article  CAS  PubMed  Google Scholar 

  24. DeMichele A, Clark AS, Tan KS, et al. CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: phase II activity, safety, and predictive biomarker assessment. Clin Cancer Res. 2015;21(5):995–1001. doi:10.1158/1078-0432.CCR-14-2258.

    Article  CAS  PubMed  Google Scholar 

  25. Infante JR, Shapiro GI, Witteven O, Gerecitano JF, Ribrag V, Chugh R et al., editors. A phase I study of the single-agent CDK4/6 inhibitor LEE011 in patients with advanced solid tumors and lymphomas. 2014 American Society of Clinical Oncology (ASCO) Annual Meeting; May 30–June 3, 2014; Chicago, IL (USA): J Clin Oncol. 2014;32:5s, (suppl; abstr 2528^).

  26. Gelbert LM, Cai S, Lin X, et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Investig New Drugs. 2014;32(5):825–37. doi:10.1007/s10637-014-0120-7.

    Article  CAS  Google Scholar 

  27. Asghar U, Witkiewicz AK, Turner NC, Knudsen ES. The history and future of targeting cyclin-dependent kinases in cancer therapy. Nat Rev Drug Discov. 2015;14(2):130–46. doi:10.1038/nrd4504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Raub TJ, Wishart GN, Kulanthaivel P, et al. Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft. Drug Metab Dispos. 2015;43(9):1360–71. doi:10.1124/dmd.114.062745.

    Article  CAS  PubMed  Google Scholar 

  29. Shapiro GI, Rosen LS, Tolcher AW, Goldman JW, Gandhi L, Papadopoulos KP et al., editors. A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer. 2013 American Society of Clinical Oncology (ASCO) Annual Meeting; May 31–June 4, 2013; Chicago, IL (USA): J Clin Oncol. 2013;31(suppl; abstr 2500).

  30. Patnaik A, Rosen LS, Tolaney SM, et al. Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov. 2016;6(7):740–53. doi:10.1158/2159-8290.CD-16-0095. This phase I study reported the safety and promising antitumoral efficacy of abemaciclib in heavily pre-treated breast cancer patients.

    Article  CAS  PubMed  Google Scholar 

  31. Crown JP, Finn RS, Ettl J, Boer K, Patel R, Thummala AR et al., editors. Efficacy and safety of first-line palbociclib plus letrozole compared with letrozole alone in patients aged ≥65 years with estrogen receptor-positive, HER2-negative advanced breast cancer: a subgroup analysis by age of the PALOMA-1/TRIO-18 trial. 2015 American Society of Clinical Oncology (ASCO) Annual Meeting; May 29–June 2, 2015; Chicago, IL (USA): J Clin Oncol. 2015;33(suppl; abstr 571).

  32. Finn RS, Crown JP, Lang I, Kulyk SO, Schmidt M, Patel R et al., editors. The effect of palbociclib (P) in combination with letrozole (L) on bone metastases in women with ER+/HER2− metastatic breast cancer (MBC): subanalysis from a randomized phase II study. 2015 American Society of Clinical Oncology (ASCO) Annual Meeting; May 29–June 2, 2015; Chicago, IL (USA): J Clin Oncol. 2015;33(suppl; abstr 572).

  33. Cristofanilli M, Turner NC, Bondarenko I, et al. Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol. 2016;17(4):425–39. doi:10.1016/s1470-2045(15)00613-0. Palbociclib and fulvestrant improved PFS in patients with ER-positive metastatic disease and progression on prior endocrine therapy.

    Article  CAS  PubMed  Google Scholar 

  34. Loibl S, Turner N, Ro J, Cristofanilli M, Iwata H, Im S-A et al., editors. Palbociclib (PAL) in combination with fulvestrant (F) in pre-/peri-menopausal (PreM) women with metastatic breast cancer (MBC) and prior progression on endocrine therapy—results from Paloma-3. 2016 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3–7, 2016; Chicago, IL (USA): J Clin Oncol. 2016;34(suppl; abstr 524).

  35. Juric D, Munster PN, Campone M, Ismail-Khan RR, García-Estevez L, Hamilton EP et al., editors. Ribociclib (LEE011) and letrozole in estrogen receptor-positive (ER+), HER2-negative (HER2−) advanced breast cancer (aBC): phase Ib safety, preliminary efficacy and molecular analysis. 2016 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3–7, 2016; Chicago, IL (USA): J Clin Oncol. 2016;34(suppl; abstr 568).

