Suscripción a Biblioteca: Guest
Critical Reviews™ in Oncogenesis

Publicado 4 números por año

ISSN Imprimir: 0893-9675

ISSN En Línea: 2162-6448

SJR: 0.395 SNIP: 0.322 CiteScore™:: 2.5 H-Index: 54

Indexed in

Acceder(open in a new tab)
Más
Comprar $90.00(open in a new tab) Comprobar suscripción Descargar registro MARC(open in a new tab) Obtener permisos(open in a new tab)

Sensitization of Cancers Resistant to HER2 Antibodies

Volumen 25, Edición 3, 2020, pp. 175-207
DOI: 10.1615/CritRevOncog.2020036080
Get accessGet access
Sagun Parakh
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia; School of Cancer Medicine, Monash University, Melbourne, Australia; Department of Medical Oncology, Austin Hospital, Melbourne, Australia
Hui K. Gan
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia; Department of Medical Oncology, Austin Hospital, Melbourne, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia
Andrew M. Scott
Tumour Targeting Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Australia; School of Cancer Medicine, La Trobe University, Melbourne, Australia; Department of Molecular Imaging and Therapy, Austin Health, Melbourne, Australia; Department of Medicine, University of Melbourne, Melbourne, Australia

SINOPSIS

Human epidermal growth factor receptor 2 (HER2) oncogene addiction has led to the development of anti-HER2 therapies which have revolutionized the management of patients with HER2-positive cancers, with trastuzumab being the cornerstone of treatment of HER2-positive breast cancer. Despite the success of these biologics in breast cancer patients, not all patients with HER2-positive tumors respond to treatment, and many eventually develop resistance to therapy. Developing therapies that that circumvent current resistance mechanisms and improve patient outcomes further remains an area of unmet clinical need. Based on insights gained from established anti-HER2 therapies and our understanding of known resistance mechanisms a number of novel anti-HER2 treatments are being developed. These include novel HER2 antibody-drug conjugates that have shown activity in HER2 high and low tumors, novel HER2 antibodies, T cell bispecific antibodies, and HER2 antibodies in combination with phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors, immunotherapy and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. In this article, we review resistance mechanisms to approved HER2 antibodies and provide an overview of emerging therapeutic agents.

PALABRAS CLAVE: HER2, antibodies, resistance
REFERENCIAS

  1. Casalini P, Iorio MV, Galmozzi E, Menard S. Role of HER receptors family in development and differentiation. J Cell Physiol. 2004;200(3):343-50.

  2. Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TP, Leahy DJ, Lemmon MA, Sliwkowski MX, Ward CW, Yokoyama S. An open-and-shut case? Recent insights into the activation of EGF/ErbB receptors. Mol Cell. 2003;12(3):541-52.

  3. Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, Seeburg PH, Libermann TA, Schlessinger J, Francke U. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science. 1985;230(4730):1132-9.

  4. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2(2):127.

  5. Cho H-S, Mason K, Ramyar KX, Stanley AM, Gabelli SB, Denney DW, Leahy DJ. Structure of the extracellular region of HER2 alone and in complex with the Herceptin Fab. Nature. 2003;421(6924):756-60.

  6. Garrett TP, McKern NM, Lou M, Elleman TC, Adams TE, Lovrecz GO, Zhu HJ, Walker F, Frenkel MJ, Hoyne PA, Jorissen RN, Nice EC, Burgess AW, Ward CW. Crystal structure of a truncated epidermal growth factor receptor extracellular domain bound to transforming growth factor a. Cell. 2002;110(6):763-73.

  7. Wang L-M, Kuo A, Alimandi M, Veri MC, Lee C-C, Kapoor V, Ellmore N, Chen XH, Pierce JH. ErbB2 expression increases the spectrum and potency of ligand-mediated signal transduction through ErbB4. Proc Natl Acad Sci U S A. 1998;95(12):6809-14.

  8. Tzahar E, Waterman H, Chen X, Levkowitz G, Karunagaran D, Lavi S, Ratzkin BJ, Yarden Y. A hierarchical network of interreceptor interactions determines signal transduction by Neu differentiation factor/neuregulin and epidermal growth factor. Mol Cell Biol. 1996;16(10):5276-87.

  9. Pressl MF, Cordon-Cardo C, Slamon DJ. Expression of the HER-Z/neu proto-oncogene in normal human adult and fetal tissues. Liver. 1990;7:7.

  10. Ross JS, Fletcher JA, Linette GP, Stec J, Clark E, Ayers M, Symmans F, Pusztai L, Bloom KJ. The Her-2/neu gene and protein in breast cancer 2003: Biomarker and target of therapy. Oncologist. 2003;8(4):307-25.

  11. Ross JS, Fletcher JA, Bloom KJ, Linette GP, Stec J, Symmans WF, Pusztai L, Hortobagyi GN. Targeted therapy in breast cancer the HER-2/neu gene and protein. Mol Cell Proteomics. 2004;3(4):379-98.

  12. Huang G, Chantry A, Epstein RJ. Overexpression of ErbB2 impairs ligand-dependent downregulation of epidermal growth factor receptors via a post-transcriptional mechanism. J Cell Biochem. 1999;74(1):23-30.

  13. Worthylake R, Opresko LK, Wiley HS. ErbB-2 amplification inhibits down-regulation and induces constitutive activation of both ErbB-2 and epidermal growth factor receptors. J Biol Chem. 1999;274(13):8865-74.

  14. Timms JF, White SL, O'Hare MJ, Waterfield MD. Effects of ErbB-2 overexpression on mitogenic signalling and cell cycle progression in human breast luminal epithelial cells. Oncogene. 2002;21(43):6573.

  15. Hudziak RM, Schlessinger J, Ullrich A. Increased expression of the putative growth factor receptor p185HER2 causes transformation and tumorigenesis of NIH 3T3 cells. Proc Natl Acad Sci U S A. 1987;84(20):7159-63.

  16. Chazin V, Kaleko M, Miller A, Slamon D. Transformation mediated by the human HER-2 gene independent of the epidermal growth factor receptor. Oncogene. 1992;7(9):1859-66.

  17. Ignatoski KMW, Grewal NK, Markwart S, Livant DL, Ethier SP. p38MAPK induces cell surface a 4 integrin downregulation to facilitate erbB-2-mediated invasion. Neoplasia. 2003;5(2):128-34.

  18. Benz CC, Scott GK, Sarup JC, Johnson RM, Tripathy D, Coronado E, Shepard HM, Osborne CK. Estrogen-dependent, tamoxifen-resistant tumorigenic growth of MCF-7 cells transfected with HER2/neu. Breast Cancer Res Treat. 1992;24(2):85-95.

  19. de Hoon JP, Veeck J, Vriens BE, Calon TG, van Engeland M, Tjan-Heijnen VC. Taxane resistance in breast cancer: A closed HER2 circuit? Biochim Biophys Acta. 2012;1825(2):197-206.

  20. Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62:233.

  21. Zhang W, Ding W, Chen Y, Feng M, Ouyang Y, Yu Y, He Z. Up-regulation of breast cancer resistance protein plays a role in HER2-mediated chemoresistance through PI3K/Akt and nuclear factor-kappa B signaling pathways in MCF7 breast cancer cells. Acta Biochim Biophys Sin. 2011 Aug 1;43(8):647-53.

  22. Gilani RA, Kazi AA, Shah P, Schech AJ, Chumsri S, Sabnis G, Jaiswal AK, Brodie AH. The importance of HER2 signaling in the tumor-initiating cell population in aromatase inhibitor-resistant breast cancer. Breast Cancer Res Treat. 2012;135(3):681-92.

  23. Kang HJ, Yi YW, Hong YB, Kim HJ, Jang YJ, Seong YS, Bae I. HER2 confers drug resistance of human breast cancer cells through activation of NRF2 by direct interaction. Sci Rep. 2014;4:7201.

  24. Yonesaka K, Zejnullahu K, Okamoto I, Satoh T, Cappuzzo F, Souglakos J, Ercan D, Rogers A, Roncalli M, Takeda M, Fujisaka Y, Philips J, Shimizu T, Maenishi O, Cho Y, Sun J, Destro A, Taira K, Takeda K, Okabe T, Swanson J, Itoh H, Takada M, Lifshits E, Okuno K, Engelman JA, Shivdasani RA, Nishio K, Fukuoka M, Varella-Garcia M, Nakagawa K, Janne PA. Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab. Sci Transl Med. 2011;3(99):99ra86.

  25. Bertotti A, Migliardi G, Galimi F, Sassi F, Torti D, Isella C, Cora D, Di Nicolantonio F, Buscarino M, Petti C, Ribero D, Russolillo N, Muratore A, Massucco P, Pisacane A, Molinaro L, Valtorta E, Sartore-Bianchi A, Risio M, Capussotti L, Gambacorta M, Siena S, Medico E, Sapino A, Marsoni S, Comoglio PM, Bardelli A, Trusolino L. A molecularly annotated platform of patient-derived xenografts ("xenopatients") identifies HER2 as an effective therapeutic target in cetuximab-resistant colorectal cancer. Cancer Discov. 2011(6):508-23.

  26. Way TD, Lin JK. Role of HER2/HER3 co-receptor in breast carcinogenesis. Future Oncol. 2005 1:6,841-9.

  27. Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, Sliwkowski MX, Stern HM. A central role for HER3 in HER2-amplified breast cancer: Implications for targeted therapy. Cancer Res. 2008 Jul 15;68(14):5878-87.

  28. Yan M, Schwaederle M, Arguello D, Millis SZ, Gatalica Z, Kurzrock R. HER2 expression status in diverse cancers: Review of results from 37,992 patients. Cancer Metastasis Rev. 2015;34(1):157-64.

  29. AACR Project Genie Consortium. AACR Project GENIE: Powering precision medicine through an international consortium. Cancer Discov. 2017;7(8):818-31.

  30. Burstein HJ. The distinctive nature of HER2-positive breast cancers. N Engl J Med. 2005;353(16):1652-4.

  31. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177-82.

  32. Andrulis IL, Bull SB, Blackstein ME, Sutherland D, Mak C, Sidlofsky S, Pritzker KP, Hartwick RW, Hanna W, Lickley L, Wilkinson R, Qizilbash A, Ambus U, Lipa M, Weizel H, Katz A, Baida M, Mariz S, Stoik G, Dacamara P, Strongitharm D, Geddie W, McCready D. neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto breast cancer study group. J Clin Oncol. 1998;16(4):1340-9.

  33. Seshadri R, Firgaira F, Horsfall D, McCaul K, Setlur V, Kitchen P. Clinical significance of HER-2/neu oncogene amplification in primary breast cancer. The south Australian breast cancer study group. J Clin Oncol. 1993;11(10):1936-42.

  34. Gabos Z, Sinha R, Hanson J, Chauhan N, Hugh J, Mackey JR, Abdulkarim B. Prognostic significance of human epidermal growth factor receptor positivity for the development of brain metastasis after newly diagnosed breast cancer. J Clin Oncol. 2006;24(36):5658-63.

  35. Fendly BM, Winget M, Hudziak RM, Lipari MT, Napier MA, Ullrich A. Characterization of murine monoclonal antibodies reactive to either the human epidermal growth factor receptor or HER2/neu gene product. Cancer Res. 1990;50(5):1550-8.

  36. Shak S. Overview of the trastuzumab (Herceptin) ant-HER2 monoclonal antibody clinical program in HER2-overexpressing metastatic breast cancer. Herceptin multinational investigator study group. Semin Oncol. 1999;26(4 Suppl 12):71-7.

