Publication Cover
Expert Review of Precision Medicine and Drug Development
Personalized medicine in drug development and clinical practice
Volume 5, 2020 - Issue 1
76
Views
3
CrossRef citations to date
0
Altmetric
Review

Moving beyond endocrine therapy for luminal metastatic breast cancer in the precision medicine era: looking for new targets

&
Pages 7-22 | Received 13 Nov 2019, Accepted 21 Jan 2020, Published online: 03 Feb 2020

References

  • Cardoso F, Senkus E, Costa A, et al. 4th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 4). Ann Oncol. 2018;29(8):1634–1657.
  • Allred DC, Brown P, Medina D. The origins of estrogen receptor alpha-positive and estrogen receptor alpha-negative human breast cancer. Breast Cancer Res. 2004;6(6):240–245.
  • Polyak K. Heterogeneity in breast cancer. J Clin Invest. 2011;121(10):3786–3788.
  • Cohen O, Buendia-Buendia J, Wander S, et al. Evolutionary analysis of 462 serial metastatic biopsies from 208 patients with estrogen receptor-positive (ER+) metastatic breast cancer (MBC) using whole exome sequencing (WES) [abstract]. Cancer Res. 2019;79(Suppl4):Abstractnr PD9–02.
  • Stephens PJ, Tarpey PS, Davies H, et al. The landscape of cancer genes and mutational processes in breast cancer. Nature. 2012;486(7403):400–404.
  • Lefebvre C, Bachelot T, Filleron T, et al. Mutational profile of metastatic breast cancers: a retrospective analysis. Mardis ER, editor. PLOS Med. 2016;13(12):e1002201.
  • Razavi P, Chang MT, Xu G, et al. The genomic landscape of endocrine-resistant advanced breast cancers. Cancer Cell. 2018;34(3):427–438.e6.
  • Angus L, Smid M, Wilting SM, et al. The genomic landscape of metastatic breast cancer highlights changes in mutation and signature frequencies. Nat Genet. 2019;51(10):1450–1458.
  • Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–752.
  • Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the st gallen international expert consensus on the primary therapy of early breast Cancer 2013. Ann Oncol. 2013;24(9):2206–2223.
  • Kim HK, Park KH, Kim Y, et al. Discordance of the PAM50 intrinsic subtypes compared with immunohistochemistry-based surrogate in breast cancer patients: potential implication of genomic alterations of discordance. Cancer Res Treat. 2019;51(2):737–747.
  • Bastien RR, Rodríguez-Lescure Á, Ebbert MT, et al. PAM50 breast cancer subtyping by RT-qPCR and concordance with standard clinical molecular markers. BMC Med Genomics. 2012;5(44):1–12.
  • Gao J, Aksoy BA, Dogrusoz U, et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci Signal. 2013;6:269.
  • Spoerke JM, Gendreau S, Walter K, et al. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nat Commun. 2016;7(1):11579.
  • Reck M, Rabe KF. Precision diagnosis and treatment for advanced non–small-cell lung cancer. N Engl J Med. 2017;377(9):849–861.
  • Pernas S, Tolaney SM. HER2-positive breast cancer: new therapeutic frontiers and overcoming resistance. Ther Adv Med Oncol. 2019;11:1–16.
  • Seebacher NA, Stacy AE, Porter GM, et al. Clinical development of targeted and immune based anti-cancer therapies. J Exp Clin Cancer Res. 2019;38(156):1–39.
  • Rouzier R, Perou CM, Symmans WF, et al. Breast cancer molecular subtypes respond differently to preoperative chemotherapy. Clin Cancer Res. 2005;11(16):5678–5685.
  • Jordan VC. Tamoxifen: A most unlikely pioneering medicine. Nat Rev Drug Discov. 2003;2(3):205–213.
  • Robertson JFR, Bondarenko IM, Trishkina E, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016;388(10063):2997–3005.
  • Hoefnagel LDC, Moelans CB, Meijer SL, et al. Prognostic value of estrogen receptor α and progesterone receptor conversion in distant breast cancer metastases. Cancer. 2012;118(20):4929–4935.
  • Drury SC, Detre S, Leary A, et al. Changes in breast cancer biomarkers in the IGF1R/PI3K pathway in recurrent breast cancer after tamoxifen treatment. Endocr Relat Cancer. 2011;18(5):565–577.