  36. Novartis. MONALEESA-2 trial of Novartis’ LEE011 (ribociclib) stopped due to positive efficacy results at interim analysis in HR+/HER2− advanced breast cancer [press release]. 2016. https://www.novartis.com/news/media-releases/monaleesa-2-trial-novartis-lee011-ribociclib-stopped-due-positive-efficacy. Accessed August 29, 2016.

  37. Dickler M, Tolaney SM, Rugo HS, Cortes J, Dieras V, Patt DA et al., editors. MONARCH-1: results from a phase 2 study of abemaciclib, a CDK4 and CDK6 inhibitor, as monotherapy, in patients with HR+/HER2− breast cancer, after chemotherapy for metastatic disease. 2016 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3–7, 2016; Chicago, IL (USA): J Clin Oncol. 2016;34(suppl; abstr 510).

  38. Thomas E, Tabernero J, Fornier M, et al. Phase II clinical trial of ixabepilone (BMS-247550), an epothilone B analog, in patients with taxane-resistant metastatic breast cancer. J Clin Oncol. 2007;25(23):3399–406. doi:10.1200/JCO.2006.08.9102.

    Article  CAS  PubMed  Google Scholar 

  39. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914–23. doi:10.1016/S0140-6736(11)60070-6.

    Article  CAS  PubMed  Google Scholar 

  40. Kaufman PA, Awada A, Twelves C, et al. Phase III open-label randomized study of eribulin mesylate versus capecitabine in patients with locally advanced or metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2015;33(6):594–601. doi:10.1200/JCO.2013.52.4892.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Wang P, Bahreini A, Gyanchandani R, et al. Sensitive detection of mono- and polyclonal ESR1 mutations in primary tumors, metastatic lesions, and cell-free DNA of breast cancer patients. Clin Cancer Res. 2016;22(5):1130–7. doi:10.1158/1078-0432.CCR-15-1534.

    Article  CAS  PubMed  Google Scholar 

  42. Jeselsohn R, Yelensky R, Buchwalter G, et al. Emergence of constitutively active estrogen receptor-alpha mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res. 2014;20(7):1757–67. doi:10.1158/1078-0432.CCR-13-2332.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Fribbens C, O’Leary B, Kilburn L, et al. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2016. doi:10.1200/JCO.2016.67.3061.

    PubMed  Google Scholar 

  44. Courtney KD, Corcoran RB, Engelman JA. The PI3K pathway as drug target in human cancer. J Clin Oncol. 2010;28(6):1075–83. doi:10.1200/JCO.2009.25.3641.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Arpino G, Wiechmann L, Osborne CK, Schiff R. Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev. 2008;29(2):217–33. doi:10.1210/er.2006-0045.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hoeflich KP, Guan J, Edgar KA, et al. The PI3K inhibitor taselisib overcomes letrozole resistance in a breast cancer model expressing aromatase. Genes Cancer. 2016;7(3-4):73–85. doi:10.18632/genesandcancer.100.

    PubMed  PubMed Central  Google Scholar 

  47. Miller TW, Balko JM, Arteaga CL. Phosphatidylinositol 3-kinase and antiestrogen resistance in breast cancer. J Clin Oncol. 2011;29(33):4452–61. doi:10.1200/JCO.2010.34.4879.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Bosch A, Li Z, Bergamaschi A, et al. PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci Transl Med. 2015;7(283):283ra51. doi:10.1126/scitranslmed.aaa4442.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Maira SM, Pecchi S, Huang A, et al. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012;11(2):317–28. doi:10.1158/1535-7163.MCT-11-0474.

    Article  CAS  PubMed  Google Scholar 

  50. Sanchez CG, Ma CX, Crowder RJ, et al. Preclinical modeling of combined phosphatidylinositol-3-kinase inhibition with endocrine therapy for estrogen receptor-positive breast cancer. Breast Cancer Res. 2011;13(2):R21. doi:10.1186/bcr2833.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mayer IA, Abramson VG, Isakoff SJ, et al. Stand up to cancer phase Ib study of pan-phosphoinositide-3-kinase inhibitor buparlisib with letrozole in estrogen receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2014;32(12):1202–9. doi:10.1200/JCO.2013.54.0518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ma CX, Luo J, Naughton M, et al. A phase I trial of BKM120 (buparlisib) in combination with fulvestrant in postmenopausal women with estrogen receptor-positive metastatic breast cancer. Clin Cancer Res. 2016;22(7):1583–91. doi:10.1158/1078-0432.CCR-15-1745.

