Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar : PubMed/NCBI

Hudis CA: Trastuzumab-mechanism of action and use in clinical practice. N Engl J Med. 357:39–51. 2007. View Article : Google Scholar : PubMed/NCBI

Adamczyk A, Niemiec J, Janecka A, Harazin-Lechowska A, Ambicka A, Grela-Wojewoda A, Domagała-Haduch M, Cedrych I, Majchrzyk K, Kruczak A, et al: Original paper prognostic value of PIK3CA mutation status, PTEN and androgen receptor expression for metastasis-free survival in HER2-positive breast cancer patients treated with trastuzumab in adjuvant setting. Pol J Pathol. 66:133–141. 2015. View Article : Google Scholar : PubMed/NCBI

Loibl S and Gianni L: HER2-positive breast cancer. Lancet. 389:2415–2429. 2017. View Article : Google Scholar : PubMed/NCBI

Arteaga CL and Engelman JA: ERBB receptors: From oncogene discovery to basic science to mechanism-based cancer therapeutics. Cancer Cell. 25:282–303. 2014. View Article : Google Scholar : PubMed/NCBI

Petrelli F, Tomasello G, Barni S, Lonati V, Passalacqua R and Ghidini M: Clinical and pathological characterization of HER2 mutations in human breast cancer: A systematic review of the literature. Breast Cancer Res Treat. 166:339–349. 2017. View Article : Google Scholar : PubMed/NCBI

Yarden Y and Sliwkowski MX: Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2:127–137. 2001. View Article : Google Scholar : PubMed/NCBI

Wang Q, Liu P, Spangle JM, Von T, Roberts TM, Lin NU, Krop IE, Winer EP and Zhao JJ: PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers. Oncogene. 35:3607–3612. 2016. View Article : Google Scholar : PubMed/NCBI

Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA and Arteaga CL: Human breast cancer cells selected for resistance to trastuzumab in vivo overexpress epidermal growth factor receptor and ErbB ligands and remain dependent on the ErbB receptor network. Clin Cancer Res. 13:4909–4919. 2007. View Article : Google Scholar : PubMed/NCBI

Larionov AA: Current therapies for human epidermal growth factor receptor 2-positive metastatic breast cancer patients. Front Oncol. 8:892018. View Article : Google Scholar : PubMed/NCBI

Junttila TT, Akita RW, Parsons K, Fields C, Lewis Phillips GD, Friedman LS, Sampath D and Sliwkowski MX: Ligand-independent HER2/HER3/PI3K complex is disrupted by trastuzumab and is effectively inhibited by the PI3K inhibitor GDC-0941. Cancer Cell. 15:429–440. 2009. View Article : Google Scholar : PubMed/NCBI

Yakes FM, Chinratanalab W, Ritter CA, King W, Seelig S and Arteaga CL: Herceptin-induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res. 62:4132–4141. 2002.PubMed/NCBI

Fry EA, Taneja P and Inoue K: Oncogenic and tumor-suppressive mouse models for breast cancer engaging HER2/neu. Int J Cancer. 140:495–503. 2017. View Article : Google Scholar : PubMed/NCBI

Parsa Y, Mirmalek SA, Kani FE, Aidun A, Salimi-Tabatabaee SA, Yadollah-Damavandi S, Jangholi E, Parsa T and Shahverdi E: A review of the clinical implications of breast cancer biology. Electron Physician. 8:2416–2424. 2016. View Article : Google Scholar : PubMed/NCBI

Nami B and Wang Z: HER2 in breast cancer stemness: A negative feedback loop towards trastuzumab resistance. Cancers (Basel). 9(pii): E402017. View Article : Google Scholar : PubMed/NCBI

Gajria D and Chandarlapaty S: HER2-amplified breast cancer: Mechanisms of trastuzumab resistance and novel targeted therapies. Expert Rev Anticancer Ther. 11:263–275. 2011. View Article : Google Scholar : PubMed/NCBI

Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Diéras V, Guardino E, et al: Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 367:1783–1791. 2012. View Article : Google Scholar : PubMed/NCBI

Rimawi MF, Mayer IA, Forero A, Nanda R, Goetz MP, Rodriguez AA, Pavlick AC, Wang T, Hilsenbeck SG, Gutierrez C, et al: Multicenter phase II study of neoadjuvant lapatinib and trastuzumab with hormonal therapy and without chemotherapy in patients with human epidermal growth factor receptor 2-overexpressing breast cancer: TBCRC 006. J Clin Oncol. 31:1726–1731. 2013. View Article : Google Scholar : PubMed/NCBI

Robidoux A, Tang G, Rastogi P, Geyer CE Jr, Azar CA, Atkins JN, Fehrenbacher L, Bear HD, Baez-Diaz L, Sarwar S, et al: Lapatinib as a component of neoadjuvant therapy for HER2-positive operable breast cancer (NSABP protocol B-41): An open-label, randomised phase 3 trial. Lancet Oncol. 14:1183–1192. 2013. View Article : Google Scholar : PubMed/NCBI

Joensuu H: Escalating and de-escalating treatment in HER2-positive early breast cancer. Cancer Treat Rev. 52:1–11. 2017. View Article : Google Scholar : PubMed/NCBI