  • Schiff R, Massarweh S, Shou J, et al. Breast cancer endocrine resistance: how growth factor signaling and estrogen receptor coregulators modulate response. Clin Cancer Res. 2003;9(1 Pt 2):447S–54S.
  • Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62(1):233–247.
  • Yamnik RL, Digilova A, Davis DC, et al. S6 kinase 1 regulates estrogen receptor α in control of breast cancer cell proliferation. J Biol Chem. 2009;284(10):6361–6369.
  • Miller TW, Hennessy BT, González-Angulo AM, et al. Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Invest. 2010;120(7):2406–2413.
  • Buckley MF, Sweeney KJE, Hamilton JA, et al. Expression and amplification of cyclin genes in human breast cancer. Oncogene. 1993;8(8):2127–2133.
  • Dickson C, Fantl V, Gillett C, et al. Amplification of chromosome band 11q13 and a role for cyclin D1 in human breast cancer. Cancer Lett. 1995;90(1):43–50.
  • Slamon DJ, Neven P, Chia S, et al. Overall survival (OS) results of the phase III MONALEESA-3 trial of postmenopausal patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor 2-negative (HER2−) advanced breast cancer (ABC) treated with fulvestrant (FUL) ± ribociclib (RIB) [abstract]. Ann Oncol. 2019;30(Supplement_5):Abstractnr LBA7_PR.
  • Sledge GW, Toi M, Neven P, et al. MONARCH 2: overall survival of abemaciclib plus fulvestrant in patients with HR+, HER2- advanced breast cancer [abstract]. Ann Oncol. 2019;30(Supplement_5):Abstractnr LBA6_PR.
  • Spring LM, Wander SA, Zangardi M, et al. CDK 4/6 inhibitors in breast cancer: current controversies and future directions. Curr Oncol Rep. 2019;21(25):1–9.
  • Pernas S, Tolaney SM, Winer EP, et al. CDK4/6 inhibition in breast cancer: current practice and future directions. Ther Adv Med Oncol. 2018;10:1–15.
  • Marra A, Curigliano G. Are all cyclin-dependent kinases 4/6 inhibitors created equal? Npj Breast Cancer. 2019;5(27):1–9.
  • McCartney A, Migliaccio I, Bonechi M, et al. Mechanisms of resistance to CDK4/6 inhibitors: potential implications and biomarkers for clinical practice. Front Oncol. 2019;9(666):1–8.
  • Formisano L, Lu Y, Servetto A, et al. Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nat Commun. 2019;10(1373):1–14.
  • Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–529.
  • Cook M, Al Rabadi L, Mitri ZI. Everolimus and exemestane for the treatment of metastatic hormone receptor-positive breast cancer patients previously treated with CDK4/6 inhibitor based therapies [abstract]. J Clin Oncol. 2019;37(15_suppl):1058.
  • André F, Ciruelos E, Rubovszky G, et al. Alpelisib for PIK3CA-mutated, hormone receptor-positive advanced breast cancer. N Engl J Med. 2019;380(20):1929–1940.
  • Vasan N, Razavi P, Johnson JL, et al. Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Ka inhibitors. Science. 2019;366(6466):714–723.
  • O’leary B, Cutts RJ, Liu Y, et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 2018;8(11):1390–1403.
  • Martin L-A, Pancholi S, Ribas R, et al. Resistance to palbociclib depends on multiple targetable mechanisms highlighting the potential of drug holidays and drug switching to improve therapeutic outcome [abstract]. Cancer Res. 2017;77(4Supplement):Abstractnr P3-03-09.
  • Cornell L, Wander SA, Visal T, et al. MicroRNA-mediated suppression of the TGF-β pathway confers transmissible and reversible CDK4/6 inhibitor resistance. Cell Rep. 2019;26(10):2667–2680.e7.
  • Liu P, Cheng H, Roberts TM, et al. Targeting the phosphoinositide 3-kinase pathway in cancer. Nat Rev Drug Discov. 2009;8(8):627–644.