  37. Baselga J, Tripathy D, Mendelsohn J, Baughman S, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J, Rosen PP, Twaddell T, Henderson IC, Norton L. Phase II study of weekly intravenous recombinant humanized anti-p185HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer. J Clin Oncol. 1996;14(3):737-44.

  38. Pegram MD, Lipton A, Hayes DF, Weber BL, Baselga JM, Tripathy D, Baly D, Baughman SA, Twaddell T, Glaspy JA, Slamon DJ. Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic Breast cancer refractory to chemotherapy treatment. J Clin Oncol. 1998;16(8):2659-71.

  39. Pegram M, Hsu S, Lewis G, Pietras R, Beryt M, Sliwkowskiz M , Coombs D, Baly D, Kabbinavar F, Slamon D. Inhibitory effects of combinations of HER-2/neu antibody and chemotherapeutic agents used for treatment of human breast cancers. Oncogene. 1999;18:2241-51.

  40. Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol. 1999;17(9):2639-48.

  41. Balduzzi S, Mantarro S, Guarneri V, Tagliabue L, Pistotti V, Moja L, D'Amico R. Trastuzumab-containing regimens for metastatic breast cancer. Cochrane Database Syst Rev. 2014;2014(6):CD006242.

  42. Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-92.

  43. Marty M, Cognetti F, Maraninchi D, Snyder R, Mauriac L, Tubiana-Hulin M Chan S, Grimes D, Anton A, Lluch A, Kennedy J, O'Byrne K, Conte P, Green M, Ward C, Mayne K, Extra JM. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: The M77001 study group. J Clin Oncol. 2005;23(19):4265-74.

  44. Kaufman B, Mackey JR, Clemens MR, Bapsy PP, Vaid A, Wardley A, Tjulandin S, Jahn M, Lehle M, Feyereislova A, Revil C, Jones A. 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):5529-37.

  45. Huober J, Fasching PA, Barsoum M, Petruzelka L, Wall-wiener D, Thomssen C, Reimer T, Paepke S, Azim HA, Ragosch V, Kubista E, Baumgartner AK, Beckmann MW, May C, Nimmrich I, Harbeck N. Higher efficacy of letrozole in combination with trastuzumab compared to letrozole mono-therapy 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.

  46. Gasparini G, Gion M, Mariani L, Papaldo P, Crivellari D, Filippelli G, Morabito A, Silingardi V, Torino F, Spada A, Zancan M, De Sio L, Caputo A, Cognetti F, Lambiase A, Amadori D. Randomized phase II trial of weekly paclitaxel alone versus trastuzumab plus weekly paclitaxel as first-line therapy of patients with Her-2 positive advanced breast cancer. Breast Cancer Res Treat. 2007;101(3):355-65.

  47. Blackwell KL, Burstein HJ, Storniolo AM, Rugo H, Sledge G, Koehler M, Ellis C, Casey M, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-refractory metastatic breast cancer. J Clin Oncol. 2010;28(7):1124-30.

  48. von Minckwitz G, du Bois A, Schmidt M, Maass N, Cufer T, de Jongh FE, Maartense E, Zielinski C, Kaufmann M, Bauer W, Baumann KH, Clemens MR, Duerr R, Uleer C, Andersson M, Stein RC, Nekljudova V, Loibl S. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: A german breast group 26/breast international group 03-05 study. J Clin Oncol. 2009;27(12):1999-2006.

  49. Perez EA, Romond EH, Suman VJ, Jeong JH, Davidson NE, Geyer CE Jr, Martino S, Mamounas EP, Kaufman PA, Wolmark N. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol. 2011;29(25):3366-73.

  50. Chen L, Zhou W, Hu X, Yi M, Ye C, Yao G. Short-duration versus 1-year adjuvant trastuzumab in early HER2 positive breast cancer: A meta-analysis of randomized controlled trials. Cancer Treat Rev. 2019;75:12-9.

  51. Pivot X, Romieu G, Debled M, Pierga JY, Kerbrat P, Bachelot T, Lortholary A, Espie M, Fumoleau P, Serin D, Jacquin JP, Jouannaud C, Rios M, Abadie-Lacourtoisie S, Tubiana-Mathieu N, Cany L, Catala S, Khayat D, Pauporte I, Kramar A. 6 months versus 12 months of adjuvant trastuzumab for patients with HER2-positive early breast cancer (PHARE): A randomised phase 3 trial. Lancet Oncol. 2013;14(8):741-8.

  52. Pivot X, Romieu G, Debled M, Pierga JY, Kerbrat P, Bachelot T, Lortholary A, Espie M, Fumoleau P, Serin D, Jacquin JP, Jouannaud C, Rios M, Abadie-Lacourtoisie S, Venat-Bouvet L, Cany L, Catala S, Khayat D, Gambotti L, Pauporte I, Faure-Mercier C, Paget-Bailly S, Henriques J, Grouin JM; PHARE trial investigators. 6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): Final analysis of a multicentre, open-label, phase 3 randomised trial. Lancet. 2019;393(10191):2591-8.

  53. Perez EA, Romond EH, Suman VJ, Jeong JH, Sledge G, Geyer CE Jr, Martino S, Rastogi P, Gralow J, Swain SM, Winer EP, Colon-Otero G, Davidson NE, Mamounas E, Zujewski JA, Wolmark N. Trastuzumab plus adjuvant chemotherapy for human epidermal growth factor receptor 2-positive breast cancer: Planned joint analysis of overall survival from NSABP B-31 and NCCTG N9831. J Clin Oncol. 2014;32(33):3744-52.

  54. Moja L, Tagliabue L, Balduzzi S, Parmelli E, Pistotti V, Guarneri V, D'Amico R. Trastuzumab containing regimens for early breast cancer. Cochrane Database Syst Rev. 2012;2012(4):CD006243.

  55. Fujimoto-Ouchi K, Sekiguchi F, Yasuno H, Moriya Y, Mori K, Tanaka Y. Antitumor activity of trastuzumab in combination with chemotherapy in human gastric cancer xenograft models. Cancer Chemother Pharmacol. 2007;59(6):795-805.

  56. Gong SJ, Jin CJ, Rha SY, Chung HC. Growth inhibitory effects of trastuzumab and chemotherapeutic drugs in gastric cancer cell lines. Cancer Lett. 2004;214(2):215-24.

  57. Cortes-Funes H, Rivera F, Ales I, Marquez A, Velasco A, Colomer R, Garcia-Carbonero R, Sastre J, Guerra J, Gravalos C. Phase II of trastuzumab and cisplatin in patients (pts) with advanced gastric cancer (AGC) with HER2/neu overexpression/amplification. J Clin Oncol. 2007 Jun;25(18 Suppl):4613.

  58. Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687-97. Erratum in: Lancet. 2010;376(9749):1302.

  59. Adams CW, Allison DE, Flagella K, Presta L, Clarke J, Dybdal N, McKeever K, Sliwkowski MX. Humanization of a recombinant monoclonal antibody to produce a therapeutic HER dimerization inhibitor, pertuzumab. Cancer Immunol Immunother. 2006;55(6):717-27.

  60. Agus DB, Akita RW, Fox WD, Lewis GD, Higgins B, Pisacane PI, Lofgren JA, Tindell C, Evans DP, Maiese K, Scher HI, Sliwkowski MX. Targeting ligand-activated ErbB2 signaling inhibits breast and prostate tumor growth. Cancer Cell. 2002;2(2):127-37.

  61. Musolino A, Naldi N, Bortesi B, Pezzuolo D, Capelletti M, Missale G, Laccabue D, Zerbini A, Camisa R, Bisagni G, Neri TM, Ardizzoni A. Immunoglobulin G fragment C receptor polymorphisms and clinical efficacy of trastuzumab-based therapy in patients with HER-2/ neupositive metastatic breast cancer. J Clin Oncol. 2008;26(11):1789-96.

  62. Faratian D, Zweemer AJ, Nagumo Y, Sims AH, Muir M, Dodds M, Mullen P, Um I, Kay C, Hasmann M, Harrison DJ, Langdon SP. Trastuzumab and pertuzumab produce changes in morphology and estrogen receptor signaling in ovarian cancer xenografts revealing new treatment strategies. Clin Cancer Res. 2011;17(13):4451-61.

  63. Pohl M, Stricker I, Schoeneck A, Schulmann K, Klein-Scory S, Schwarte-Waldhoff I, Hasmann M, Tannapfel A, Schmiegel W, Reinacher-Schick A. Antitumor activity of the HER2 dimerization inhibitor pertuzumab on human colon cancer cells in vitro and in vivo. J Cancer Res Clin Oncol. 2009;135(10):1377-86.

  64. Yamashita-Kashima Y, Iijima S, Yorozu K, Furugaki K, Kurasawa M, Ohta M, Fujimoto-Ouchi K. Pertuzumab in combination with trastuzumab shows significantly enhanced antitumor activity in HER2-positive human gastric cancer xenograft models. Clin Cancer Res. 2011;17(15):5060-70.

  65. Swain SM, Baselga J, Kim SB, Ro J, Semiglazov V, Campone M, Ciruelos E, Ferrero JM, Schneeweiss A, Heeson S, Clark E, Ross G, Benyunes MC, Cortes J; CLEOPATRA Study Group. Pertuzumab, trastuzumab, and docetaxel in HER2-positive metastatic breast cancer. N Engl J Med. 2015;372(8):724-34.

  66. Amiri-Kordestani L, Wedam S, Zhang L, Tang S, Tilley A, Ibrahim A, Justice R, Pazdur R, Cortazar P. First FDA approval of neoadjuvant therapy for breast cancer: Pertuzumab for the treatment of patients with HER2-positive breast cancer. Clin Cancer Res. 2014;20(21):5359-64.

  67. Gianni L, Pienkowski T, Im YH, Roman L, Tseng LM, Liu MC, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im SA, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi G, Szado T, Ratnayake J, Ross G, Valagussa P. Efficacy and safety of neoadjuvant pertuzumab and trastuzumab in women with locally advanced, inflammatory, or early HER2-positive breast cancer (Neo-Sphere): A randomised multicentre, open-label, phase 2 trial. Lancet Oncol. 2012;13(1):25-32.

  68. Gianni L, Pienkowski T, Im Y-H, Tseng L-M, Liu M-C, Lluch A, Staroslawska E, de la Haba-Rodriguez J, Im S-A, Pedrini JL, Poirier B, Morandi P, Semiglazov V, Srimuninnimit V, Bianchi GV, McNally V, Douthwaite H, Ross G, Valagussa P. Five-year analysis of the phase II NeoSphere trial evaluating four cycles of neoadjuvant docetaxel (D) and/or trastuzumab (T) and/or pertuzumab (P) [Abstract]. J Clin Oncol. 2015;30(15 Suppl):505.

  69. Schneeweiss A, Chia S, Hickish T, Harvey V, Eniu A, Hegg R, Tausch C, Seo JH, Tsai YF, Ratnayake J, McNally V, Ross G, Cortes J. Pertuzumab plus trastuzumab in combination with standard neoadjuvant anthracycline-containing and anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: A randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278-84.

  70. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, Suter T, Arahmani A, Rouchet N, Clark E, Knott A, Lang I, Levy C, Yardley DA, Bines J, Gelber RD, Piccart M, Baselga J; APHINITY Steering Committee and Investigators. Adjuvant pertuzumab and trastuzumab in early HER2-positive breast cancer. N Engl J Med. 2017;377(2): 122-31. Errata in: N Engl J Med. 2017;377(7):702; N Engl J Med. 2018;379(16):1585.

  71. Verma S, Miles D, Gianni L, Krop IE, Welslau M, Baselga J, Pegram M, Oh DY, Dieras V, Guardino E, Fang L, Lu MW, Olsen S, Blackwell K, EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367(19):1783-91.