Ban M, Viculin J, Tomic S, Capkun V, Strikic A, Mise BP, Utrobicic I and Vrdoljak E: Retrospective analysis of efficacy of trastuzumab in adjuvant treatment of HER 2 positive early breast cancer-single institution experience. Neoplasma. 63:761–767. 2016. View Article : Google Scholar : PubMed/NCBI

Cameron D, Piccart-Gebhart MJ, Gelber RD, Procter M, Goldhirsch A, de Azambuja E, Castro G Jr, Untch M, Smith I, Gianni L, et al: 11 years' follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive early breast cancer: Final analysis of the HERceptin Adjuvant (HERA) trial. Lancet. 389:1195–1205. 2017. View Article : Google Scholar : PubMed/NCBI

De P, Hasmann M and Leyland-Jones B: Molecular determinants of trastuzumab efficacy: What is their clinical relevance? Cancer Treat Rev. 39:925–934. 2013. View Article : Google Scholar : PubMed/NCBI

Maximiano S, Magalhães P, Guerreiro MP and Morgado M: Trastuzumab in the treatment of breast cancer. BioDrugs. 30:75–86. 2016. View Article : Google Scholar : PubMed/NCBI

Figueroa-Magalhães MC, Jelovac D, Connolly RM and Wolff AC: Treatment of HER2-positive breast cancer. Breast. 23:128–136. 2014. View Article : Google Scholar : PubMed/NCBI

Zhu ZL, Zhang J, Chen ML and Li K: Efficacy and safety of trastuzumab added to standard treatments for HER2-positive metastatic breast cancer patients. Asian Pac J Cancer Prev. 14:7111–7116. 2013. View Article : Google Scholar : PubMed/NCBI

Osoba D, Slamon DJ, Burchmore M and Murphy M: Effects on quality of life of combined trastuzumab and chemotherapy in women with metastatic breast cancer. J Clin Oncol. 20:3106–3113. 2002. View Article : Google Scholar : PubMed/NCBI

Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 344:783–792. 2001. View Article : Google Scholar : PubMed/NCBI

Rugo HS, Barve A, Waller CF, Hernandez-Bronchud M, Herson J, Yuan J, Sharma R, Baczkowski M, Kothekar M, Loganathan S, et al: Effect of a proposed trastuzumab biosimilar compared with trastuzumab on overall response rate in patients with ERBB2 (HER2)-positive metastatic breast cancer: A randomized clinical trial. JAMA. 317:37–47. 2017. View Article : Google Scholar : PubMed/NCBI

Laakmann E, Müller V, Schmidt M and Witzel I: Systemic treatment options for HER2-positive breast cancer patients with brain metastases beyond trastuzumab: A literature review. Breast Care (Basel). 12:168–171. 2017. View Article : Google Scholar : PubMed/NCBI

Franklin MC, Carey KD, Vajdos FF, Leahy DJ, de Vos AM and Sliwkowski MX: Insights into ErbB signaling from the structure of the ErbB2-pertuzumab complex. Cancer Cell. 5:317–328. 2004. View Article : Google Scholar : PubMed/NCBI

Tiwari SR, Mishra P, Raska P, Calhoun B, Abraham J, Moore H, Budd GT, Fanning A, Valente S, Stewart R, et al: Retrospective study of the efficacy and safety of neoadjuvant docetaxel, carboplatin, trastuzumab/pertuzumab (TCH-P) in nonmetastatic HER2-positive breast cancer. Breast Cancer Res Treat. 158:189–193. 2016. View Article : Google Scholar : PubMed/NCBI

Scheuer W, Friess T, Burtscher H, Bossenmaier B, Endl J and Hasmann M: Strongly enhanced antitumor activity of trastuzumab and pertuzumab combination treatment on HER2-positive human xenograft tumor models. Cancer Res. 69:9330–9336. 2009. View Article : Google Scholar : PubMed/NCBI

Perez EA, Barrios C, Eiermann W, Toi M, Im YH, Conte P, Martin M, Pienkowski T, Pivot X, Burris H III, et al: Trastuzumab emtansine with or without pertuzumab versus trastuzumab plus taxane for human epidermal growth factor receptor 2-positive, advanced breast cancer: Primary results from the phase III MARIANNE study. J Clin Oncol. 35:141–148. 2017. View Article : Google Scholar : PubMed/NCBI

Cairns L and Curigliano G: Highlights from the 38th SABCS annual meeting, 8th-12th December 2015, San Antonio, USA. Ecancermedicalscience. 10:6182016. View Article : Google Scholar : PubMed/NCBI

Welslau M, Diéras V, Sohn JH, Hurvitz SA, Lalla D, Fang L, Althaus B, Guardino E and Miles D: Patient-reported outcomes from EMILIA, a randomized phase 3 study of trastuzumab emtansine (T-DM1) versus capecitabine and lapatinib in human epidermal growth factor receptor 2-positive locally advanced or metastatic breast cancer. Cancer. 120:642–651. 2014. View Article : Google Scholar : PubMed/NCBI

Krop IE, Kim SB, Martin AG, LoRusso PM, Ferrero JM, Badovinac-Crnjevic T, Hoersch S, Smitt M and Wildiers H: Trastuzumab emtansine versus treatment of physician's choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): Final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 18:743–754. 2017. View Article : Google Scholar : PubMed/NCBI

Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, et al: Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 28:1124–1130. 2010. View Article : Google Scholar : PubMed/NCBI

Spector NL, Xia W, Burris H III, Hurwitz H, Dees EC, Dowlati A, O'Neil B, Overmoyer B, Marcom PK, Blackwell KL, et al: Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies. J Clin Oncol. 23:2502–2512. 2005. View Article : Google Scholar : PubMed/NCBI

Guarneri V, Frassoldati A, Bottini A, Cagossi K, Bisagni G, Sarti S, Ravaioli A, Cavanna L, Giardina G, Musolino A, et al: Preoperative chemotherapy plus trastuzumab, lapatinib, or both in human epidermal growth factor receptor 2-positive operable breast cancer: Results of the randomized phase II CHER-LOB study. J Clin Oncol. 30:1989–1995. 2012. View Article : Google Scholar : PubMed/NCBI

Xu ZQ, Zhang Y, Li N, Liu PJ, Gao L, Gao X and Tie XJ: Efficacy and safety of lapatinib and trastuzumab for HER2-positive breast cancer: A systematic review and meta-analysis of randomised controlled trials. BMJ Open. 7:e0130532017. View Article : Google Scholar : PubMed/NCBI

Solinas C, Ceppi M, Lambertini M, Scartozzi M, Buisseret L, Garaud S, Fumagalli D, de Azambuja E, Salgado R, Sotiriou C, et al: Tumor-infiltrating lymphocytes in patients with HER2-positive breast cancer treated with neoadjuvant chemotherapy plus trastuzumab, lapatinib or their combination: A meta-analysis of randomized controlled trials. Cancer Treat Rev. 57:8–15. 2017. View Article : Google Scholar : PubMed/NCBI

Hanker AB, Pfefferle AD, Balko JM, Kuba MG, Young CD, Sánchez V, Sutton CR, Cheng H, Perou CM, Zhao JJ, et al: Mutant PIK3CA accelerates HER2-driven transgenic mammary tumors and induces resistance to combinations of anti-HER2 therapies. Proc Natl Acad Sci USA. 110:14372–14377. 2013. View Article : Google Scholar : PubMed/NCBI

Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, et al: PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 6:117–127. 2004. View Article : Google Scholar : PubMed/NCBI

Singh JC, Jhaveri K and Esteva FJ: HER2-positive advanced breast cancer: Optimizing patient outcomes and opportunities for drug development. Br J Cancer. 111:1888–1898. 2014. View Article : Google Scholar : PubMed/NCBI

Vu T and Claret FX: Trastuzumab: Updated mechanisms of action and resistance in breast cancer. Front Oncol. 2:622012. View Article : Google Scholar : PubMed/NCBI

Rexer BN, Chanthaphaychith S, Dahlman K and Arteaga CL: Direct inhibition of PI3K in combination with dual HER2 inhibitors is required for optimal antitumor activity in HER2+ breast cancer cells. Breast Cancer Res. 16:R92014. View Article : Google Scholar : PubMed/NCBI

Narayan M, Wilken JA, Harris LN, Baron AT, Kimbler KD and Maihle NJ: Trastuzumab-induced HER reprogramming in ‘resistant’ breast carcinoma cells. Cancer Res. 69:2191–2194. 2009. View Article : Google Scholar : PubMed/NCBI

Diermeier S, Horváth G, Knuechel-Clarke R, Hofstaedter F, Szöllosi J and Brockhoff G: Epidermal growth factor receptor coexpression modulates susceptibility to Herceptin in HER2/neu overexpressing breast cancer cells via specific erbB-receptor interaction and activation. Exp Cell Res. 304:604–619. 2005. View Article : Google Scholar : PubMed/NCBI

Blancafort A, Giró-Perafita A, Oliveras G, Palomeras S, Turrado C, Campuzano Ò, Carrión-Salip D, Massaguer A, Brugada R, Palafox M, et al: Dual fatty acid synthase and HER2 signaling blockade shows marked antitumor activity against breast cancer models resistant to anti-HER2 drugs. PLoS One. 10:e01312412015. View Article : Google Scholar : PubMed/NCBI

O'Donovan N, Byrne AT, O'Connor AE, McGee S, Gallagher WM and Crown J: Synergistic interaction between trastuzumab and EGFR/HER-2 tyrosine kinase inhibitors in HER-2 positive breast cancer cells. Invest New Drugs. 29:752–759. 2011. View Article : Google Scholar : PubMed/NCBI

Perez EA, Suman VJ, Davidson NE, Sledge GW, Kaufman PA, Hudis CA, Martino S, Gralow JR, Dakhil SR, Ingle JN, et al: Cardiac safety analysis of doxorubicin and cyclophosphamide followed by paclitaxel with or without trastuzumab in the North central cancer treatment group N9831 adjuvant breast cancer trial. J Clin Oncol. 26:1231–1238. 2008. View Article : Google Scholar : PubMed/NCBI

