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Sensitization of chemotherapy by anti-HER

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Abstract

This article reviews the current state of efforts targeting human epidermal growth factor receptor-2 (erbB2/HER2) in breast cancer therapy. The results of recently conducted clinical studies with trastuzumab and several other compounds are presented. Trastuzumab, a humanised monoclonal antibody (mAb) directed against the extracellular domain of HER2, has been shown to be active against HER2-overexpressing metastatic breast cancer, either as a single agent or when used in combination with chemotherapy. In preclinical models, trastuzumab has shown additive and even synergistic anti-tumor activity with the chemotherapeutic agents. In a large, randomised, phase III trial, the combination of trastuzumab and chemotherapy was shown to improve the response rate and survival in patients with metastatic breast cancer. The high incidence of cardiotoxicity seen with the combination of trastuzumab plus anthracycline drugs prompted several clinical studies combining trastuzumab with other chemotherapeutic agents, including taxanes, vinorelbine and platinum salts. This article summarises the available data on trastuzumab-based combination chemotherapies and novel drugs targeting HER2 and signal transduction molecules for the treatment of breast cancer.

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Abbreviations

HER2:

Human epidermal growth factor receptor 2

EGFR:

Epidermal growth factor receptor

mAb:

monoclonal antibody

CI:

Combination index

OS:

Overall survival

DFS:

Disease free survival

IHC:

Immunohistochemistry

FISH:

Fluorescencein situ hybridization

MBC:

Metastatic breast cancer

LVEF:

Left ventricular ejection fraction

COX-2:

Cyclooxygenase 2

References

  1. Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, Slamon DJ, MurphyM, Novotny WF, Burchmore M, Shak S, Stewart SJ, Press M, VogelC: Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-over-expressing metastatic breast cancer.J Clin Oncol 20:719–726, 2002.

    Article  PubMed  CAS  Google Scholar 

  2. Slamon DJ, Leyland-Jones B, Shak S, FuchsH, Paton V, Baamonde A, Fleming T, Eiermann W, WolterJ, Pegram M, Baselga J, NortonL: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.N Engl J Med 344:783–792, 2001.

    Article  PubMed  CAS  Google Scholar 

  3. Piccart MJ: Proposed treatment guidelines for HER2-positive metastatic breast cancer in Europe.Ann Oncol 12:S89–94, 2001.

    Article  PubMed  Google Scholar 

  4. Ligibel JA, Winer EP: Trastuzumab/chemotherapy combinations in metastatic breast cancer.Semin Oncol 29:38–43, 2002.

    PubMed  CAS  Google Scholar 

  5. Arteaga CL, Moulder SL, Yakes FM: HER (erbB) tyrosine kinase inhibitors in the treatment of breast cancer.Semin Oncol 29:4–10,2002.

    PubMed  CAS  Google Scholar 

  6. Pegram M, Hsu S, Lewis G, Pietras R, BerytM, Sliwkowski M, Coombs D, Baly D, Kabbinavar F, SlamonD: Inhibitory effects of combinations of HER-2/ neu antibody and chemotherapeutic agents used for treatment of human breast cancers.Oncogene 18:2241–2251,1999.

    Article  PubMed  CAS  Google Scholar 

  7. Pegram MD, Lopez A, Konecny G, Slamon DJ: Trastuzumab and chemotherapeutics: drug interactions and synergies.Semin Oncol 27:21–25; discussion 92–100, 2000.

    PubMed  CAS  Google Scholar 

  8. Pietras RJ, Pegram MD, Finn RS, Maneval DA, Slamon DJ, Fendly BM, Chazin VR, Howell SB: Remission of human breast cancer xenografts on therapy with humanized monoclonal antibody to HER-2 receptor and DNA-reactive drugs.Oncogene 17:2235–2249, 1998.

    Article  PubMed  CAS  Google Scholar 

  9. Nahta R, Esteva FJ, Trent S, Yang C, Schmidt EV, Hortobagyi GN, Iglehart JD, KempkesB: HER-2-targeted therapy: lessons learned and future directions.Clin Cancer Res 9:5078–5084, 2003.