  72. von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schnee-weiss A, Redondo A, Fischer HH, Jacot W, Conlin AK, Arce-Salinas C, Wapnir IL, Jackisch C, DiGiovanna MP, Fasching PA, Crown JP, Wulfing P, Shao Z, Rota Caremoli E, Wu H, Lam LH, Tesarowski D, Smitt M, Douthwaite H, Singel SM, Geyer CE Jr. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380(7):617-28.

  73. Spector NL, Blackwell KL. Understanding the mechanisms behind trastuzumab therapy for human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2009;27(34):5838-47.

  74. Tse C, Gauchez AS, Jacot W, Lamy PJ. HER2 shedding and serum HER2 extracellular domain: Biology and clinical utility in breast cancer. Cancer Treat Rev. 2012;38(2):133-42.

  75. Scaltriti M, Rojo F, Ocana A, Anido J, Guzman M, Cortes J, Di Cosimo S, Matias-Guiu X, Ramon y Cajal S, Arribas J, Baselga J. Expression of p95HER2, a truncated form of the HER2 receptor, and response to anti-HER2 therapies in breast cancer. J Natl Cancer Inst. 2007;99(8):628-38.

  76. Chumsri S, Sperinde J, Liu H, Gligorov J, Spano JP, Antoine M, Moreno Aspitia A, Tan W, Winslow J, Petropoulos CJ, Chenna A, Bates M, Weidler JM, Huang W, Dueck A, Perez EA. High p95HER2/HER2 ratio associated with poor outcome in trastuzumab-treated HER2-positive metastatic breast cancer NCCTG N0337 and NCCTG 98-32-52 (Alliance). Clin Cancer Res. 2018;24(13):3053-8.

  77. Anido J, Scaltriti M, Bech Serra JJ, Santiago Josefat B, Todo FR, Baselga J, Arribas J. Biosynthesis of tumorigenic HER2 C-terminal fragments by alternative initiation of translation. EMBO J. 2006;25(13):3234-44.

  78. Pedersen K, Angelini PD, Laos S, Bach-Faig A, Cunning-ham MP, Ferrer-Ramon C, Luque-Garcia A, Garcia-Castillo J, Parra-Palau JL, Scaltriti M, Ramon y Cajal S, Baselga J, Arribas J. A naturally occurring HER2 carboxy-terminal fragment promotes mammary tumor growth and metastasis. Mol Cell Biol. 2009;29(12):3319-31.

  79. Parra-Palau JL, Pedersen K, Peg V, Scaltriti M, Angelini PD, Escorihuela M, Mancilla S, Sanchez Pla A, Ramon Y Cajal S, Baselga J, Arribas J. A major role of p95/611-CTF, a carboxy-terminal fragment of HER2, in the down-modulation of the estrogen receptor in HER2-positive breast cancers. Cancer Res. 2010;70(21):8537-46.

  80. Sasso M, Bianchi F, Ciravolo V, Tagliabue E, Campiglio M. HER2 splice variants and their relevance in breast cancer. J Nucleic Acids Investig. 2011;2(1):e9.

  81. Doherty JK, Bond C, Jardim A, Adelman JP, Clinton GM. The HER-2/neu receptor tyrosine kinase gene encodes a secreted autoinhibitor. Proc Natl Acad Sci U S A. 1999;96(19):10869-74.

  82. Castagnoli L, Ladomery M, Tagliabue E, Pupa SM. The d16HER2 splice variant: A friend or foe of HER2-positive cancers? Cancers. 2019;11(7):902.

  83. Zhang S, Huang WC, Li P, Guo H, Poh SB, Brady SW, Xiong Y, Tseng LM, Li SH, Ding Z, Sahin AA, Esteva FJ, Hortobagyi GN, Yu D. Combating trastuzumab resistance by targeting SRC, a common node downstream of multiple resistance pathways. Nat Med. 2011;17(4):461-9.

  84. Mitra D, Brumlik MJ, Okamgba SU, Zhu Y, Duplessis TT, Parvani JG, Lesko SM, Brogi E, Jones FE. An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance. Mol Cancer Ther. 2009;8(8):2152-62.

  85. Jackson C, Browell D, Gautrey H, Tyson-Capper A. Clinical significance of HER-2 splice variants in breast cancer progression and drug resistance. Int J Cell Biol. 2013;2013:973584.

  86. Nahta R, Esteva FJ. Molecular mechanisms of trastuzumab resistance. Breast Cancer Res. 2006;8(6):667-74.

  87. Zhuang G, Brantley-Sieders DM, Vaught D, Yu J, Xie L, Wells S, Jackson D, Muraoka-Cook R, Arteaga C, Chen J. Elevation of receptor tyrosine kinase EphA2 mediates resistance to trastuzumab therapy. Cancer Res. 2010;70(1):299-308.

  88. Shattuck DL, Miller JK, Carraway KL, Sweeney C. Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells. Cancer Res. 2008;68(5):1471-7.

  89. Fujita N, Sato S, Katayama K, Tsuruo T. Akt-dependent phosphorylation of p27Kip1promotes binding to 14-3-3 and cytoplasmic localization. J Biol Chem. 2002;277(32): 28706-13.

  90. She QB, Solit DB, Ye Q, O'Reilly KE, Lobo J, Rosen N. The BAD protein integrates survival signaling by EGFR/ MAPK and PI3K/Akt kinase pathways in PTEN-deficient tumor cells. Cancer Cell. 2005;8(4):287-97.

  91. Burgering BM, Medema RH. Decisions on life and death: FOXO Forkhead transcription factors are in command when PKB/Akt is off duty. J Leukoc Biol. 2003;73(6):689-701.

  92. Tzivion G, Dobson M, Ramakrishnan G. FoxO transcrip-tion factors; Regulation by AKT and 14-3-3 proteins. Bio-chim Biophys Acta. 2011;1813(11):1938-45.

  93. Vogt PK, Kang S, Elsliger MA, Gymnopoulos M. Cancer-specific mutations in phosphatidylinositol 3-kinase. Trends Biochem Sci. 2007;32(7):342-9.

  94. Berns K, Horlings HM, Hennessy BT, Madiredjo M, Hijmans EM, Beelen K, Linn SC, Gonzalez-Angulo AM, Stemke-Hale K, Hauptmann M, Beijersbergen RL, Mills GB, van de Vijver MJ, Bernards R. A functional genetic approach identifies the PI3K pathway as a major deter-minant of trastuzumab resistance in breast cancer. Cancer Cell. 2007;12(4):395-402.

  95. Liang K, Esteva FJ, Albarracin C, Stemke-Hale K, Lu Y, Bianchini G, Yang CY, Li Y, Li X, Chen CT, Mills GB, Hortobagyi GN, Mendelsohn J, Hung MC, Fan Z. Recombinant human erythropoietin antagonizes trastuzumab treatment of breast cancer cells via Jak2-mediated Src activation and PTEN inactivation. Cancer Cell. 2010;18(5):423-35.

  96. Razis E, Bobos M, Kotoula V, Eleftheraki AG, Kalofonos HP, Pavlakis K, Papakostas P, Aravantinos G, Rigakos G, Efstratiou I, Petraki K, Bafaloukos D, Kostopoulos I, Pectasides D, Kalogeras KT, Skarlos D, Fountzilas G. Evaluation of the association of PIK3CA mutations and PTEN loss with efficacy of trastuzumab therapy in metastatic breast cancer. Breast Cancer Res Treat. 2011;128(2):447-56.

  97. Liang J, Slingerland JM. Multiple roles of the PI3K/ PKB (Akt) pathway in cell cycle progression. Cell Cycle. 2003;2(4):336-42.

  98. Campbell CI, Petrik JJ, Moorehead RA. ErbB2 enhances mammary tumorigenesis, oncogene-ndependent recurrence and metastasis in a model of IGF-IR-mediated mammary tumorigenesis. Mol Cancer. 2010;9(1):235.

  99. Wu G, Mambo E, Guo Z, Hu S, Huang X, Gollin SM, Trink B, Ladenson PW, Sidransky D, Xing M. Uncommon mutation, but common amplifications, of the PIK3CA gene in thyroid tumors. J Clin Endocrinol Metab. 2005;90(8):4688-93.

  100. Ritter CA, Perez-Torres M, Rinehart C, Guix M, Dugger T, Engelman JA, 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. 2007;13(16):4909-19.

  101. Palyi-Krekk Z, Barok M, Isola J, Tammi M, Szollo J, Nagy P. Hyaluronan-induced masking of ErbB2 and CD44-enhanced trastuzumab internalisation in trastuzumab resistant breast cancer. Eur J Cancer. 2007;43(16):2423-33.

  102. Nam KH, Noh TW, Chung SH, Lee SH, Lee MK, Hong SW, Chung WY, Lee EJ, Park CS. Expression of the membrane mucins MUC4 and MUC15, potential markers of malignancy and prognosis, in papillary thyroid carcinoma. Thyroid. 2011;21(7):745-50.

  103. Bruyere E, Jonckheere N, Frenois F, Mariette C, Van Seuningen I. The MUC4 membrane-bound mucin regulates esophageal cancer cell proliferation and migration properties: Implication for S100A4 protein. Biochem Biophys Res Commun. 2011;413(2):325-9.

  104. Kargi A, Dinf ZA, Basok O, Ufvet A. MUC4 expression and its relation to ErbB2 expression, apoptosis, proliferation, differentiation, and tumor stage in non-small cell lung cancer (NSCLC). Pathol Res Pract. 2006;202(8): 577-83.

  105. Srivastava SK, Bhardwaj A, Singh S, Arora S, Wang B, Grizzle WE, Singh AP. MicroRNA-150 directly targets MUC4 and suppresses growth and malignant behavior of pancreatic cancer cells. Carcinogenesis. 2011;32(12):1832-9.

  106. Carraway KL, Perez A, Idris N, Jepson S, Arango M, Komatsu M, Haq B, Price-Schiavi SA, Zhang J, Carraway CA. Muc4/sialomucin complex, the intramembrane ErbB2 ligand, in cancer and epithelia: To protect and to survive. Prog Nucleic Acid Res Mol Biol. 2002;71:149-85.

  107. Li G, Zhao L, Li W, Fan K, Qian W, Hou S, Wang H, Dai J, Wei H, Guo Y. Feedback activation of STAT3 mediates trastuzumab resistance via upregulation of MUC1 and MUC4 expression. Oncotarget. 2014;5(18):8317-29.

  108. Workman HC, Miller JK, Ingalla EQ, Kaur RP, Yamamoto DI, Beckett LA, Young LJ, Cardiff RD, Borowsky AD, Carraway KL, Sweeney C, Carraway KL 3rd. The membrane mucin MUC4 is elevated in breast tumor lymph node metastases relative to matched primary tumors and confers aggressive properties to breast cancer cells. Breast Cancer Res. 2009;11(5):R70.

  109. Price-Schiavi SA, Jepson S, Li P, Arango M, Rudland PS, Yee L, Carraway KL. Rat Muc4 (sialomucin complex) reduces binding of anti-ErbB2 antibodies to tumor cell surfaces, a potential mechanism for herceptin resistance. Int J Cancer. 2002;99(6):783-91.

  110. Akiyama T, Matsuda S, Namba Y, Saito T, Toyoshima K, Yamamoto T. The transforming potential of the c-erbB-2 protein is regulated by its autophosphorylation at the carboxyl-terminal domain. Mol Cell Biol. 1991;11(2):833-42.

  111. Nagy P, Friedlander E, Tanner M, Kapanen AI, Carraway KL, Isola J, Jovin TM. Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a Herceptin-resistant, MUC4-expressing breast cancer cell line. Cancer Res. 2005;65(2):473-82.