Dokmanovic M, King KE, Mohan N, Endo Y and Wu WJ: Cardiotoxicity of ErbB2-targeted therapies and its impact on drug development, a spotlight on trastuzumab. Expert Opin Drug Metab Toxicol. 13:755–766. 2017. View Article : Google Scholar : PubMed/NCBI

Keefe DL: Trastuzumab-associated cardiotoxicity. Cancer. 95:1592–1600. 2002. View Article : Google Scholar : PubMed/NCBI

Baselga J, Gelmon KA, Verma S, Wardley A, Conte P, Miles D, Bianchi G, Cortes J, McNally VA, Ross GA, et al: Phase II trial of pertuzumab and trastuzumab in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer that progressed during prior trastuzumab therapy. J Clin Oncol. 28:1138–1144. 2010. View Article : Google Scholar : PubMed/NCBI

Portera CC, Walshe JM, Rosing DR, Denduluri N, Berman AW, Vatas U, Velarde M, Chow CK, Steinberg SM, Nguyen D, et al: Cardiac toxicity and efficacy of trastuzumab combined with pertuzumab in patients with [corrected] human epidermal growth factor receptor 2-positive metastatic breast cancer. Clin Cancer Res. 14:2710–2716. 2008. View Article : Google Scholar : PubMed/NCBI

Burris HA III, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, Tan-Chiu E, Krop IE, Michaelson RA, Girish S, et al: Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 29:398–405. 2011. View Article : Google Scholar : PubMed/NCBI

LoRusso PM, Weiss D, Guardino E, Girish S and Sliwkowski MX: Trastuzumab emtansine: A unique antibody-drug conjugate in development for human epidermal growth factor receptor 2-positive cancer. Clin Cancer Res. 17:6437–6447. 2011. View Article : Google Scholar : PubMed/NCBI

Kowalczyk L, Bartsch R, Singer CF and Farr A: Adverse events of trastuzumab emtansine (T-DM1) in the treatment of HER2-positive breast cancer patients. Breast Care (Basel). 12:401–408. 2017. View Article : Google Scholar : PubMed/NCBI

Watanabe J, Ito Y, Saeki T, Masuda N, Takano T, Takao S, Nakagami K, Tsugawa K, Nakagawa S, Kanatani K and Nakayama T: Safety evaluation of trastuzumab emtansine in japanese patients with HER2-positive advanced breast cancer. In Vivo. 31:493–500. 2017. View Article : Google Scholar : PubMed/NCBI

Blackwell KL, Pegram MD, Tan-Chiu E, Schwartzberg LS, Arbushites MC, Maltzman JD, Forster JK, Rubin SD, Stein SH and Burstein HJ: Single-agent lapatinib for HER2-overexpressing advanced or metastatic breast cancer that progressed on first- or second-line trastuzumab-containing regimens. Ann Oncol. 20:1026–1031. 2009. View Article : Google Scholar : PubMed/NCBI

Ahmad S, Gupta S, Kumar R, Varshney GC and Raghava GP: Herceptin resistance database for understanding mechanism of resistance in breast cancer patients. Sci Rep. 4:44832014. View Article : Google Scholar : PubMed/NCBI

Rabindran SK, Discafani CM, Rosfjord EC, Baxter M, Floyd MB, Golas J, Hallett WA, Johnson BD, Nilakantan R, Overbeek E, et al: Antitumor activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 64:3958–3965. 2004. View Article : Google Scholar : PubMed/NCBI

Tsou HR, Overbeek-Klumpers EG, Hallett WA, Reich MF, Floyd MB, Johnson BD, Michalak RS, Nilakantan R, Discafani C, Golas J, et al: Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity. J Med Chem. 48:1107–1131. 2005. View Article : Google Scholar : PubMed/NCBI

Keyvanjah K, DiPrimeo D, Li A, Obaidi M, Swearingen D and Wong A: Pharmacokinetics of neratinib during coadministration with lansoprazole in healthy subjects. Br J Clin Pharmacol. 83:554–561. 2017. View Article : Google Scholar : PubMed/NCBI

Saura C, Garcia-Saenz JA, Xu B, Harb W, Moroose R, Pluard T, Cortés J, Kiger C, Germa C, Wang K, et al: Safety and efficacy of neratinib in combination with capecitabine in patients with metastatic human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 32:3626–3633. 2014. View Article : Google Scholar : PubMed/NCBI

Burstein HJ, Sun Y, Dirix LY, Jiang Z, Paridaens R, Tan AR, Awada A, Ranade A, Jiao S, Schwartz G, et al: Neratinib, an irreversible ErbB receptor tyrosine kinase inhibitor, in patients with advanced ErbB2-positive breast cancer. J Clin Oncol. 28:1301–1307. 2010. View Article : Google Scholar : PubMed/NCBI

Echavarria I, López-Tarruella S, Márquez-Rodas I, Jerez Y and Martin M: Neratinib for the treatment of HER2-positive early stage breast cancer. Expert Rev Anticancer Ther. 17:669–679. 2017. View Article : Google Scholar : PubMed/NCBI

Canonici A, Gijsen M, Mullooly M, Bennett R, Bouguern N, Pedersen K, O'Brien NA, Roxanis I, Li JL, Bridge E, et al: Neratinib overcomes trastuzumab resistance in HER2 amplified breast cancer. Oncotarget. 4:1592–1605. 2013. View Article : Google Scholar : PubMed/NCBI