    Article  CAS  PubMed  Google Scholar 

  53. Baselga J, Im S-A, Iwata H, Clemons M, Ito Y, Awada A et al., editors. PIK3CA status in circulating tumor DNA predicts efficacy of buparlisib plus fulvestrant in postmenopausal women with endocrine-resistant HR+/HER2− advanced breast cancer: first results from the randomized, phase III BELLE-2 trial. 38th Annual San Antonio Breast Cancer Symposium; Dec 8–12, 2015; San Antonio, TX (USA): Cancer Res. 2016;76(4 suppl):abstr S6-01. This phase III study reported PFS improvement with pan-PI3K inhibition in ER-positive metastatic disease after progression on AI .

  54. Ndubaku CO, Heffron TP, Staben ST, et al. Discovery of 2-{3-[2-(1-isopropyl-3-methyl-1H-1,2-4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl]-1H-pyrazol-1-yl}-2-methylpropanamide (GDC-0032): a beta-sparing phosphoinositide 3-kinase inhibitor with high unbound exposure and robust in vivo antitumor activity. J Med Chem. 2013;56(11):4597–610. doi:10.1021/jm4003632.

    Article  CAS  PubMed  Google Scholar 

  55. Edgar KA, Song K, Schmidt S, Kirkpatrick D, Phu L, Nannini M et al., editors. The PI3K inhibitor, taselisib (GDC-0032), has enhanced potency in PIK3CA mutant models through a unique mechanism of action. Proceedings from the 107th Annual Meeting of the American Association for Cancer Research; April 16–20, 2016; New Orleans, LA (USA): (abstr 370).

  56. Juric D, Infante JR, Krop I, Kurkjian C, Patel MR, Graham RA et al., editors. Evaluation of tolerability and anti-tumor activity of GDC-0032, a PI3K inhibitor with enhanced activity against PIK3CA mutant tumors, administered to patients with advanced solid tumors. European Cancer Congress 2013 (ECCO-ESMO-ESTRO); September 27–October 1, 2013. Amsterdam, The Netherlands.

  57. Saura C, Sachdev J, Patel MR, Cervantes A, Juric D, Infante JR et al., editors. Phase Ib study of the PI3K inhibitor taselisib (GDC-0032) in combination with letrozole in patients with hormone receptor-positive advanced breast cancer. 37th Annual San Antonio Breast Cancer Symposium; December 9–13, 2014; San Antonio, TX (USA): Cancer Res. 2015;75(9 suppl):abstr PD5-2.

  58. Juric D, Saura C, Cervantes A, Kurkjian C, Patel MR, Sachdev J et al., editors. Ph1b study of the PI3K inhibitor GDC-0032 in combination with fulvestrant in patients with hormone receptor-positive advanced breast cancer. 36th Annual San Antonio Breast Cancer Symposium; December 10–14, 2013; San Antonio, TX (USA): Cancer Res. 2013;73(24 suppl):abstr PD1-3.

  59. Baird R, van Rossum A, Oliver DP, Beelen K, Garcia-Corbacho J, Mandjes IA et al., editors. POSEIDON trial phase 1b results: safety and preliminary efficacy of the isoform selective PI3K inhibitor taselisib (GDC-0032) combined with tamoxifen in hormone receptor (HR) positive, HER2-negative metastatic breast cancer (MBC) patients (pts)—including response monitoring by plasma circulating tumor (ct) DNA. 2016 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3–7, 2016; Chicago, IL (USA): J Clin Oncol. 2016;34(suppl; abstr 2520).

  60. Dickler M, Saura C, Richards D, Krop I, Cervantes A, Bedard PL et al., editors. A phase II study of the PI3K inhibitor taselisib (GDC-0032) combined with fulvestrant in patients with HER2-negative, hormone receptor-positive advanced breast cancer. 2016 American Society of Clinical Oncology (ASCO) Annual Meeting; June 3–7, 2016; Chicago, IL (USA): J Clin Oncol. 2016;34(suppl; abstr 520). Data from this phase II study revealed promising activity of the beta-sparing PI3K inhibitor, taselisib, in combination with fulvestrant in PIK3CA-mutant tumors.