  • Schmid P, Zaiss M, Harper-Wynne C, et al. Fulvestrant plus vistusertib vs fulvestrant plus everolimus vs fulvestrant alone for women with hormone receptor-positive metastatic breast cancer: the MANTA Phase 2 randomized clinical trial. JAMA Oncol. 2019;5(11):1556–1563.
  • Crowder RJ, Phommaly C, Tao Y, et al. PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer. Cancer Res. 2009;69(9):3955–3962.
  • Schöffski P, Cresta S, Mayer IA, et al. A phase Ib study of pictilisib (GDC-0941) in combination with paclitaxel, with and without bevacizumab or trastuzumab, and with letrozole in advanced breast cancer. Breast Cancer Res. 2018;20(109):1–12.
  • 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):811–821.
  • Baselga J, Im SA, Iwata H, et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant in postmenopausal, hormone receptor-positive, HER2-negative, advanced breast cancer (BELLE-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2017;18(7):904–916.
  • Di Leo A, Johnston S, Lee KS, et al. Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2018;19(1):87–100.
  • Campone M, Im SA, Iwata H, et al. Buparlisib plus fulvestrant versus placebo plus fulvestrant for postmenopausal, hormone receptor-positive, human epidermal growth factor receptor 2-negative, advanced breast cancer: overall survival results from BELLE-2. Eur J Cancer. 2018;103:147–154.
  • Dickler MN, Saura C, Richards DA, et al. Phase II study of Taselisib (GDC-0032) in combination with fulvestrant in patients with HER2-negative, hormone receptor–positive advanced breast cancer. Clin Cancer Res. 2018;24(18):4380–4387.
  • Baselga J, Dent SF, Cortés J, et al. Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA -mutant (MUT), locally advanced or metastatic breast cancer (MBC): primary analysis from SANDPIPER [abstract]. J Clin Oncol. 2018;36(18_suppl):Abstract nr LBA1006.
  • Oliveira M, Baird R, van Rossum A, et al. Phase II of POSEIDON: A phase Ib/randomized phase II trial of tamoxifen plus taselisib or placebo in hormone receptor positive, HER2 negative, metastatic breast cancer patients with prior exposure to endocrine treatment [abstract]. Cancer Res. 2017;77(Suppl 4):Abstract nr OT2-01-11.
  • Lu Y-S, Ro J, Tseng L-M, et al. A phase Ib dose de-escalation study of combined tamoxifen and goserelin acetate with alpelisib (BYL719) or buparlisib (BKM120) in premenopausal patients with HR+/HER2– locally advanced or metastatic breast cancer [abstract]. Cancer Res. 2016;76(Suppl4):Abstractnr P4-13-27.
  • Mayer IA, Abramson VG, Formisano L, et al. A phase Ib study of alpelisib (BYL719), a PI3Ka-specific inhibitor, with letrozole in ER+/HER2- metastatic breast cancer. Clin Cancer Res. 2017;23(1):26–34.
  • Juric D, Janku F, Rodón J, et al. Alpelisib plus fulvestrant in PIK3CA -altered and PIK3CA -wild-type estrogen receptor-positive advanced breast cancer: A Phase 1b clinical trial. JAMA Oncol. 2019;5(2):e184475.
  • Rugo HS, Bianchi GV, Chia SKL, et al. BYLieve: A phase II study of alpelisib (ALP) with fulvestrant (FUL) or letrozole (LET) for treatment of PIK3CA mutant, hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (aBC) progressing on/a. J Clin Oncol. 2018;36(15_suppl):TPS1107-TPS1107.
  • Rugo HS, Ruiz Borrego M, Chia SKL, et al. Alpelisib (ALP) + endocrine therapy (ET) in patients (pts) with PIK3CA- mutated hormone receptor-positive (HR+), human epidermal growth factor-2-negative (HER2-) advanced breast cancer (ABC): first interim BYLieve study results [abstract]. J Clin Oncol. 2019;37(15_suppl):1040.
  • YANG X, NIU B, WANG L, et al. Autophagy inhibition enhances colorectal cancer apoptosis induced by dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor NVP-BEZ235. Oncol Lett. 2016;12(1):102–106.
  • Kudoh A, Oishi T, Itamochi H, et al. Dual inhibition of phosphatidylinositol 3′-kinase and mammalian target of rapamycin using NVP-BEZ235 as a novel therapeutic approach for mucinous adenocarcinoma of the ovary. Int J Gynecol Cancer. 2014;24(3):444–453.