Mohd Nafi SN, Generali D, Kramer-Marek G, Gijsen M, Strina C, Cappelletti M, Andreis D, Haider S, Li JL, Bridges E, et al: Nuclear HER4 mediates acquired resistance to trastuzumab and is associated with poor outcome in HER2 positive breast cancer. Oncotarget. 5:5934–5949. 2014.PubMed/NCBI

Jankowitz RC, Abraham J, Tan AR, Limentani SA, Tierno MB, Adamson LM, Buyse M, Wolmark N and Jacobs SA: Safety and efficacy of neratinib in combination with weekly paclitaxel and trastuzumab in women with metastatic HER2-positive breast cancer: An NSABP foundation research program phase I study. Cancer Chemother Pharmacol. 72:1205–1212. 2013. View Article : Google Scholar : PubMed/NCBI

Kourie HR, Chaix M, Gombos A, Aftimos P and Awada A: Pharmacodynamics, pharmacokinetics and clinical efficacy of neratinib in HER2-positive breast cancer and breast cancer with HER2 mutations. Expert Opin Drug Metab Toxicol. 12:947–957. 2016. View Article : Google Scholar : PubMed/NCBI

Chan A: Neratinib in HER-2-positive breast cancer: Results to date and clinical usefulness. Ther Adv Med Oncol. 8:339–350. 2016. View Article : Google Scholar : PubMed/NCBI

Kourie HR, El Rassy E, Clatot F, de Azambuja E and Lambertini M: Emerging treatments for HER2-positive early-stage breast cancer: Focus on neratinib. Onco Targets Ther. 10:3363–3372. 2017. View Article : Google Scholar : PubMed/NCBI

Chan A, Delaloge S, Holmes FA, Moy B, Iwata H, Harvey VJ, Robert NJ, Silovski T, Gokmen E, von Minckwitz G, et al: Neratinib after trastuzumab-based adjuvant therapy in patients with HER2-positive breast cancer (ExteNET): A multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 17:367–377. 2016. View Article : Google Scholar : PubMed/NCBI

Tian C, Ding P, Yuan Z, Li H, Zhao Y, Sun L, Guo Q, Wang Z, Sun L, Zhang L and Jiang Z: A novel dual EGFR/HER2 inhibitor KU004 induces cell cycle arrest and apoptosis in HER2-overexpressing cancer cells. Apoptosis. 20:1599–1612. 2015. View Article : Google Scholar : PubMed/NCBI

Choi YJ, Li X, Hydbring P, Sanda T, Stefano J, Christie AL, Signoretti S, Look AT, Kung AL, von Boehmer H and Sicinski P: The requirement for cyclin D function in tumor maintenance. Cancer Cell. 22:438–451. 2012. View Article : Google Scholar : PubMed/NCBI

Yu Q, Geng Y and Sicinski P: Specific protection against breast cancers by cyclin D1 ablation. Nature. 411:1017–1021. 2001. View Article : Google Scholar : PubMed/NCBI

Iwata H: Clinical development of CDK4/6 inhibitor for breast cancer. Breast Cancer. 25:402–406. 2018. View Article : Google Scholar : PubMed/NCBI

Walker AJ, Wedam S, Amiri-Kordestani L, Bloomquist E, Tang S, Sridhara R, Chen W, Palmby TR, Fourie Zirkelbach J, Fu W, 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. 22:4968–4972. 2016. View Article : Google Scholar : PubMed/NCBI

Kwapisz D: Cyclin-dependent kinase 4/6 inhibitors in breast cancer: Palbociclib, ribociclib, and abemaciclib. Breast Cancer Res Treat. 166:41–54. 2017. View Article : Google Scholar : PubMed/NCBI

Gianni L, Bisagni G, Colleoni M, Del Mastro L, Zamagni C, Mansutti M, Zambetti M, Frassoldati A, De Fato R, Valagussa P and Viale G: Neoadjuvant treatment with trastuzumab and pertuzumab plus palbociclib and fulvestrant in HER2-positive, ER-positive breast cancer (NA-PHER2): An exploratory, open-label, phase 2 study. Lancet Oncol. 19:249–256. 2018. View Article : Google Scholar : PubMed/NCBI

Witkiewicz AK, Cox D and Knudsen ES: CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models. Genes Cancer. 5:261–272. 2014.PubMed/NCBI

Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, Ramm S, Palmer AC, Yuzugullu H, Varadan V, et al: Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell. 29:255–269. 2016. View Article : Google Scholar : PubMed/NCBI

Sievers EL and Senter PD: Antibody-drug conjugates in cancer therapy. Annu Rev Med. 64:15–29. 2013. View Article : Google Scholar : PubMed/NCBI

Lianos GD, Vlachos K, Zoras O, Katsios C, Cho WC and Roukos DH: Potential of antibody-drug conjugates and novel therapeutics in breast cancer management. Onco Targets Ther. 7:491–500. 2014.PubMed/NCBI

Padayachee ER, Biteghe FAN, Malindi Z, Bauerschlag D and Barth S: Human antibody fusion proteins/antibody drug conjugates in breast and ovarian cancer. Transfus Med Hemother. 44:303–310. 2017. View Article : Google Scholar : PubMed/NCBI