  61. Gonzalez-Angulo AM, Juric D, Argilés G, Schellens J, Burris H, Berlin J et al., editors. Safety, pharmacokinetics, and preliminary activity of the α-specific PI3K inhibitor BYL719: results from the first-in-human study. 2013 American Society of Clinical Oncology (ASCO) Annual Meeting; May 31–June 4, 2013; Chicago, IL (USA): J Clin Oncol. 2013;31(suppl; abstr 2531).

  62. Mayer IA, Abramson V, Formisano L, et al. A phase Ib study of alpelisib (BYL719), a PI3Kalpha-specific inhibitor, with letrozole in ER+/HER2-negative metastatic breast cancer. Clin Cancer Res. 2016. doi:10.1158/1078-0432.CCR-16-0134.

    Google Scholar 

  63. Janku F, Juric D, Cortes J, Rugo H, Burris HA, Schuler M et al., editors. Phase I study of the PI3K alpha inhibitor BYL719 plus fulvestrant in patients with PIK3CA-altered and wild type ER+/HER2− locally advanced or metastatic breast cancer. 37th Annual San Antonio Breast Cancer Symposium; December 9–13, 2014; San Antonio, TX (USA): Cancer Res. 2015;75(9 suppl):abstr PD5-5.

  64. Krop IE, Mayer IA, Ganju V, et al. Pictilisib for oestrogen receptor-positive, aromatase inhibitor-resistant, advanced or metastatic breast cancer (FERGI): a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2016;17(6):811–21. doi:10.1016/S1470-2045(16)00106-6.

    Article  CAS  PubMed  Google Scholar 

  65. West AC, Johnstone RW. New and emerging HDAC inhibitors for cancer treatment. J Clin Invest. 2014;124(1):30–9. doi:10.1172/JCI69738.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Krusche CA, Wulfing P, Kersting C, et al. Histone deacetylase-1 and -3 protein expression in human breast cancer: a tissue microarray analysis. Breast Cancer Res Treat. 2005;90(1):15–23. doi:10.1007/s10549-004-1668-2.

    Article  CAS  PubMed  Google Scholar 

  67. Seo J, Min SK, Park HR, et al. Expression of histone deacetylases HDAC1, HDAC2, HDAC3, and HDAC6 in invasive ductal carcinomas of the breast. J Breast Cancer. 2014;17(4):323–31. doi:10.4048/jbc.2014.17.4.323.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Kim HM, Kim CS, Lee JH, et al. CG0006, a novel histone deacetylase inhibitor, induces breast cancer cell death via histone-acetylation and chaperone-disrupting pathways independent of ER status. Breast Cancer Res Treat. 2011;130(2):365–75. doi:10.1007/s10549-010-1310-4.

    Article  CAS  PubMed  Google Scholar 

  69. De los Santos M, Martinez-Iglesias O, Aranda A. Anti-estrogenic actions of histone deacetylase inhibitors in MCF-7 breast cancer cells. Endocr Relat Cancer. 2007;14(4):1021–8. doi:10.1677/ERC-07-0144.

    Article  CAS  PubMed  Google Scholar 

  70. Thomas S, Thurn KT, Bicaku E, Marchion DC, Munster PN. Addition of a histone deacetylase inhibitor redirects tamoxifen-treated breast cancer cells into apoptosis, which is opposed by the induction of autophagy. Breast Cancer Res Treat. 2011;130(2):437–47. doi:10.1007/s10549-011-1364-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Munster PN, Thurn KT, Thomas S, et al. A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. Br J Cancer. 2011;104(12):1828–35. doi:10.1038/bjc.2011.156.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Woods DM, Sodre AL, Villagra A, Sarnaik A, Sotomayor EM, Weber J. HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol Res. 2015;3(12):1375–85. doi:10.1158/2326-6066.CIR-15-0077-T.

    Article  CAS  PubMed  Google Scholar 

  73. Ma CX, Reinert T, Chmielewska I, Ellis MJ. Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer. 2015;15(5):261–75. doi:10.1038/nrc3920.