  112. Nahta R. Molecular mechanisms of trastuzumab-based treatment in HER2-overexpressing breast cancer. ISRN Oncol. 2012;2012.428062.

  113. Nahta R, Yuan LX, Zhang B, Kobayashi R, Esteva FJ. Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells. Cancer Res. 2005;65(23):11118-28.

  114. Lu Y, Zi X, Zhao Y, Mascarenhas D, Pollak M. Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin). J Natl Cancer Inst. 2001;93(24):1852-7.

  115. Gallardo A, Lerma E, Escuin D, Tibau A, Munoz J, Ojeda B, Barnadas A, Adrover E, Sanchez-Tejada L, Giner D, Ortiz-Martinez F, Peiro G. Increased signalling of EGFR and IGF1R, and deregulation of PTEN/PI3K/Akt pathway are related with trastuzumab resistance in HER2 breast carcinomas. Br J Cancer. 2012;106(8):1367-73.

  116. Minuti G, Cappuzzo F, Duchnowska R, Jassem J, Fabi A, O'Brien T, Mendoza AD, Landi L, Biernat W, Czartoryska-Arlukowicz B, Jankowski T, Zuziak D, Zok J, Szostakiewicz B, Foszczynska-Kloda M, Tempinska-Szalach A, Rossi E, Varella-Garcia M. Increased MET and HGF gene copy numbers are associated with trastuzumab failure in HER2-positive metastatic breast cancer. Br J Cancer. 2012;107(5):793-9.

  117. Bootcov MR, Bauskin AR, Valenzuela SM, Moore AG, Bansal M, He XY, Zhang HP, Donnellan M, Mahler S, Pryor K, Walsh BJ, Nicholson RC, Fairlie WD, Por SB, Robbins JM, Breit SN. MIC-1, a novel macrophage inhibitory cytokine, is a divergent member of the TGF-beta super-family. Proc Natl Acad Sci U S A. 1997;94(21):11514-9.

  118. Joshi JP, Brown NE, Griner SE, Nahta R. Growth differentiation factor 15 (GDF15)-mediated HER2 phosphorylation reduces trastuzumab sensitivity of HER2-overexpressing breast cancer cells. Biochem Pharmacol. 2011;82(9):1090-9.

  119. Kim KK, Lee JJ, Yang Y, You KH, Lee JH. Macrophage inhibitory cytokine-1 activates AKT and ERK-1/2 via the transactivation of ErbB2 in human breast and gastric cancer cells. Carcinogenesis. 2008;29(4):704-12.

  120. Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med. 2000;6(4):443-6.

  121. Gennari R, Menard S, Fagnoni F, Ponchio L, Scelsi M, Tagliabue E, Castiglioni F, Villani L, Magalotti C, Gibelli N, Oliviero B, Ballardini B, Da Prada G, Zambelli A, Costa A. Pilot study of the mechanism of action of preoperative trastuzumab in patients with primary operable breast tumors overexpressing HER2. Clin Cancer Res. 2004;10(17):5650-5.

  122. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, Brown DN, Kellokumpu-Lehtinen PL, Bono P, Kataja V, Desmedt C, Piccart-Gebhart MJ, Loibl S, Untch M, Denkert C, Smyth MJ, Joensuu H, Sotiriou C. Tumor infiltrating lymphocytes (TILs) indicate trastuzumab benefit in early-stage HER2-positive breast cancer (HER2+ BC) [Abstract]. Cancer Res. 2013;73(24 Suppl):S1-05.

  123. Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, Kellokumpu-Lehtinen PL, Bono P, Kataja V, Desmedt C, Piccart MJ, Loibl S, Denkert C, Smyth MJ, Joensuu H, Sotiriou C. Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: Results from the FinHER trial. Ann Oncol. 2014;25(8):1544-50.

  124. Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, Martino S, Wang M, Jones VE, Saphner TJ, Wolff AC, Wood WC, Davidson NE, Sledge GW, Sparano JA, Badve SS. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014; 32(27):2959-66.

  125. Stein MN, Shin J, Gudzowaty O, Bernstein AM, Liu JM. Antibody-dependent cell cytotoxicity to breast cancer targets despite inhibitory KIR signaling. Anticancer Res. 2006;26(3A):1759-63.

  126. Trotta R, Dal Col J, Yu J, Ciarlariello D, Thomas B, Zhang X, Allard J 2nd, Wei M, Mao H, Byrd JC, Perrotti D, Caligiuri MA. TGF-beta utilizes SMAD3 to inhibit CD16-mediated IFN-gamma production and antibody-dependent cellular cytotoxicity in human NK cells. J Immunol. 2008;181(6):3784-92.

  127. Barok M, Tanner M, Koninki K, Isola J. Trastuzumab-DM1 is highly effective in preclinical models of HER2-positive gastric cancer. Cancer Lett. 2011;306(2):171-9.

  128. Tan X, Jin G, Myers J, Diesl V, Follettie M, Lam MH, Musto S, Khandke K, Charati M, Graziani E, Maderna A, Subramanyam C, Koehn F, Dushin R, Arndt K, O'Donnell CJ, Gerber HP, Loganzo F. Tumor cells selected for resistance to an antibody-drug conjugate retain sensitivity to ADCs with modified linkers and payloads. Cancer Res. 2013;73(8 Suppl):4629.

  129. Li G, Fields C, Parsons K, Guo J, Phillips GL. 223 trastuzumab-DM1: Mechanisms of action and mechanisms of resistance. Eur J Cancer Suppl. 2010;8(7):73.

  130. Baselga J, Lewis Phillips GD, Verma S, Ro J, Huober J, Guardino AE, Samant MK, Olsen S, de Haas SL, Pegram MD. Relationship between tumor biomarkers and efficacy in EMILIA, a phase III study of trastuzumab emtansine in HER2-positive metastatic breast cancer. Clin Cancer Res. 2016;22(15):3755-63. Erratum in: Clin Cancer Res. 2018;24(21):5486.

  131. Kim SB, Wildiers H, Krop IE, Smitt M, Yu R, Lysbet de Haas S, Gonzalez-Martin A. Relationship between tumor biomarkers and efficacy in TH3RESA, a phase III study of trastuzumab emtansine (T-DM1) vs. treatment of physician's choice in previously treated HER2-positive advanced breast cancer. Int J Cancer. 2016;139(10):2336-42.

  132. Burris HA 3rd, Rugo HS, Vukelja SJ, Vogel CL, Borson RA, Limentani S, Tan-Chiu E, Krop IE, Michaelson RA, Girish S, Amler L, Zheng M, Chu YW, Klencke B, O'Shaughnessy JA. 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. 2011;29(4):398-405.

  133. Yu SF, Zheng B, Go M, Lau J, Spencer S, Raab H, Soriano R, Jhunjhunwala S, Cohen R, Caruso M, Polakis P, Flygare J, Polson AG. A novel anti-CD22 anthracycline-based antibody-drug conjugate (ADC) that overcomes resistance to auristatin-based ADCs. Clin Cancer Res. 20155;21(14):3298-306.

  134. Chen R, Hou J, Newman E, Kim Y, Donohue C, Liu X, Thomas SH, Forman SJ, Kane SE. CD30 downregulation, MMAE resistance, and MDR1 upregulation are all associated with resistance to brentuximab vedotin. Mol Cancer Ther. 2015;14(6):1376-84.

  135. Li G, Guo J, Shen BQ, Yadav DB, Sliwkowski MX, Crocker LM, Lacap JA, Phillips GDL. Mechanisms of acquired resistance to trastuzumab emtansine in breast cancer cells. Mol Cancer Ther. 2018;17(7):1441-53.

  136. Sung M, Tan X, Lu B, Golas J, Hosselet C, Wang F, Tylaska L, King L, Zhou D, Dushin R, Myers JS, Rosfjord E, Lucas J, Gerber HP, Loganzo F. Caveolae-mediated endocytosis as a novel mechanism of resistance to trastuzumab emtansine (T-DM1). Mol Cancer Ther. 2018;17(1):243-53.

  137. Wang H, Wang W, Xu Y, Yang Y, Chen X, Quan H, Lou L. Aberrant intracellular metabolism of T-DM1 confers T-DM1 resistance in human epidermal growth factor receptor 2-positive gastric cancer cells. Cancer Sci. 2017;108(7):1458-1468.

  138. Rios-Luci C, Garcia-Alonso S, Diaz-Rodriguez E, Nadal-Serrano M, Arribas J, Ocana A, Pandiella A. Resistance to the antibody-drug conjugate T-DM1 is based in a reduction in lysosomal proteolytic activity. Cancer Res. 2017;77(17):4639-51.

  139. Hamblett KJ, Jacob AP, Gurgel JL, Tometsko ME, Rock BM, Patel SK, Milburn RR, Siu S, Ragan SP, Rock DA, Borths CJ, O'Neill JW, Chang WS, Weidner MF, Bio MM, Quon KC, Fanslow WC. SLC46A3 is required to transport catabolites of noncleavable antibody maytansine conjugates from the lysosome to the cytoplasm. Cancer Res. 2015;75(24):5329-40.

  140. Sabbaghi M, Gil-Gomez G, Guardia C, Servitja S, Arpi O, Garcia-Alonso S, Menendez S, Arumi-Uria M, Serrano L, Salido M, Muntasell A, Martinez-Garcia M, Zazo S, Chamizo C, Gonzalez-Alonso P, Madoz-Gurpide J, Eroles P, Arribas J, Tusquets I, Lluch A, Pandiella A, Rojo F, Rovira A, Albanell J. Defective cyclin B1 induction in trastuzumab-emtansine (T-DM1) acquired resistance in HER2-positive breast cancer. Clin Cancer Res. 2017;23(22):7006-19.

  141. Saatci O, Borgoni S, Akbulut O, Durmus S, Raza U, Eyupoglu E, Alkan C, Akyol A, Kutuk O, Wiemann S, Sahin O. Targeting PLK1 overcomes T-DM1 resistance via CDK1-dependent phosphorylation and inactivation of Bcl-2/xL in HER2-positive breast cancer. Oncogene. 2018;37(17):2251-69.

  142. Ogitani Y, Aida T, Hagihara K, Yamaguchi J, Ishii C, Harada N, Soma M, Okamoto H, Oitate M, Arakawa S, Hirai T, Atsumi R, Nakada T, Hayakawa I, Abe Y, Agatsuma T. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res. 2016;22(20):5097-108.

  143. Tamura K, Shitara K, Naito Y, Shimomura A, Fujiwara Y, Yonemori K, Shimizu C, Shimoi T, Kuboki Y, Matsubara N, Kitano A, Jikoh T, Fujisaki Y, Yver A, Doi T. Show less. Single agent activity of DS-8201a, a HER2-targeting anti-body-drug conjugate, in breast cancer patients previously treated with T-DM1: Phase 1 dose escalation. Ann Oncol. 2016;27(Suppl 6):vi552-87.

  144. Modi S, Tsurutani J, Tamura K, Park H, Sagara Y, Murthy R, Iwata H, Krop IE, Doi T, Redfern C, Moreno-Aspitia A, Redman R, Lee C, Sugihara M, Fujisaki Y, Takahashi S. Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-low expressing breast cancer: Updated results of a large phase 1 study [Abstract]. Cancer Res. 2019;79(4 Suppl):P6-17.

  145. Iwata H, Tamura K, Doi T, Tsurutani J, Modi S, Park H, Krop IE, Sagara Y, Redfern CH, Murthy RK, Redman RA, Shitara K, Fujisaki Y, Sugihara M, Zhang L, Shahidi J, Yver A, Takahashi S. Trastuzumab deruxtecan (DS-8201a) in subjects with HER2-expressing solid tumors: Long-term results of a large phase 1 study with multiple expansion cohorts. J Clin Oncol. 2018;36(15 Suppl):2501.