  • Wang Y, Yu Q, He X, et al. Activation of AR sensitizes breast carcinomas to NVP-BEZ235’s therapeutic effect mediated by PTEN and KLLN upregulation. Mol Cancer Ther. 2014;13(2):517–527.
  • Ma CX, Sanchez C, Gao F, et al. A phase I study of the AKT inhibitor MK-2206 in combination with hormonal therapy in postmenopausal women with estrogen receptor-positive metastatic breast cancer. Clin Cancer Res. 2016;22(11):2650–2658.
  • Jones RH, Carucci M, Casbard AC, et al. Capivasertib (AZD5363) plus fulvestrant versus placebo plus fulvestrant after relapse or progression on an aromatase inhibitor in metastatic ER-positive breast cancer (FAKTION): A randomized, double-blind, placebo-controlled, phase II trial [abstract]. J Clin Oncol. 2019;37(15_suppl):1005.
  • Banerji U, Dean EJ, Alejandro Perez-Fidalgo J, et al. A Phase I open-label study to identify a dosing regimen of the Pan-AKT inhibitor AZD5363 for evaluation in solid tumorsand in PIK3CA-mutated breast and gynecologic cancers. Clin Cancer Res. 2018;24(9):2050–2059.
  • Kalinsky K, Hong F, Mccourt C, et al. AZD5363 in Patients (Pts) with tumors with AKT mutations: NCI-MATCH subprotocol EAY131-Y, A trial of the ECOG-ACRIN Cancer Research Group (EAY131-Y). Eur J Cancer. 2018;103(Suppl 1):e13–e20.
  • Kim SB, Maslyar DJ, Dent R, et al. Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 2017;18(10):1360–1372.
  • Simpson A, Petnga W, Macaulay VM, et al. Insulin-like growth factor (IGF) pathway targeting in cancer: role of the IGF axis and opportunities for future combination studies. Target Oncol. 2017;12(5):571–597.
  • Wiseman LR, Johnson MD, Wakeling AE, et al. Type I IGF receptor and acquired tamoxifen resistance in oestrogen-responsive human breast cancer cells. Eur J Cancer. 1993;29(16):2256–2264.
  • Baselga J, Morales SM, Awada A, et al. A phase II study of combined ridaforolimus and dalotuzumab compared with exemestane in patients with estrogen receptor-positive breast cancer. Breast Cancer Res Treat. 2017;163(3):535–544.
  • Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010;10(2):116–129.
  • Elsheikh SE, Green AR, Lambros MBK, et al. FGFR1 amplification in breast carcinomas: A chromogenic in situ hybridisation analysis. Breast Cancer Res. 2007;9:2.
  • 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):2085–2094.
  • Formisano L, Stauffer KM, Young CD, et al. Association of FGFR1 with ERα maintains ligand-independent ER transcription and mediates resistance to estrogen deprivation in ER + breast cancer. Clin Cancer Res. 2017;23(20):6138–6151.
  • Seckl M, Badman PD, Liu X, et al. RADICAL trial: A phase Ib/IIa study to assess the safety and efficacy of AZD4547 in combination with either anastrozole or letrozole in ER positive breast cancer patients progressing on these aromatase inhibitors (AIs) [abstract]. J Clin Oncol. 2017;35(15_suppl):1059.
  • Hyman DM, Tran B, Corral Jaime J, et al. Phase Ib study of BGJ398 in combination with BYL719 in patients (pts) with select advanced solid tumors [abstract]. J Clin Oncol. 2016;34(15_suppl):2500.
  • Hui R, Pearson A, Castan JC, et al. Lucitanib for the treatment of HR+ HER2- metastatic breast cancer (MBC) patients (pts): results from the multicohort phase II FINESSE trial [abstract]. Ann Oncol. 2018;29(Suppl):8.
  • Hui R, Pearson A, Cortés J, et al. Lucitanib for the treatment of HR +/HER2 - metastatic breast cancer: results from the multicohort phase II FINESSE study [abstract]. Clin Cancer Res. 2020 Jan 15; 26 (2): 354-363.