Li JY, Perry SR, Muniz-Medina V, Wang X, Wetzel LK, Rebelatto MC, Hinrichs MJ, Bezabeh BZ, Fleming RL, Dimasi N, et al: A biparatopic HER2-targeting antibody-drug conjugate induces tumor regression in primary models refractory to or ineligible for HER2-targeted therapy. Cancer Cell. 29:117–129. 2016. View Article : Google Scholar : PubMed/NCBI

Tsui FW, Martin A, Wang J and Tsui HW: Investigations into the regulation and function of the SH2 domain-containing protein-tyrosine phosphatase, SHP-1. Immunol Res. 35:127–136. 2006. View Article : Google Scholar : PubMed/NCBI

Liu CY, Chen KF, Chao TI, Chu PY, Huang CT, Huang TT, Yang HP, Wang WL, Lee CH, Lau KY, et al: Sequential combination of docetaxel with a SHP-1 agonist enhanced suppression of p-STAT3 signaling and apoptosis in triple negative breast cancer cells. J Mol Med (Berl). 95:965–975. 2017. View Article : Google Scholar : PubMed/NCBI

Liu CY, Tseng LM, Su JC, Chang KC, Chu PY, Tai WT, Shiau CW and Chen KF: Erratum to: Novel sorafenib analogues induce apoptosis through SHP-1 dependent STAT3 inactivation in human breast cancer cells. Breast Cancer Res. 19:52017. View Article : Google Scholar : PubMed/NCBI

Wu Y, Li R, Zhang J, Wang G, Liu B, Huang X, Zhang T and Luo R: Protein tyrosine phosphatase SHP-1 sensitizes EGFR/HER-2 positive breast cancer cells to trastuzumab through modulating phosphorylation of EGFR and HER-2. Onco Targets Ther. 8:2577–2587. 2015.PubMed/NCBI

Puig T, Turrado C, Benhamú B, Aguilar H, Relat J, Ortega-Gutiérrez S, Casals G, Marrero PF, Urruticoechea A, Haro D, et al: Novel inhibitors of fatty acid synthase with anticancer activity. Clin Cancer Res. 15:7608–7615. 2009. View Article : Google Scholar : PubMed/NCBI

Grunt TW, Wagner R, Grusch M, Berger W, Singer CF, Marian B, Zielinski CC and Lupu R: Interaction between fatty acid synthase- and ErbB-systems in ovarian cancer cells. Biochem Biophys Res Commun. 385:454–459. 2009. View Article : Google Scholar : PubMed/NCBI

Menendez JA and Lupu R: Fatty acid synthase (FASN) as a therapeutic target in breast cancer. Expert Opin Ther Targets. 21:1001–1016. 2017. View Article : Google Scholar : PubMed/NCBI

Hayward SL, Francis DM, Kholmatov P and Kidambi S: Targeted delivery of MicroRNA125a-5p by engineered lipid nanoparticles for the treatment of HER2 positive metastatic breast cancer. J Biomed Nanotechnol. 12:554–568. 2016. View Article : Google Scholar : PubMed/NCBI

Campbell DF, Saenz R, Bharati IS, Seible D, Zhang L, Esener S, Messmer B, Larsson M and Messmer D: Enhanced anti-tumor immune responses and delay of tumor development in human epidermal growth factor receptor 2 mice immunized with an immunostimulatory peptide in poly(D,L-lactic-co-glycolic) acid nanoparticles. Breast Cancer Res. 17:482015. View Article : Google Scholar : PubMed/NCBI

Li J, Wang F, Sun D and Wang R: A review of the ligands and related targeting strategies for active targeting of paclitaxel to tumours. J Drug Target. 24:590–602. 2016. View Article : Google Scholar : PubMed/NCBI

Chandrika BB, Steephan M, Kumar TR, Sabu A and Haridas M: Hesperetin and naringenin sensitize HER2 positive cancer cells to death by serving as HER2 tyrosine kinase inhibitors. Life Sci. 160:47–56. 2016. View Article : Google Scholar : PubMed/NCBI

Nishio S, Ushijima K, Yamaguchi T, Sasajima Y, Tsuda H, Kasamatsu T, Kage M, Ono M, Kuwano M and Kamura T: Nuclear Y-box-binding protein-1 is a poor prognostic marker and related to epidermal growth factor receptor in uterine cervical cancer. Gynecol Oncol. 132:703–708. 2014. View Article : Google Scholar : PubMed/NCBI

He L, Che M, Hu J, Li S, Jia Z, Lou W, Li C, Yang J, Sun S, Wang H and Chen X: Twist contributes to proliferation and epithelial-to-mesenchymal transition-induced fibrosis by regulating YB-1 in human peritoneal mesothelial cells. Am J Pathol. 185:2181–2193. 2015. View Article : Google Scholar : PubMed/NCBI

Ma JW, Hung CM, Lin YC, Ho CT, Kao JY and Way TD: Aloe-emodin inhibits HER-2 expression through the downregulation of Y-box binding protein-1 in HER-2-overexpressing human breast cancer cells. Oncotarget. 7:58915–58930. 2016.PubMed/NCBI