  146. Shitara K, Iwata H, Takahashi S, Tamura K, Park H, Modi S, Tsurutani J, Kadowaki S, Yamaguchi K, Iwasa S, Saito K, Fujisaki Y, Sugihara M, Shahidi J, Doi T. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive gastric cancer: A dose-expansion, phase 1 study. Lancet Oncol. 2019;20(6):827-36. Erratum in: Lancet Oncol. 2019;20(6):e293.

  147. Tamura K, Tsurutani J, Takahashi S, Iwata H, Krop IE, Redfern C, Sagara Y, Doi T, Park H, Murthy RK, Redman RA, Jikoh T, Lee C, Sugihara M, Shahidi J, Yver A, Modi S. Trastuzumab deruxtecan (DS-8201a) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab emtansine: A dose-expansion, phase 1 study. Lancet Oncol. 2019;20(6):816-26. Erratum in: Lancet Oncol. 2019;20(6):e293.

  148. Tamura K, Modi S, Tsurutani J, Takahashi S, Krop I, Iwata H, Wada R, Yin O, Garimella T, Sugihara M, Zhang L, Lee C, Yver A, Baselga J. Abstract P6-17-10: Dose justification for DS-8201a, a HER2-targeted antibody-drug conjugate, for HER2-positive breast cancer: Observed clinical data and exposure-response analyses [Abstract]. AACR Cancer Res. 2019;79(4 Suppl):P6-17-10.

  149. Dokter W, Ubink R, van der Lee M, van der Vleuten M, van Achterberg T, Jacobs D, Loosveld E, van den Dobbelsteen D, Egging D, Mattaar E, Groothuis P, Beusker P, Coumans R, Elgersma R, Menge W, Joosten J, Spijker H, Huijbregts T, de Groot V, Eppink M, de Roo G, Verheijden G, Timmers M. Preclinical profile of the HER2-targeting ADC SYD983/SYD985: Introduction of a new duocarmycin-based linker-drug platform. Mol Cancer Ther. 2014;13(11):2618-29.

  150. van der Lee MM, Groothuis PG, Ubink R, van der Vleuten MA, van Achterberg TA, Loosveld EM, Damming D, Jacobs DC, Rouwette M, Egging DF, van den Dobbelsteen D, Beusker PH, Goedings P, Verheijden GF, Lemmens JM, Timmers M, Dokter WH. The preclinical profile of the duocarmycin-based HER2-targeting ADC SYD985 predicts for clinical benefit in low HER2-expressing breast cancers. Mol Cancer Ther. 2015;14(3):692-703.

  151. Menderes G, Bonazzoli E, Bellone S, Black J, Altwerger G, Masserdotti A, Pettinella F, Zammataro L, Buza N, Hui P, Wong S, Litkouhi B, Ratner E, Silasi DA, Huang GS, Azodi M, Schwartz PE, Santin AD. SYD985, a novel duo-carmycin-based HER2-targeting antibody-drug conjugate, shows promising antitumor activity in epithelial ovarian carcinoma with HER2/Neu expression. Gynecol Oncol. 2017;146(1):179-86.

  152. Saura C, Thistlethwaite F, Banerji U, Lord S, Moreno V, MacPherson I, Boni V, Rolfo CD, de Vries EGE, Van Herpen CML, Rottey S, Geenen JJJ, Eskens F, Martin MG, Mommers E, Koper NP, Mulder R, Aftimos PG. A phase I expansion cohorts study of SYD985 in heavily pretreated patients with HER2-positive or HER2-low metastatic breast cancer. J Clin Oncol. 2018;36(15 Suppl):1014.

  153. Hamblett K, Barnscher S, Davies R, Hammond P, Hernandez A, Wickman G, Fung VK, Ding T, Garnett G, Galey AS, Zwierzchowski P, Clavette BC, Winters GC, Rich JR. Abstract P6-17-13: ZW49, a HER2 targeted bipara- topic antibody drug conjugate for the treatment of HER2 expressing cancers [Abstract]. Cancer Res. 2019;79(4 Suppl):P6-17-13.

  154. Hamblett KJ, Hammond PW, Barnscher SD, Fung VK, Davies RH, Wickman GR, Fung VK, Ding T, Garnett G, Galey AS, Zwierzchowski P, Clavette BC, Winters GC, Rich JR, Rowse GJ, Babcook JS, Hausman D. ZW49, a HER2-targeted biparatopic antibody-drug conjugate for the treatment of HER2-expressing cancers [Abstract]. Cancer Res. 2019;79(4 Suppl):P6-17-13.

  155. Li J, Toader D, Perry SR, Muniz-Medina V, Wetzel L, Rebelatto MC, Hinrichs MJM, Fleming R, Bezabeh B, Thompson P, Dimasi N, Lam B, Yu XQ, Gao C, Dixit R, Coats S, Osbourn J, Wu H. MEDI4276, a HER2-targeting antibody tubulysin conjugate, displays potent in vitro and in vivo activity in preclinical studies [Abstract]. Cancer Res. 2016;76(14 Suppl):2970.

  156. Pegram M, Hamilton E, Tan A, Storniolo A, Elgeioushi N, Marshall S, Abdullah S, Patel M. 47O phase 1 study of bispecific HER2 antibody-drug conjugate MEDI4276 in patients with advanced HER2-positive breast or gastric cancer [Abstract]. Ann Oncol. 2018;29(Suppl 3):mdy048.05.

  157. Rinnerthaler G, Gampenrieder SP, Greil R. HER2 directed antibody-drug-conjugates beyond T-DM1 in breast cancer. Int J Mol Sci. 2019;20(5):1115.

  158. Newman DJ. The "utility" of highly toxic marine-sourced compounds. Marine Drugs. 2019;17(6):324.

  159. Humphreys RC, Kirtely J, Hewit A, Biroc S, Knudsen N, Skidmore L, Wahl A. Site specific conjugation of ARX-788, an antibody drug conjugate (ADC) targeting HER2, generates a potent and stable targeted therapeutic for multiple cancers [Abstract]. Cancer Res. 2015;75(15 Suppl):639.

  160. Bergstrom DA, Bodyak N, Yurkovetskiy A, Park PU, De-Vit M, Yin M, Poling L, Thomas JD, Gumerov D, Xiao D, Ter-Ovanesyan E, Qin LL, Uttard A, Johnson A, Lowinger TB. Abstract LB-231: A novel, highly potent HER2-targeted antibody-drug conjugate (ADC) for the treatment of low HER2-expressing tumors and combination with trastuzumab-based regimens in HER2-driven tumors. Cancer Res. 2015;75(15 Suppl):LB-231.

  161. Yurkovetskiy A, Gumerov D, Ter-Ovanesyan E, Conlon P, Devit M, Bu C, Bodyak N, Lowinger T, Bergstrom D. Non-clinical pharmacokinetics of XMT-1522, a HER2 targeting auristatin-based antibody drug conjugate. Cancer Res. 2017;77(13 Suppl):48.

  162. Bergstrom D, Bodyak N, Park P, Yurkovetskiy A, DeVit M, Yin M, L Poling, Thomas JD, Gumerov D, Xiao D, Ter-Ovanesyan E, Qin L, Uttard A, Johnson A, Lowinger TB. Abstract P4-14-28 : XMT-1522 induces tumor regressions in pre-clinical models representing HER2-positive and HER2 low-expressing breast cancer. Cancer Res. 2017;77(13 Suppl):48.

  163. Le Joncour V, Martins A, Puhka M, Isola J, Salmikangas M, Laakkonen P, Joensuu H, Barok M. A novel anti-her2 antibody-drug conjugate XMT-1522 for HER2-positive breast and gastric cancers resistant to trastuzumab emtansine. Mol Cancer Ther. 2019;18(10):1721-30. doi: 10.1158/1535-7163.MCT-19-0207. Epub 2019 Jul 10. PMID: 31292166.

  164. Khattar M, Traore T, Horton K, Gallery M, Brauer P, Riceberg J, Bodyak N, Protopopova M, Zhang Q, Lowinger TB, Veiby P, Huszar D, Wang F. Synergy of an anti-HER2 ADC TAK-522 (XMT-1522) in combination with anti-PD1 monoclonal antibody (mAb) in a syngeneic breast cancer model expressing human HER2. Cancer Res. 2018;78.

  165. Hamilton EP, Barve MA, Bardia A, Beeram M, Bendell JC, Mosher R, Hailman E, Bergstrom DA, Burris HA, Soliman HH. Phase 1 dose escalation of XMT-1522, a novel HER2-targeting antibody-drug conjugate (ADC), in patients (pts) with HER2-expressing breast, lung and gastric tumors [Abstract]. J Clin Oncol. 2018;36(15 Suppl):2546.

  166. Yao X, Jiang J, Wang X, Huang C, Li D, Xie K, Xu Q, Li H, Li Z, Lou L, Fang J. A novel humanized anti-HER2 antibody conjugated with MMAE exerts potent anti-tumor activity. Breast Cancer Res Treat. 2015;153(1):123-33.

  167. Li H, Yu C, Jiang J, Huang C, Yao X, Xu Q, Yu F, Lou L, Fang J. An anti-HER2 antibody conjugated with monomethyl auristatin E is highly effective in HER2-positive human gastric cancer. Cancer Biol Ther. 2016;17(4):346-54.

  168. Gong J, Shen L, Wang W, Fang J. Safety, pharmacokinetics and efficacy of RC48-ADC in a phase I study in patients with HER2-overexpression advanced solid cancer [Abstract]. J Clin Oncol. 2018;36(15 Suppl):e16059.

  169. Wang J, Xu B, Wang W, Fang J. An open-label, dose-escalation phase I study to evaluate RC48-ADC, a novel antibody-drug conjugate, in patients with HER2-positive metastatic breast cancer. J Clin Oncol. 2018;36(15 Suppl):1030.

  170. Xu B, Wang J, Zhang Q, Liu Y, Feng JF, Wang W, Fang J. An open-label, multicenter, phase Ib study to evaluate RC48-ADC in patients with HER2-positive metastatic breast cancer [Abstract]. J Clin Oncol. 2018;36(15 Suppl):1030.

  171. Sheng X, Zhou AP, Yao X, Shi Y, Luo H, Shi B, Liu J, Yu G, He Z, Hu C, Han W, Fang J, Guo J. A phase II study of RC48-ADC in HER2-positive patients with locally advanced or metastatic urothelial carcinoma [Abstract]. J Clin Oncol. 2019;37(15 Suppl):4509.

  172. Aviles P, Dominguez JM, Guillen MJ, Munoz-Alonso MJ, Mateo C, Rodriguez-Acebes R, Molina-Guijarro JM, Francesch A, Martinez-Leal JF, Munt S, Galmarini CM, Cuevas C. MI130004, a Novel antibody-drug conjugate combining trastuzumab with a molecule of marine origin, shows outstanding in vivo activity against HER2-express- ing tumors. Mol Cancer Ther. 2018;17(4):786-94.

  173. Nordstrom JL, Gorlatov S, Zhang W, Yang Y, Huang L, Burke S, Li H, Ciccarone V, Zhang T, Stavenhagen J, Koenig S, Stewart SJ, Moore PA, Johnson S, Bonvini E. Anti-tumor activity and toxicokinetics analysis of MGAH22, an anti-HER2 monoclonal antibody with enhanced Fcy receptor binding properties. Breast Cancer Res. 2011;13(6):R123.