  • Campone M, Bachelot T, Penault-Llorca F, et al. A phase Ib dose allocation study of oral administration of lucitanib given in combination with fulvestrant in patients with estrogen receptor-positive and FGFR1-amplified or non-amplified metastatic breast cancer. Cancer Chemother Pharmacol. 2019;83(4):743–753.
  • Musolino A, Campone M, Neven P, et al. Phase II, randomized, placebo-controlled study of dovitinib in combination with fulvestrant in postmenopausal patients with HR+, HER2- breast cancer that had progressed during or after prior endocrine therapy. Breast Cancer Res. 2017;19(1):18.
  • Koboldt DC, Fulton RS, McLellan MD, et al. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70.
  • Robinson DR, Wu Y-M, Vats P, et al. Activating ESR1 mutations in hormone-resistant metastatic breast cancer. Nat Genet. 2013;45(12):1446–1451.
  • Jeselsohn R, Buchwalter G, De Angelis C, et al. ESR1 mutations-a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol. 2015;12(10):573–583.
  • 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;34(25):2961–2968.
  • Chandarlapaty S, Chen D, He W, et al. Prevalence of ESR1 mutations in cell-free DNA and outcomes in metastatic breast cancer: a secondary analysis of the BOLERO-2 clinical trial. JAMA Oncol. 2016;2(10):1310–1315.
  • Fanning SW, Jeselsohn R, Dharmarajan V, et al. The SERM/SERD bazedoxifene disrupts ESR1 helix 12 to overcome acquired hormone resistance in breast cancer cells. Elife. 2018;7:e37161.
  • Bihani T, Patel HK, Arlt H, et al. Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), has antitumor activity in multiple ER+ breast cancer patient-derived xenograft models. Clin Cancer Res. 2017;23(16):4793–4804.
  • Laine M, Fanning SW, Greene M, et al. Lasofoxifene as a potential treatment for ER+ metastatic breast cancer [abstract]. J Clin Oncol. 2019;37(15_suppl):1056.
  • Nardone A, Weir H, Delpuech O, et al. The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance. Br J Cancer. 2019;120(3):331–339.
  • Sermonix Receives FDA Fast Track Designation for Investigational Drug Lasofoxifene [Internet]. Bloomberg. 2019. [cited 2019 Dec 1]. Available from: https://www.bloomberg.com/press-releases/2019-05-28/sermonix-receives-fda-fast-track-designation-for-investigational-drug-lasofoxifene.
  • Goetz MP, Suman VJ, Reid JM, et al. First-in-Human Phase I study of the tamoxifen Metabolite Z-Endoxifen in women with endocrine-refractory metastatic breast cancer. J Clin Oncol. 2017;35(30):3391–3400.
  • Bardia A, Aftimos P, Bihani T, et al. EMERALD: phase III trial of elacestrant (RAD1901) vs endocrine therapy for previously treated ER+ advanced breast cancer. Futur Oncol. 2019;15(28):3209–3218.
  • Garner F, Shomali M, Paquin D, et al. RAD1901: A novel, orally bioavailable selective estrogen receptor degrader that demonstrates antitumor activity in breast cancer xenograft models. Anticancer Drugs. 2015;26(9):948–956.
  • Patel H, Tao N, Arlt H, et al. Anti-tumor activity of elacestrant (RAD1901) in models harboring ESR1 mutations resistant to standard of care therapies [abstract]. Proc 2018 San Antonio Breast Cancer Symp ; 2018 Dec 4–8; San Antonio, TX Philadelphia: AACR; Cancer Res 2019;79(4 Suppl)Abstract nr P6-20-08. American Association for Cancer Research (AACR)
  • Patel H, Tao N, Arlt H, et al. Elacestrant (RAD1901) demonstrates anti-tumor activity in models resistant to CDK4/6 inhibitors [abstract]. Cancer Res. 2019;79(Suppl4):Abstractnr P4-13-03.
  • Wardell SE, Ellis MJ, Alley HM, et al. Efficacy of SERD/SERM Hybrid-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant breast cancer. Clin Cancer Res. 2015;21(22):5121–5130.
  • Jeselsohn R, Guo H, Rees R, et al. Results from the phase Ib/II clinical trial of bazedoxifene and palbociclib in hormone receptor positive metastatic breast cancer [abstract]. Cancer Res. 2019;79(Suppl4):Abstractnr PD1–05.