Housa D, Housová J, Vernerová Z and Haluzík M: Adipocytokines and cancer. Physiol Res. 55:233–244. 2006.PubMed/NCBI

Vona-Davis L and Rose DP: Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer. 14:189–206. 2007. View Article : Google Scholar : PubMed/NCBI

Provatopoulou X, Georgiou GP, Kalogera E, Kalles V, Matiatou MA, Papapanagiotou I, Sagkriotis A, Zografos GC and Gounaris A: Serum irisin levels are lower in patients with breast cancer: Association with disease diagnosis and tumor characteristics. BMC Cancer. 15:8982015. View Article : Google Scholar : PubMed/NCBI

Shukla S, Bhaskaran N, Babcook MA, Fu P, Maclennan GT and Gupta S: Apigenin inhibits prostate cancer progression in TRAMP mice via targeting PI3K/Akt/FoxO pathway. Carcinogenesis. 35:452–460. 2014. View Article : Google Scholar : PubMed/NCBI

Seo HS, Ju JH, Jang K and Shin I: Induction of apoptotic cell death by phytoestrogens by up-regulating the levels of phospho-p53 and p21 in normal and malignant estrogen receptor α-negative breast cells. Nutr Res. 31:139–146. 2011. View Article : Google Scholar : PubMed/NCBI

Seo HS, Jo JK, Ku JM, Choi HS, Choi YK, Woo JK, Kim HI, Kang SY, Lee KM, Nam KW, et al: Induction of caspase-dependent extrinsic apoptosis by apigenin through inhibition of signal transducer and activator of transcription 3 (STAT3) signalling in HER2-overexpressing BT-474 breast cancer cells. Biosci Rep. 35(pii): e002762015. View Article : Google Scholar : PubMed/NCBI

Liu Q, Xu X, Zhao M, Wei Z, Li X, Zhang X, Liu Z, Gong Y and Shao C: Berberine induces senescence of human glioblastoma cells by downregulating the EGFR-MEK-ERK signaling pathway. Mol Cancer Ther. 14:355–363. 2015. View Article : Google Scholar : PubMed/NCBI

Chu SC, Yu CC, Hsu LS, Chen KS, Su MY and Chen PN: Berberine reverses epithelial-to-mesenchymal transition and inhibits metastasis and tumor-induced angiogenesis in human cervical cancer cells. Mol Pharmacol. 86:609–623. 2014. View Article : Google Scholar : PubMed/NCBI

Pierpaoli E, Damiani E, Orlando F, Lucarini G, Bartozzi B, Lombardi P, Salvatore C, Geroni C, Donati A and Provinciali M: Antiangiogenic and antitumor activities of berberine derivative NAX014 compound in a transgenic murine model of HER2/neu-positive mammary carcinoma. Carcinogenesis. 36:1169–1179. 2015. View Article : Google Scholar : PubMed/NCBI

Guerram M, Jiang ZZ, Yousef BA, Hamdi AM, Hassan HM, Yuan ZQ, Luo HW, Zhu X and Zhang LY: The potential utility of acetyltanshinone IIA in the treatment of HER2-overexpressed breast cancer: Induction of cancer cell death by targeting apoptotic and metabolic signaling pathways. Oncotarget. 6:21865–21877. 2015. View Article : Google Scholar : PubMed/NCBI

Tian HL, Yu T, Xu NN, Feng C, Zhou LY, Luo HW, Chang DC, Le XF and Luo KQ: A novel compound modified from tanshinone inhibits tumor growth in vivo via activation of the intrinsic apoptotic pathway. Cancer Lett. 297:18–30. 2010. View Article : Google Scholar : PubMed/NCBI

Guan YQ, Li Z and Liu JM: Death signal transduction induced by co-immobilized TNF-α plus IFN-γ and the development of polymeric anti-cancer drugs. Biomaterials. 31:9074–9085. 2010. View Article : Google Scholar : PubMed/NCBI

Namjoshi P, Showalter L, Czerniecki BJ and Koski GK: T-helper 1-type cytokines induce apoptosis and loss of HER-family oncodriver expression in murine and human breast cancer cells. Oncotarget. doi.org/10.18632/oncotarget.10298.

Mittal D, Caramia F, Michiels S, Joensuu H, Kellokumpu-Lehtinen PL, Sotiriou C, Loi S and Smyth MJ: Improved treatment of breast cancer with anti-HER2 therapy requires interleukin-21 signaling in CD8+ T cells. Cancer Res. 76:264–274. 2016. View Article : Google Scholar : PubMed/NCBI

Hung SW, Chiu CF, Chen TA, Chu CL, Huang CC, Shyur LF, Liang CM and Liang SM: Recombinant viral protein VP1 suppresses HER-2 expression and migration/metastasis of breast cancer. Breast Cancer Res Treat. 136:89–105. 2012. View Article : Google Scholar : PubMed/NCBI

Takai N and Narahara H: Human endometrial and ovarian cancer cells: Histone deacetylase inhibitors exhibit antiproliferative activity, potently induce cell cycle arrest, and stimulate apoptosis. Curr Med Chem. 14:2548–2553. 2007. View Article : Google Scholar : PubMed/NCBI