  174. Bang YJ, Giaccone G, Im SA, Oh DY, Bauer TM, Nord-strom JL, Li H, Chichili GR, Moore PA, Hong S, Stewart SJ, Baughman JE, Lechleider RJ, Burris HA. First-in-human phase 1 study of margetuximab (MGAH22), an Fc-modified chimeric monoclonal antibody, in patients with HER2-positive advanced solid tumors. Ann Oncol. 2017;28(4):855-61.

  175. Rugo HS, Im SA, Wright GLS, Escriva de Romani S, De-Laurentiis M, Cortes J, Bahadur SW, Haley BB, Oyola RH, Riseberg DA, Musolino A, Cardoso F, Curigliano G, Kaufman PA, Pegram MD, Edlich S, Hong S, Rock EP, Gradishar WJ. SOPHIA primary analysis: A phase 3 (P3) study of margetuximab (M)+ chemotherapy (C) versus trastuzumab (T)+ C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx) [Abstract]. J Clin Oncol. 2019;37(15 Suppl):1000.

  176. Meric-Bernstam F, Beeram M, Mayordomo JI, Hanna DL, Ajani JA, Blum Murphy MAB, Murthy RK, Piha-Paul SA, Bauer TM, Bendell JC, El-Khoueiry AB, Lenz HJ, Press MF, Royer N, Hausman DF, Hamilton EP. Single agent activity of ZW25, a HER2-targeted bispecific antibody, in heavily pretreated HER2-expressing cancers [Abstract]. J Clin Oncol. 2018;36(15 Suppl):2500.

  177. Hausman DF, Hamilton EP, Beeram M, Thimmarayappa J, Ng G, Meric-Bernstam F. Phase 1 study of ZW25, a bispecific anti-HER2 antibody, in patients with advanced HER2-expressing cancers [Abstract]. J Clin Oncol. 2018;36(15 Suppl):2500.

  178. Fiedler W, Stoeger H, Perotti A, Gastl G, Weidmann J, Dietrich B, Baumeister H, Danielczyk A, Goletz S, Salzberg M, De Dosso S. Phase I study of TrasGEX, a glyco-optimised anti-HER2 monoclonal antibody, in patients with HER2-positive solid tumours. ESMO Open. 2018;3(4):e000381.

  179. Ko BK, Lee SY, Lee YH, Hwang IS, Persson H, Rockberg J, Borrebaeck C, Park D, Kim KT, Uhlen M, Lee JS. Combination of novel HER2-targeting antibody 1E11 with trastuzumab shows synergistic antitumor activity in HER2-positive gastric cancer. Mol Oncol. 2015;9(2):398-408.

  180. Kim AY, Zer C, Williams JC, Press MF, Park JM. Novel murine anti-HER2 monoclonal antibodies to induce apoptosis and regulate miR-21 in breast cancer cell [Abstract]. J Clin Oncol. 2013;31(15 Suppl):3081.

  181. Ye X, Bai W, Zhu H, Zhang X, Chen Y, Wang L, Yang A, Zhao J, Jia L. MiR-221 promotes trastuzumab-resistance and metastasis in HER2-positive breast cancers by targeting PTEN. BMB Rep. 2014;47(5):268-73.

  182. Croset A, Macoin J, Ollier R, Pluess M, Delon C, Skegro D, et al. 139 GBR1302: A BEAT bispecific antibody for the treatment of HER2 positive cancers. Eur J Cancer. 2014;50:48.

  183. Back J, Wermke M, Macoin J, Croset A, Kauh JS, Reddy V. GBR 1302: Effect of CD3-HER2, a bispecific t cell engager antibody, in trastuzumab-resistant cancers. J Clin Oncol. 2018;36:12053.

  184. Wermke M, Schmidt H, Nolte H, Ochsenreither S, Back J, Salhi Y, Bayever E. A phase I study of the bispecific anti-body T-cell engager GBR 1302 in subjects with HER2-positive cancers. J Clin Oncol. 2017;35(15 Suppl):TPS3091.

  185. Wermke M, Alt J, KAUH J, Back J, Salhi Y, Reddy V, Bayever E, Ochsenreither S. Preliminary biomarker and pharmacodynamic data from a phase 1 study of single-agent bispecific antibody t cell engager gbr 1302 in subjects with her2-positive cancers [Abstract]. J Clin Oncol. 2018;36(5 Suppl):69.

  186. Hinner MJ, Aiba RSB, Jaquin TJ, Berger S, Durr MC, Schlosser C, Allersdorfer A, Wiedenmann A, Matschiner G, Schuler J, Moebius U, Rothe C, Matis L, Olwill SA. Tumor-localized costimulatory T-cell engagement by the 4-1BB/HER2 bispecific antibody-nticalin fusion PRS-343. Clin Cancer Res. 2019;25(19):5878-89.

  187. Li SY, Liu Y. Immunotherapy of melanoma with the immune costimulatory monoclonal antibodies targeting CD137. Clin Pharmacol. 2013;5(Suppl 1):47-53.

  188. Arribas J, Baselga J, Pedersen K, Parra-Palau JL. p95HER2 and breast cancer. Cancer Res. 2011;71(5):1515-9.

  189. Rius Ruiz I, Vicario R, Morancho B, Morales CB, Arenas EJ, Herter S, Freimoser-Grundschober A, Somandin J, Sam J, Ast O, Barriocanal AM, Luque A, Escorihuela M, Varela I, Cuartas I, Nuciforo P, Fasani R, Peg V, Rubio I, Cortes J, Serra V, Escriva-de-Romani S, Sperinde J, Chenna A, Huang W, Winslow J, Albanell J, Seoane J, Scaltriti M, Baselga J, Tabernero J, Umana P, Bacac M, Saura C, Klein C, Arribas J. p95HER2-T cell bispecific antibody for breast cancer treatment. Sci Transl Med. 2018;10(461):eaat1445.

  190. Liu J, Wu X, Lin L, Pan H, Wang Y, Li Y, Zhao Y, Wang Z. Bp-Bs, a novel T-cell engaging bispecific antibody with biparatopic Her2 binding, has potent anti-tumor activities. Mol Ther Oncolytics. 2019;14:66-73.

  191. Kiewe P, Thiel E. Ertumaxomab: A trifunctional antibody for breast cancer treatment. Expert Opin Investig Drugs. 2008;17(10):1553-8.

  192. Kiewe P, Hasmuller S, Kahlert S, Heinrigs M, Rack B, Marme A, Korfel A, Jager M, Lindhofer H, Sommer H, Thiel E, Untch M. Phase I trial of the trifunctional anti-HER2 x anti-CD3 antibody ertumaxomab in metastatic breast cancer. Clin Cancer Res. 2006;12(10):3085-91.

  193. Haense N, Atmaca A, Pauligk C, Steinmetz K, Marme F, Haag GM, Rieger M, Ottmann OG, Ruf P, Lindhofer H, Al-Batran SE. A phase I trial of the trifunctional anti Her2 x anti CD3 antibody ertumaxomab in patients with advanced solid tumors. BMC Cancer. 2016;16:420.

  194. Geuijen C, Rovers E, Nijhuis R, den Blanken-Smit R, Visser T, Bartelink W, Kramer A, Zondag-van der Zande V, Clements C, Kaldenberg L, Nieuwenhuizen N, van Loo PF, Roovers R, Gallenne T, Price L, Shamsili SVD, Bakker L, Logtenberg T, de Kruif J, Throsby M. Preclinical activity of MCLA-128, an ADCC enhanced bispecific IgG1 antibody targeting the HER2: HER3 heterodimer [Abstract]. J Clin Oncol. 2014;32(15 Suppl):560.

  195. Alsina M, Boni V, Schellens JH, Moreno V, Bol K, Westendorp M, Sirulnik LA, Tabernero J, Calvo E. First-in-human phase 1/2 study of MCLA-128, a full length IgG1 bispecific antibody targeting HER2 and HER3: Final phase 1 data and preliminary activity in HER2+ metastatic breast cancer (MBC) [Abstract]. J Clin Oncol. 2017;35(15 Suppl):2522.

  196. Alsina M, Varga A, Amatu A, Schellens J, Witteveen P, Boni V, Moreno V, Bol K, Lourbakos A, Magin Ferrer M, Wasserman E. 664P phase I/II study of single agent MCLA-128, a full length IgG1 bispecific antibody targeting the HER3 pathway: Overall safety at the recommended phase II dose (R2PD) and preliminary activity in HER2+ metastatic gastric/gastroesophageal junction cancer (GC/GEJ) [Abstract]. Ann Oncol. 2018;29(Suppl 8):mdy282.048.

  197. Huang S, Li F, Liu H, Ye P, Fan X, Yuan X, Wu Z, Chen J, Jin C, Shen B, Feng J, Zhang B. Structural and functional characterization of MBS301, an afucosylated bispecific anti-HER2 antibody. MAbs. 2018;10(6):864-75.

  198. Zhang B, Lahdenranta J, Du J, Kirouac D, Nguyen S, Overland R, Paragas V, Kudla A, Nielsen U, McDonagh C, Onsum M. MM-111, a bispecific HER2 and HER3 antibody, synergistically combines with trastuzumab and paclitaxel in preclinical models of gastric cancer [Abstract]. Cancer Res. 2013;73(8 Suppl):4633.

  199. Isakoff SJ, Engelman JA, Irie HY, Luo J, Brachmann SM, Pearline RV, Cantley LC, Brugge JS. Breast cancer-associated PIK3CA mutations are oncogenic in mammary epi-thelial cells. Cancer Res. 200;65(23):10992-1000.

  200. Saal LH, Holm K, Maurer M, Memeo L, Su T, Wang X, Yu JS, Malmstrom PO, Mansukhani M, Enoksson J, Hibshoosh H, Borg A, Parsons R. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65(7):2554-9.

  201. Hernandez-Aya LF, Gonzalez-Angulo AM. Targeting the phosphatidylinositol 3-kinase signaling pathway in breast cancer. Oncologist. 2011;16(4):404-14.

  202. Rexer BN, Chanthaphaychith S, Dahlman KB, 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. 2014;16(1):R9.

  203. Lu CH, Wyszomierski SL, Tseng LM, Sun MH, Lan KH, Neal CL, Mills GB, Hortobagyi GN, Esteva FJ, Yu D. Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin Cancer Res. 2007 Oct 1;13(19):5883-8.

  204. Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Hortobagyi GN, Hung MC, Yu D. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6(2):117-27.

  205. O'Brien NA, Browne BC, Chow L, Wang Y, Ginther C, Arboleda J, Duffy MJ, Crown J, O'Donovan N, Slamon DJ. Activated phosphoinositide 3-kinase/AKT signaling confers resistance to trastuzumab but not lapatinib. Mol Cancer Ther. 2010;9(6):1489-502. doi: 10.1158/1535-7163.MCT-09-1171. Epub 2010 May 25. Erratum in: Mol Cancer Ther. 2011;10(11):2211.

  206. Chakrabarty A, Sanchez V, Kuba MG, Rinehart C, Arteaga CL. Feedback upregulation of HER3 (ErbB3) expression and activity attenuates antitumor effect of PI3K inhibitors. Proc Natl Acad Sci U S A. 2012;109(8):2718-23.

  207. Serra V, Scaltriti M, Prudkin L, Eichhorn PJ, Ibrahim YH, Chandarlapaty S, Markman B, Rodriguez O, Guzman M, Rodriguez S, Gili M, Russillo M, Parra JL, Singh S, Arribas J, Rosen N, Baselga J. PI3K inhibition results in enhanced HER signaling and acquired ERK dependency in HER2-overexpressing breast cancer. Oncogene. 2011 Jun 2;30(22):2547-57.