  • Hamilton EP, Patel MR, Armstrong AC, et al. A first-in-human study of the new oral selective estrogen receptor degrader AZD9496 for ER+/HER2- advanced breast cancer. Clin Cancer Res. 2018;24(15):3510–3518.
  • Dickler M, Villanueva R, Perez Fidalgo J, et al. A first-in-human phase I study to evaluate the oral selective estrogen receptor degrader (SERD), GDC-0927, in postmenopausal women with estrogen receptor positive (ER+) HER2-negative metastatic breast cancer (BC) [abstract]. Cancer Res. 2018;78(Suppl4):Abstractnr PD5–10.
  • Yardley DA, Ismail-Khan R, Klein P. Results of ENCORE 301, a 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 (ER+) breast cancer progressing on a non. J Clin Oncol. 2011;29(27_suppl):268.
  • Yeruva SLH, Zhao F, Miller KD, et al. E2112: randomized phase III trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. Npj Breast Cancer. 2018;4(1):1.
  • 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):1828–1835.
  • Jiang Z, Li W, Hu X, et al. Tucidinostat plus exemestane for postmenopausal patients with advanced, hormone receptor-positive breast cancer (ACE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(6):806–815.
  • Lal P, Tan LK, Chen B. Correlation of HER-2 status with estrogen and progesterone receptors and histologic features in 3,655 invasive breast carcinomas. Am J Clin Pathol. 2005;123(4):541–546.
  • Blows FM, Driver KE, Schmidt MK, et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: A collaborative analysis of data for 10,159 cases from 12 studies. PLoS Med. 2010;7(5):5.
  • Montemurro F, Di Cosimo S, Arpino G. Human epidermal growth factor receptor 2 (her2)-positive and hormone receptor-positive breast cancer: new insights into molecular interactions and clinical implications. Ann Oncol. 2013;24(11):2715–2724.
  • Swain SM, Baselga J, Kim S-B, et al. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724–734.
  • Montemurro F, Rossi V, Cossu Rocca M, et al. Hormone-receptor expression and activity of trastuzumab with chemotherapy in HER2-positive advanced breast cancer patients. Cancer. 2012;118(1):17–26.
  • Tripathy D, Kaufman PA, Brufsky AM, et al. First-line treatment patterns and clinical outcomes in patients with HER2-positive and hormone receptor-positive metastatic breast cancer from registHER. Oncologist. 2013;18(5):501–510.
  • Kaufman B, Mackey JR, Clemens MR, et al. Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. J Clin Oncol. 2009;27(33):5529–5537.
  • Huober J, Fasching PA, Barsoum M, et al. Higher efficacy of letrozole in combination with trastuzumab compared to letrozole monotherapy as first-line treatment in patients with HER2-positive, hormone-receptor-positive metastatic breast cancer – results of the eLEcTRA trial. Breast. 2012;21(1):27–33.
  • Rimawi M, Ferrero JM, De La Haba-Rodriguez J, et al. First-line trastuzumab plus an aromatase inhibitor, with or without pertuzumab, in human epidermal growth factor receptor 2-positive and hormone receptor-positive metastatic or locally advanced breast cancer (PERTAIN): A randomized, open-label phase II tr. J Clin Oncol. 2018;36(28):2826–2835.
  • Andersson M, Lidbrink E, Bjerre K, et al. Phase III randomized study comparing docetaxel plus trastuzumab with vinorelbine plus trastuzumab as first-line therapy of metastatic or locally advanced human epidermal growth factor receptor 2-positive breast cancer: the HERNATA study. J Clin Oncol. 2011;29(3):264–271.
  • Goel S, Wang Q, Watt AC, et al. Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 Inhibitors. Cancer Cell. 2016;29(3):255–269.
  • Witkiewicz AK, Cox D, Knudsen ES. CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models. Genes Cancer. 2014;5(7–8):261–272.
  • Tolaney SM, Wardley AM, Zambelli S, et al. MonarcHER: A randomized phase II study of abemaciclib plus trastuzumab with or without fulvestrant versus trastuzumab plus standard-of-care chemotherapy in women with HR+, HER2+ advanced breast cancer (ABC) [abstract]. Ann Oncol. 2019;30(Supplement_5):Abstractnr LBA23.