Travaglini L, Vian L, Billi M, Grignani F and Nervi C: Epigenetic reprogramming of breast cancer cells by valproic acid occurs regardless of estrogen receptor status. Int J Biochem Cell Biol. 41:225–234. 2009. View Article : Google Scholar : PubMed/NCBI

Zhang L, Wang G, Wang L, Song C, Leng Y, Wang X and Kang J: VPA inhibits breast cancer cell migration by specifically targeting HDAC2 and down-regulating Survivin. Mol Cell Biochem. 361:39–45. 2012. View Article : Google Scholar : PubMed/NCBI

Hrzenjak A, Moinfar F, Kremser ML, Strohmeier B, Staber PB, Zatloukal K and Denk H: Valproate inhibition of histone deacetylase 2 affects differentiation and decreases proliferation of endometrial stromal sarcoma cells. Mol Cancer Ther. 5:2203–2210. 2006. View Article : Google Scholar : PubMed/NCBI

Rocchi P, Tonelli R, Camerin C, Purgato S, Fronza R, Bianucci F, Guerra F, Pession A and Ferreri AM: p21Waf1/Cip1 is a common target induced by short-chain fatty acid HDAC inhibitors (valproic acid, tributyrin and sodium butyrate) in neuroblastoma cells. Oncol Rep. 13:1139–1144. 2005.PubMed/NCBI

Mawatari T, Ninomiya I, Inokuchi M, Harada S, Hayashi H, Oyama K, Makino I, Nakagawara H, Miyashita T, Tajima H, et al: Valproic acid inhibits proliferation of HER2-expressing breast cancer cells by inducing cell cycle arrest and apoptosis through Hsp70 acetylation. Int J Oncol. 47:2073–2081. 2015. View Article : Google Scholar : PubMed/NCBI

Kim J, Kundu M, Viollet B and Guan KL: AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 13:132–141. 2011. View Article : Google Scholar : PubMed/NCBI

Fan QW, Cheng C, Hackett C, Feldman M, Houseman BT, Nicolaides T, Haas-Kogan D, James CD, Oakes SA, Debnath J, et al: Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci Signal. 3:ra812010. View Article : Google Scholar : PubMed/NCBI

Fritsch C, Huang A, Chatenay-Rivauday C, Schnell C, Reddy A, Liu M, Kauffmann A, Guthy D, Erdmann D, De Pover A, et al: Characterization of the novel and specific PI3Kα inhibitor NVP-BYL719 and development of the patient stratification strategy for clinical trials. Mol Cancer Ther. 13:1117–1129. 2014. View Article : Google Scholar : PubMed/NCBI

Young CD, Arteaga CL and Cook RS: Dual inhibition of Type I and Type III PI3 kinases increases tumor cell apoptosis in HER2+ breast cancers. Breast Cancer Res. 17:1482015. View Article : Google Scholar : PubMed/NCBI

Salmaninejad A, Khoramshahi V, Azani A, Soltaninejad E, Aslani S, Zamani MR, Zal M, Nesaei A and Hosseini SM: PD-1 and cancer: Molecular mechanisms and polymorphisms. Immunogenetics. 70:73–86. 2018. View Article : Google Scholar : PubMed/NCBI

Berger KN and Pu JJ: PD-1 pathway and its clinical application: A 20year journey after discovery of the complete human PD-1 gene. Gene. 638:20–25. 2018. View Article : Google Scholar : PubMed/NCBI

Kythreotou A, Siddique A, Mauri FA, Bower M and Pinato DJ: PD-L1. J Clin Pathol. 71:189–194. 2018. View Article : Google Scholar : PubMed/NCBI

Hartkopf AD, Taran FA, Wallwiener M, Walter CB, Krämer B, Grischke EM and Brucker SY: PD-1 and PD-L1 immune checkpoint blockade to treat breast cancer. Breast Care (Basel). 11:385–390. 2016. View Article : Google Scholar : PubMed/NCBI

Schütz F, Stefanovic S, Mayer L, von Au A, Domschke C and Sohn C: PD-1/PD-L1 pathway in breast cancer. Oncol Res Treat. 40:294–297. 2017. View Article : Google Scholar : PubMed/NCBI

Tsang JY, Au WL, Lo KY, Ni YB, Hlaing T, Hu J, Chan SK, Chan KF, Cheung SY and Tse GM: PD-L1 expression and tumor infiltrating PD-1+ lymphocytes associated with outcome in HER2+ breast cancer patients. Breast Cancer Res Trea. 162:19–30. 2017. View Article : Google Scholar

Hou Y, Nitta H, Wei L, Banks PM, Parwani AV and Li Z: Evaluation of immune reaction and PD-L1 expression using multiplex immunohistochemistry in HER2-positive breast cancer: The association with response to Anti-HER2 neoadjuvant therapy. Clin Breast Cancer. 18:e237–e244. 2018. View Article : Google Scholar : PubMed/NCBI

Dirix LY, Takacs I, Jerusalem G, Nikolinakos P, Arkenau HT, Forero-Torres A, Boccia R, Lippman ME, Somer R, Smakal M, 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. 167:671–686. 2018. View Article : Google Scholar : PubMed/NCBI