  208. Andre F, O'Regan R, Ozguroglu M, Toi M, Xu B, Jerusalem G, Masuda N, Wilks S, Arena F, Isaacs C, Yap YS, Papai Z, Lang I, Armstrong A, Lerzo G, White M, Shen K, Litton J, Chen D, Zhang Y, Ali S, Taran T, Gianni L. Everolimus for women with trastuzumab-resistant, HER2-positive, advanced breast cancer (BOLERO-3): A randomised, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014;15(6):580-91.

  209. Jerusalem G, Masuda N, Andre F, Fein L, Fasolo A, O'Regan R, Wilks S, Isaacs C, Zhang Y, Taran T, Toi M. Abstract P3-15-03: Safety analysis of BOLERO-3: A phase 3 trial of daily everolimus (EVE) vs. placebo (PBO), both with weekly trastuzumab (TRAS) and vinorelbine in trastuzumab-resistant, advanced breast cancer. Cancer Res. 2013;73(24 Suppl):P3-15-03.

  210. Blackwell KL, Burstein HJ, Storniolo AM, Rugo HS, Sledge G, Aktan G, Ellis C, Florance A, Vukelja S, Bischoff J, Baselga J, O'Shaughnessy J. Overall survival benefit with lapatinib in combination with trastuzumab for patients with human epidermal growth factor receptor 2-positive metastatic breast cancer: Final results from the EGF104900 Study. J Clin Oncol. 2012 Jul 20;30(21):2585-92.

  211. Tolaney S, Burris H, Gartner E, Mayer IA, Saura C, Maurer M, Ciruelos E, Garcia AA, Campana F, Wu B, Xu Y, Jiang J, Winer E, Krop I. Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer. Breast Cancer Res Treat. 2015;149(1):151-61.

  212. Maira SM, Pecchi S, Huang A, Burger M, Knapp M, Sterker D, Schnell C, Guthy D, Nagel T, Wiesmann M, Brachmann S, Fritsch C, Dorsch M, Chene P, Shoemaker K, De Pover A, Menezes D, Martiny-Baron G, Fabbro D, Wilson CJ, Schlegel R, Hofmann F, Garcia-Echevema C, Sellers WR, Voliva CF. Identification and characterization of NVP-BKM120, an orally available pan-class I PI3-kinase inhibitor. Mol Cancer Ther. 2012;11(2):317-28.

  213. O'Brien NA, McDonald K, Tong L, von Euw E, Kalous O, Conklin D, Hurvitz SA, di Tomaso E, Schnell C, Linnartz R, Finn RS, Hirawat S, Slamon DJ. Targeting PI3K/mTOR overcomes resistance to HER2-targeted therapy independent of feedback activation of AKT. Clin Cancer Res. 2014 Jul 1;20(13):3507-20.

  214. Saura C, Bendell J, Jerusalem G, Su S, Ru Q, De Buck S, Mills D, Ruquet S, Bosch A, Urruticoechea A, Beck JT, Di Tomaso E, Sternberg DW, Massacesi C, Hirawat S, Dirix L, Baselga J. Phase Ib study of Buparlisib plus Trastuzumab in patients with HER2-positive advanced or metastatic breast cancer that has progressed on Trastuzumab-based therapy. Clin Cancer Res. 2014 Apr 1;20(7):1935-45.

  215. Pistilli B, Pluard T, Urruticoechea A, Farci D, Kong A, Bachelot T, Chan S, Han HS, Jerusalem G, Urban P, Robinson D, Mouhaer SL, Tomaso ED, Massacesi C, Saura C. Phase II study of buparlisib (BKM120) and trastuzumab in patients with HER2+ locally advanced or metastatic breast cancer resistant to trastuzumab-based therapy. Breast Cancer Res Treat. 2018;168(2):357-364.

  216. Guerin M, Rezai K, Isambert N, Campone M, Autret A, Pakradouni J, Provansal M, Camerlo J, Sabatier R, Bertucci F, Charafe-Jauffret E, Hervieu A, Extra JM, Viens P, Lokiec F, Boher JM, Gonfalves A. PIKHER2: A phase IB study evaluating buparlisib in combination with lapatinib in trastuzumab-resistant HER2-positive advanced breast cancer. Eur J Cancer. 2017;86:28-36.

  217. Shah PD, Chandarlapaty S, Dickler MN, Ulaner G, Zamora SJ, Sterlin V, Iasonos A, Coughlin CM, Morozov A, Ero J, Rosen N, Gilewski T, Fornier MN, Sklarin NT, Berger MF, Moynahan ME, Hudis CA, Baselga J, Modi S. Phase I study of LJM716, BYL719, and trastuzumab in patients (pts) with HER2-amplified (HER2+) metastatic breast cancer (MBC) [Abstract]. J Clin Oncol. 2015;33: 590.

  218. Jain S, Shah AN, Santa-Maria CA, Siziopikou K, Rademaker A, Helenowski I, Cristofanilli M, Gradishar WJ. Phase I study of alpelisib (BYL-719) and trastuzumab emtansine (T-DM1) in HER2-positive metastatic breast cancer (MBC) after trastuzumab and taxane therapy. Breast Cancer Res Treat. 2018;171(2):371-81.

  219. Elster N, Cremona M, Morgan C, Toomey S, Carr A, O'Grady A, Hennessy BT, Eustace AJ. A preclinical evaluation of the PI3K alpha/delta dominant inhibitor BAY 80-6946 in HER2-positive breast cancer models with acquired resistance to the HER2-targeted therapies trastuzumab and lapatinib. Breast Cancer Res Treat. 2015;149(2):373-83.

  220. Keegan NM, Walshe JM, Toomey S, Gullo G, Kennedy MJ, Bulger KN, McCaffrey J, Kelly CM, Egan K, O'Donovan P, Hernando A, Teiserskiene A, Parker I, Farrelly AM, Carr A, Calzaferri G, McDermott R, Keane MM, Grogan L, Breathnach OS, Morris PG, Toomey S, Hennessy BT. A phase Ib trial of copanlisib and tratuzumab in pretreated recurrent or metastatic HER2-positive breast cancer "Pan-tHER". J Clin Oncol. 2018;36(15 Suppl):1036.

  221. Merlino G, Fiascarelli A, Bigioni M, Bressan A, Irrissuto C, Pellacani A, Scaltriti M, Binaschi M. MEN1611, a novel a-selective PI3K inhibitor in solid tumors. Cancer Res. 2018;78(13 Suppl):2160.

  222. Piccart-Gebhart MJ, Aftimos PG, Duhoux FP, Wildiers H, Isambert N, Campone M, Tosi D, Varga AI, Boni V, Doger B, Corbacho JG, Jimenez-Rodriguez B, Borrego MR, Saura C, Arkenau H-T, Wardley AM, Troconiz IF, Binaschi M, Simonelli C, Pellacani AU. 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. J Clin Oncol. 2019;37(15 Suppl):TPS1101.

  223. Lyu H, Yang XH, Edgerton SM, Thor AD, Wu X, He Z, Liu B. The erbB3- and IGF-1 receptor-initiated signaling pathways exhibit distinct effects on lapatinib sensitivity against trastuzumab-resistant breast cancer cells. Oncotarget. 2016 Jan 19;7(3):2921-35.

  224. Huang X, Gao L, Wang S, McManaman JL, Thor AD, Yang X, Esteva FJ, Liu B. Heterotrimerization of the growth factor receptors erbB2, erbB3, and insulin-like growth factor-i receptor in breast cancer cells resistant to herceptin. Cancer Res. 2010 Feb 1;70(3):1204-14.

  225. Huang J, Wang S, Lyu H, Cai B, Yang X, Wang J, Liu B. The anti-erbB3 antibody MM-121/SAR256212 in combination with trastuzumab exerts potent antitumor activity against trastuzumab-resistant breast cancer cells. Mol Cancer. 2013 Nov 11;12(1):134.

  226. Sequist LV, Janne PA, Huber RM, Gray JE, Felip E, Perol M, Hirsch FR, Tan DS-W, Kuesters G, Zalutskaya A, Santillana S, Pipas JM, Shepherd FA. SHERLOC: A phase 2 study of MM-121 plus with docetaxel versus docetaxel alone in patients with heregulin (HRG) positive advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2019;37(15 Suppl):9036.

  227. Kawakami H, Okamoto I, Yonesaka K, Okamoto K, Shibata K, Shinkai Y, Sakamoto H, Kitano M, Tamura T, Nishio K, Nakagawa K. The anti-HER3 antibody patritumab abrogates cetuximab resistance mediated by heregulin in colorectal cancer cells. Oncotarget. 2014 Dec 15;5(23):11847-56.

  228. Watanabe S, Yonesaka K, Tanizaki J, Nonagase Y, Takegawa N, Haratani K, Kawakami H, Hayashi H, Takeda M, Tsurutani J, Nakagawa K. Targeting of the HER2/HER3 signaling axis overcomes ligand-mediated resistance to trastuzumab in HER2-positive breast cancer. Cancer Med. 2019;8(3):1258-68. doi: 10.1002/cam4.1995. Epub 2019 Jan 31.

  229. de Melo Gagliato D, Cortes J, Curigliano G, Loi S, Denkert C, Perez-Garcia J, Holgado E. Tumor-infiltrating lymphocytes in Breast Cancer and implications for clinical practice. Biochim Biophys Acta Rev Cancer. 2017;1868(2):527-37.

  230. Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G, Francis P, Crown JP, Hitre E, de Azambuja E, Quinaux E, Di Leo A, Michiels S, Piccart MJ, Sotiriou C. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013 Mar 1;31(7):860-7.

  231. Kim S-R, Gavin PG, Pogue-Geile KL, Song N, Finnigan M, Bandos H, Jeong J-H, Rastogi P, Romond EH, Fehrenbacher L, Mamounas EP, Swain SM, Wickerham DL, Geyer CE, Costantino JP, Wolmark N. A surrogate gene expression signature of tumor infiltrating lymphocytes (TILs) predicts degree of benefit from trastuzumab added to standard adjuvant chemotherapy in NSABP (NRG) trial B-31 for HER2+ breast cancer. Cancer Res. 2015;75(15 Suppl):2837.

  232. Holgado E, Perez-Garcia J, Gion M, Cortes J. Is there a role for immunotherapy in HER2-positive breast cancer? NPJ Breast Cancer. 2018;4(1):21.

  233. Wolpoe ME, Lutz ER, Ercolini AM, Murata S, Ivie SE, Garrett ES, Emens LA, Jaffee EM, Reilly RT. HER-2/ neu-specific monoclonal antibodies collaborate with HER-2/neu-targeted granulocyte macrophage colony-stimulating factor secreting whole cell vaccination to augment CD8+ T cell effector function and tumor-free survival in Her-2/neutransgenic mice. J Immunol. 2003;171(4):2161-9.

  234. Kim PS, Armstrong TD, Song H, Wolpoe ME, Weiss V, Manning EA, Huang LQ, Murata S, Sgouros G, Emens LA, Reilly RT, Jaffee EM. Antibody association with HER-2/neu-targeted vaccine enhances CD8 T cell responses in mice through Fc-mediated activation of DCs. J Clin Invest. 2008;118(5):1700-11.

  235. Chen G, Gupta R, Petrik S, Laiko M, Leatherman JM, Asquith JM, Daphtary MM, Garrett-Mayer E, Davidson NE, Hirt K, Berg M, Uram JN, Dauses T, Fetting J, Duus EM, Atay-Rosenthal S, Ye X, Wolff AC, Stearns V, Jaffee EM, Emens LA. A feasibility study of cyclophosphamide, trastuzumab, and an allogeneic GM-CSF-secreting breast tumor vaccine for HER2+ metastatic breast cancer. Cancer Immunol Res. 2014;2(10):949-61.