  • Ciruelos E, Villagrasa P, Paré L, et al. SOLTI-1303 PATRICIA phase II trial (STAGE 1) - Palbociclib and trastuzumab in postmenopausal patients with HER2-positive metastatic breast cancer [abstract]. Cancer Res. 2019;79(suppl4):Abstractnr PD3–03.
  • Metzger O, Mandrekar S, Loibl S, et al. PATINA: A randomized, open label, phase III trial to evaluate the efficacy and safety of palbociclib + anti-HER2 therapy + endocrine therapy (ET) vs. anti-HER2 therapy + ET after induction treatment for hormone receptor positive (HR+)/HER2-positive metast. Cancer Res. 2019;79(Suppl4):Abstractnr OT3-02-07.
  • Piccart-Gebhart MJ, Aftimos PG, Duhoux FP, et al. B-PRECISE-01 Study: A phase Ib trial of MEN1611, a PI3K Inhibitor, combined with trastuzumab ± fulvestrant for the treatment of HER2-positive advanced or metastatic breast cancer [abstract]. J Clin Oncol. 2019;37(15_suppl):TPS1101–TPS1101.
  • Dirix LY, Takacs I, Jerusalem G, et al. Avelumab, an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: a phase 1b JAVELIN Solid Tumor study. Breast Cancer Res Treat. 2018;167(3):671–686.
  • Rugo HS, Delord JP, Im SA, et al. Safety and antitumor activity of pembrolizumab in patients with estrogen receptor–positive/human epidermal growth factor receptor 2–negative advanced breast cancer. Clin Cancer Res. 2018;24(12):2804–2811.
  • Vonderheide RH, Lorusso PM, Khalil M, et al. Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells. Clin Cancer Res. 2010;16(13):3485–3494.
  • Terranova Barberio M, Thomas S, Chien AJ, et al. Phase II trial with tamoxifen in combination with vorinostat and pembrolizumab in estrogen receptor (+) hormone therapy resistant metastatic breast cancer patients (NCT02395627) [abstract]. J Clin Oncol. 2016;34(15_suppl):TPS620–TPS620.
  • Rugo H, Kabos P, Dickler M, et al. A phase 1b study of abemaciclib plus pembrolizumab for patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC) [abstract]. Cancer Res. 2018;78(Suppl4):Abstractnr P1-09-01.
  • Le Tourneau C, Delord JP, Gonçalves A, et al. Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): A multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial. Lancet Oncol. 2015;16(13):1324–1334.
  • Massard C, Michiels S, Ferté C, et al. High-Throughput Genomics and Clinical Outcome in Hard-to-Treat Advanced Cancers: results of the MOSCATO 01 Trial. Cancer Discov. 2017;7(6):586–595.
  • André F, Bachelot T, Commo F, et al. Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: A multicentre, prospective trial (SAFIR01/UNICANCER). Lancet Oncol. 2014;15(3):267–274.
  • Zardavas D, Maetens M, Irrthum A, et al. The AURORA initiative for metastatic breast cancer. Br J Cancer. 2014 November 11;111(10):1181–1187.
  • Swanton C. SAFIR01: steps towards precision treatment in breast cancer [Internet]. Lancet Oncol. 2014;15(3):242–243.
  • Condorelli R, Mosele F, Verret B, et al. Genomic alterations in breast cancer: level of evidence for actionability according to ESMO scale for clinical actionability of molecular targets (ESCAT). Ann Oncol. 2019;30(3):365–373.
  • Gonçalves A, Bachelot T, Lusque A, et al. High-throughput genome analysis and therapeutic decision for patients with HER2-negative metastatic breast cancer: first feasibility and molecular results of the randomized phase II study SAFIR02 BREAST (UCBG-0105/1304) [abstract]. Cancer Res. 2017;77(Suppl4):Abstractnr PD1–08.
  • Finn R, Jiang Y, Rugo H, et al. Biomarker analyses from the phase 3 PALOMA-2 trial of palbociclib (P) with letrozole (L) compared with placebo (PLB) plus L in postmenopausal women with ER +/HER2– advanced breast cancer (ABC) [abstract]. Ann Oncol. 2016;27(suppl_6):vi554.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.