    Article  CAS  PubMed  Google Scholar 

  74. Johnston SR. Clinical efforts to combine endocrine agents with targeted therapies against epidermal growth factor receptor/human epidermal growth factor receptor 2 and mammalian target of rapamycin in breast cancer. Clin Cancer Res. 2006;12(3 Pt 2):1061s–8. doi:10.1158/1078-0432.CCR-05-2125.

    Article  CAS  PubMed  Google Scholar 

  75. Burstein HJ, Cirrincione CT, Barry WT, et al. Endocrine therapy with or without inhibition of epidermal growth factor receptor and human epidermal growth factor receptor 2: a randomized, double-blind, placebo-controlled phase III trial of fulvestrant with or without lapatinib for postmenopausal women with hormone receptor-positive advanced breast cancer-CALGB 40302 (Alliance). J Clin Oncol. 2014;32(35):3959–66. doi:10.1200/JCO.2014.56.7941.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tryfonidis K, Basaran G, Bogaerts J, et al. A European Organisation for Research and Treatment of Cancer randomized, double-blind, placebo-controlled, multicentre phase II trial of anastrozole in combination with gefitinib or placebo in hormone receptor-positive advanced breast cancer (NCT00066378). Eur J Cancer. 2016;53:144–54. doi:10.1016/j.ejca.2015.10.012.

    Article  CAS  PubMed  Google Scholar 

  77. Johnston S, Pippen Jr J, Pivot X, et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009;27(33):5538–46. doi:10.1200/JCO.2009.23.3734.

    Article  CAS  PubMed  Google Scholar 

  78. Dickler MN, Barry WT, Cirrincione CT, et al. Phase III trial evaluating letrozole as first-line endocrine therapy with or without bevacizumab for the treatment of postmenopausal women with hormone receptor-positive advanced-stage breast cancer: CALGB 40503 (Alliance). J Clin Oncol. 2016;34(22):2602–9. doi:10.1200/JCO.2015.66.1595.

    Article  PubMed  Google Scholar 

  79. Tan WW, Dueck AC, Flynn P, et al. N0539 phase II trial of fulvestrant and bevacizumab in patients with metastatic breast cancer previously treated with an aromatase inhibitor: a North Central Cancer Treatment Group (now Alliance) trial. Ann Oncol. 2013;24(10):2548–54. doi:10.1093/annonc/mdt213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Turner N, Pearson A, Sharpe R, et al. FGFR1 amplification drives endocrine therapy resistance and is a therapeutic target in breast cancer. Cancer Res. 2010;70(5):2085–94. doi:10.1158/0008-5472.CAN-09-3746.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Soria JC, DeBraud F, Bahleda R, et al. Phase I/IIa study evaluating the safety, efficacy, pharmacokinetics, and pharmacodynamics of lucitanib in advanced solid tumors. Ann Oncol. 2014;25(11):2244–51. doi:10.1093/annonc/mdu390.

    Article  PubMed  Google Scholar 

  82. Rugo H, Delord JP, Im S-A, Ott PA, Piha-Paul SA, Bedard PL et al., editors. Preliminary efficacy and safety of pembrolizumab in patients with PD-L1 positive, estrogen receptor-positive/HER2-negative advanced breast cancer enrolled in KEYNOTE-028. 38th Annual San Antonio Breast Cancer Symposium; December 8–12, 2015; San Antonio, TX (USA): Cancer Res. 2016;76(4 suppl):abstr S5-07.

  83. Herrera-Abreu MT, Palafox M, Asghar U, et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res. 2016;76(8):2301–13. doi:10.1158/0008-5472.CAN-15-0728. This work illustrates current translational efforts to understand the mechanisms of resistance to CDK4/6 inhibitors.

    Article  CAS  PubMed  Google Scholar 

  84. Vora SR, Juric D, Kim N, et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors. Cancer Cell. 2014;26(1):136–49. doi:10.1016/j.ccr.2014.05.020.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA

    A. C. Garrido-Castro & O. Metzger-Filho

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  1. A. C. Garrido-Castro
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  2. O. Metzger-Filho
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Correspondence to O. Metzger-Filho.

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Ana Christina Garrido-Castro and Otto Metzger-Filho declare that they have no conflict of interest.

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Garrido-Castro, A.C., Metzger-Filho, O. Novel Strategies in Hormone Receptor-Positive Advanced Breast Cancer: Overcoming Endocrine Resistance. Curr Breast Cancer Rep 8, 193–205 (2016). https://doi.org/10.1007/s12609-016-0228-1

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