  236. Loi S, Giobbie-Hurder A, Gombos A, Bachelot T, Hui R, Curigliano G, Campone M, Biganzoli L, Bonnefoi H, Jerusalem G, Bartsch R, Rabaglio-Poretti M, Kammler R, Maibach R, Smyth MJ, Di Leo A, Colleoni M, Viale G, Regan MM, Andre F. Abstract GS2-06: Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive advanced breast cancer: Results from the PANACEA (IBCSG 45-13/BIG 4-3/KEYN0TE-014) study. Cancer Res. 2018;78(4 Suppl):GS2-06-GS2-06.

  237. Catenacci DV, Park H, Lockhart AC, Gold PJ, Enzinger PC, Nordstrom JL, Hong S, Hochster HS, Kelly RJ, Uronis HE, Bendell JC, Oh SC, Park SH, Kim YH, Kang YK, Lee KW, Ng MCH, Wigginton JM, Davidson-Moncada JK, Bang YJ. Phase 1b/2 study of margetuximab (M) plus pembrolizumab (P) in advanced HER2+ gastroesophageal junction (GEJ) or gastric (G) adenocarcinoma (GEA) [Abstract]. J Clin Oncol. 2018;36(4 Suppl):140.

  238. Muller P, Kreuzaler M, Khan T, Thommen DS, Martin K, Glatz K, Savic S, Harbeck N, Nitz U, Gluz O, von Bergwelt-Baildon M, Kreipe H, Reddy S, Christgen M, Zippelius A. Trastuzumab emtansine (T-DM1) renders HER2+ breast cancer highly susceptible to CTLA-4/PD-1 blockade. Sci Transl Med. 2015;7(315):315ra188.

  239. 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.

  240. Choi YJ, Li X, Hydbring P, Sanda T, Stefano J, Christie AL, Signoretti S, Look AT, Kung AL, von Boehmer H, Sicinski P. The requirement for cyclin D function in tumor maintenance. Cancer Cell. 2012;22(4):438-51.

  241. Hortobagyi GN, Stemmer SM, Burris HA, Yap YS, Sonke GS, Paluch-Shimon S, Campone M, Blackwell KL, Andre F, Winer EP, Janni W, Verma S, Conte P, Arteaga CL, Cameron DA, Petrakova K, Hart LL, Villanueva C, Chan A, Jakobsen E, Nusch A, Burdaeva O, Grischke EM, Alba E, Wist E, Marschner N, Favret AM, Yardley D, Bachelot T, Tseng LM, Blau S, Xuan F, Souami F, Miller M, Germa C, Hirawat S, O'Shaughnessy J. Ribociclib as first-line therapy for HR-positive, advanced breast cancer. N Engl J Med. 2016;375(18):1738-48. Erratum in: N Engl J Med. 2018;379(26):2582.

  242. Sledge GW Jr, Toi M, Neven P, Sohn J, Inoue K, Pivot X, Burdaeva O, Okera M, Masuda N, Kaufman PA, Koh H, Grischke EM, Frenzel M, Lin Y, Barriga S, Smith IC, Bourayou N, Llombart-Cussac A. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2-advanced breast cancer who had progressed while receiving endocrine therapy. J Clin Oncol. 2017;35(25):2875-84.

  243. Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Dieras V, Slamon DJ. Palbociclib and letrozole in advanced breast cancer. N Engl J Med. 2016;375(20):1925-36.

  244. Wang YC, Morrison G, Gillihan R, Guo J, Ward RM, Fu X, Botero MF, Healy NA, Hilsenbeck SG, Phillips GL, Chamness GC, Rimawi MF, Osborne CK, Schiff R. Different mechanisms for resistance to trastuzumab versus lapatinib in HER2-positive breast cancers: Role of estrogen receptor and HER2 reactivation. Breast Cancer Res. 2011;13(6):R121.

  245. Schedin TB, Borges VF, Shagisultanova E. Overcoming therapeutic resistance of triple positive breast cancer with CDK4/6 inhibition. Int J Breast Cancer. 2018;2018:7835095.

  246. Goel S, Wang Q, Watt AC, Tolaney SM, Dillon DA, Li W, Ramm S, Palmer AC, Yuzugullu H, Varadan V, Tuck D, Harris LN, Wong KK, Liu XS, Sicinski P, Winer EP, Krop IE, Zhao JJ. Overcoming therapeutic resistance in HER2-positive breast cancers with CDK4/6 inhibitors. Cancer Cell. 2016;29(3):255-69.

  247. Finn RS, Dering J, Conklin D, Kalous O, Cohen DJ, Desai AJ, Ginther C, Atefi M, Chen I, Fowst C, Los G, Slamon DJ. 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.

  248. Ciruelos E, Villagrasa P, Pare L, Oliveira M, de la Pena L, Pernas S, Cortes J, Soberino J, Adamo B, Vazquez S, Martinez N, Perello A, Bermejo B, Martinez E, Garau I, Mele M, Morales S, Galvan P, Pascual T, Nuciforo P, Gonzalez X, Prat A. PAM50 intrinsic subtype predicts survival outcome in HER2-positive/hormone receptor-positive metastatic breast cancer treated with palbociclib and trastuzumab: A correlative analysis of the PATRICIA (SOLTI 13-03) trial [Abstract]. Cancer Res. 2018;78(4 Suppl):P5-20-19.

  249. Tolaney SM, Bourayou N, Goel S, Hossain A, Andre F. A phase II randomized study to compare abemaciclib plus trastuzumab with or without fulvestrant to standard of care chemotherapy plus trastuzumab in hormone receptor positive, HER2-positive advanced breast cancer (monarcHER). Lancet Oncol. 2020;21(6):763-75.

  250. Pernas S, Tolaney SM. HER2-positive breast cancer: New therapeutic frontiers and overcoming resistance. Ther Adv Med Oncol. 2019;11. doi: 10.1177/1758835919833519.

  251. Huhalov A, Adams S, Paragas V, Oyama S, Overland R, Luus L, Gibbons F, Zhang B, Nguyen S, Nielsen UB, Niyikiza C, McDonagh CF, Kudla AJ. MM-111, an ErbB2/ErbB3 bispecific antibody with potent activity in ErbB2-overexpressing cells, positively combines with trastuzumab to inhibit growth of breast cancer cells driven by the ErbB2/ErbB3 oncogenic unit [Abstract]. Cancer Res. 2010;70(8 Suppl):3485.

  252. Zhang B, Nguyen S, Huhalov A, Nielsen UB, Niyikiza C, McDonagh CF, Kudla AJ, Onsum M. MM-111, a bispecific HER2 and HER3 antibody, inhibits trastuzumab-resistant tumor cell growth [Abstract]. Cancer Res. 2012;72(8 Suppl):1888.

  253. Richards DA, Braiteh FS, Garcia A, Denlinger CS, Conkling PR, Edenfield WJ, Anthony SP, Hellerstedt BA, Raju RN, Becerra C, Harb WA, Smith DA, McDonagh CF, Kawash KL, Frye S, Moyo VM. A phase 1 study of MM-111, a bispecific HER2/HER3 antibody fusion protein, combined with multiple treatment regimens in patients with advanced HER2-positive solid tumors [Abstract]. J Clin Oncol. 2014;32(15 Suppl):651.

1944 Vistas de artículos 36 Descargas de artículos Métrica
1944 PUNTOS DE VISTA 36 DESCARGAS Google
Scholar CITAS

Artículos con contenido similar:

Dopamine Receptors in Breast Cancer: Prevalence, Signaling, and Therapeutic Applications Critical Reviews™ in Oncogenesis, Vol.27, 2022, issue 2
Nira Ben-Jonathan, Eric R. Hugo, Dana C. Borcherding
HER2 Tyrosine Kinase Inhibitors in the Sensitization to Cancers Resistant to HER2 Antibodies Critical Reviews™ in Oncogenesis, Vol.25, 2020, issue 3
Heena Singla, Anjana Munshi
New Prospectives of Prostate Cancer Gene Therapy: Molecular Targets and Animal Models Critical Reviews™ in Eukaryotic Gene Expression, Vol.11, 2001, issue 1-3
Chia-Ling Hsieh, Leland W. K. Chung
CAR-T Cell Therapy: Challenges and Optimization Critical Reviews™ in Immunology, Vol.41, 2021, issue 1
Qumiao Xu, Qianqian Gao, Hongchang Zhang, Linnan Zhu, Mei Luo
Molecular Mechanisms Underlying the Role of MicroRNAs in Resistance to Epidermal Growth Factor Receptor-Targeted Agents and Novel Therapeutic Strategies for Treatment of Non-Small-Cell Lung Cancer Critical Reviews™ in Oncogenesis, Vol.18, 2013, issue 4
Elena Galvani, Godefridus J. Peters, Mina Maftouh, Elisa Giovannetti, Amir Avan

Último edicion

Machine Evaluation of Catchment Area Relevance through Text Mining Philip A. Arlen, Joseph Chakko, Geoffrey DeGennaro, Erin Kobetz, Brandon Mahal Oral Cavity Squamous Cell Carcinoma: Review of Pathology, Diagnosis, and Management Benjamin J. Rich, Stuart E. Samuels, Gregory A. Azzam, Gregory Kubicek, Laura Freedman Surgical Management of the Neck in Oral Cavity Squamous Cell Carcinoma Olivia Mihulka, Eric Nisenbaum, Elizabeth Nicolli Convolutional Neural Networks for Glioma Segmentation and Prognosis: A Systematic Review Janette Herr, Radka Stoyanova, Eric Albert Mellon Proton Beam Therapy for Breast Cancer Seraphina Choi, Isabella Dreyfuss, Crystal Seldon Taswell, Jonathan Cyriac, Michael Butkus, Cristiane Takita Management of Advanced Medullary Thyroid Carcinoma: Current Systemic Therapy Options Mark A. Jara Disparities in Electronic Cigarette Use: A Narrative Review Kyle Edwards, Aysswarya Manoharan, Taghrid Asfar, Samuel Kareff, Gilberto Lopes, Estelamari Rodriguez, Coral Olazagasti The Genetic Paradigm of Hereditary Breast and Ovarian Cancer (HBOC) in the Afro-Caribbean Population Danielle Cerbon, Daphanie Taylor, Priscila Barreto-Coelho, Estelamari Rodriguez, Matthew Schlumbrecht, Judith Hurley, Sophia H.L. George

Próximos Artículos

Neuroplasticity: Pathophysiology and Role in Major Depressive Disorder Rama Rao Malla, Sreeharshini Kadiyala, Priyamvada Bhamidipati IMMUNE EVASION IN CANCER IS REGULATED BY THE TUMOR-ASOCIATED MACROPHAGES (TAMS): TARGETING TAMS Megan Jung, Benjamin Bonavida Disparities in Electronic Cigarette Use: A Narrative Review Kyle Edwards, Aysswarya Manoharan, Taghrid Asfar, Samuel Kareff, Gilberto Lopes, Estelamari Rodriguez, Coral Olazagasti Advanced Medullary Thyroid Carcinoma: The Current Systemic Therapy Options Mark Jara Proton Beam Therapy for Breast Cancer Seraphina Choi, Crystal Taswell, Isabella Dreyfuss, Jonathan Cyriac, Michael Butkus, Cristiane Takita The Genetic Paradigm of Hereditary Breast and Ovarian Cancer in The Afro-Caribbean Population Danielle Cerbon, Daphnie Taylor, Priscila Barreto Coelho, Estelamari Rodriguez, Matthew Schlumbrecht, Judith Hurley, Sophia George
Portal Digitalde Biblioteca Digital eLibros Revistas Referencias y Libros de Ponencias Colecciones Precios y Políticas de Suscripcione Begell House Contáctenos Language English 中文 Русский Português German French Spain