    PubMed  CAS  Google Scholar 

  10. Baselga J, Tripathy D, Mendelsohn J, BaughmanS, Benz CC, Dantis L, Sklarin NT, Seidman AD, Hudis CA, Moore J, Rosen PP, Twaddell T, Henderson IC, NortonL: Phase II study of weekly intravenous recombinant humanized anti-pl85HER2 monoclonal antibody in patients with HER2/neu-overexpressing metastatic breast cancer.J Clin Oncol 14:737–744, 1996.

    PubMed  CAS  Google Scholar 

  11. Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, PatonV, 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 17:2639–2648,1999.

    PubMed  CAS  Google Scholar 

  12. Seidman AD, Former MN, Esteva FJ, TanL, Kaptain S, Bach A, Panageas KS, Arroyo C, ValeroV, Currie V, Gilewski T, Theodoulou M, Moynahan ME, MoasserM, Sklarin N, Dickler M, D’Andrea G, Cristo-fanilliM, Rivera E, Hortobagyi GN, NortonL, Hudis CA: Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification.J Clin Oncol 19:2587–2595, 2001.

    PubMed  CAS  Google Scholar 

  13. Leyland-Jones B, Gelmon K, Ayoub JP, ArnoldA, Verma S, Dias R, Ghahramani P: Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel.J Clin Oncol 21:3965–3971, 2003.

    Article  PubMed  CAS  Google Scholar 

  14. Leyland-Jones B: Dose scheduling-Herceptin.Oncology 61:31–36, 2001.

    Article  PubMed  CAS  Google Scholar 

  15. Esteva FJ, Valero V, Booser D, Guerra LT, Murray JL, Pusztai L, Cristofanilli M, Arun B, Esmaeli B, Fritsche HA, Sneige N, Smith TL, Hortobagyi GN: Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer.J Clin Oncol 20:1800–1808, 2002.

    Article  PubMed  CAS  Google Scholar 

  16. Montemurro F, Choa G, Faggiuolo R, Sperti E, Capaldi A, Donadio M, Minischetti M, Salomone A, Vietti-Ramus G, Alabiso O, Aglietta M: Safety and activity of docetaxel and trastuzumab in HER2 overexpressing metastatic breast cancer: a pilot phase H study.Am J Clin Oncol 26:95–97,2003.

    Article  PubMed  CAS  Google Scholar 

  17. Burstein HJ, Kuter I, Campos SM, Gelman RS, Tribou L, Parker LM, Manola J, Younger J, Matulonis U, Bunnell CA, Partridge AH, Richardson PG, Clarke K, Shulman LN, Winer EP: Clinical activity of trastuzumab and vinorelbine in women with HER2-overexpressing metastatic breast cancer.J Clin Oncol 19:2722–2730 2001

    PubMed  CAS  Google Scholar 

  18. Burstein HJ, Harris LN, Marcom PK, Lambert-Falls R, Havlin K, Overmoyer B, Friedlander RJ, Gargiulo J, Strenger R, Vogel CL, Ryan PD, Ellis MJ, Nunes RA, Bunnell CA, Campos SM, Hallor M, Gelman R, Winer EP: Trastuzumab and vinorelbine as first-line therapy for HER2-overexpressing metastatic breast cancer: multicenter phase II trial with clinical outcomes, analysis of serum tumor markers as predictive factors, and cardiac surveillance algorithm.J Clin Oncol 21:2889–2895, 2003.

    Article  PubMed  CAS  Google Scholar 

  19. Seidman A, Hudis C, Pierri MK, Shak S, Paton V, Ashby M, Murphy M, Stewart SJ, Keefe D: Cardiac dysfunction in the trastuzumab clinical trials experience.J Clin Oncol 20:1215–1221,2002.

    Article  PubMed  CAS  Google Scholar 

  20. Winer EP, Burstein HJ: New combinations with Herceptin in metastatic breast cancer.Oncology 61:50–57, 2001.

    Article  PubMed  CAS  Google Scholar 

  21. Gianni L: The future of targeted therapy: combining novel agents.Oncology 63:47–56,2002.

    Article  PubMed  CAS  Google Scholar 

  22. Bell R: Ongoing trials with trastuzumab in metastatic breast cancer.Ann Oncol 12:S69–73, 2001.

    Article  PubMed  Google Scholar 

  23. 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-pl85HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment.J Clin Oncol 16:2659–2671,1998.

    PubMed  CAS  Google Scholar 

  24. Crown J, Pegram M: Platinum-taxane combinations in metastatic breast cancer: an evolving role in the era of molecularly targeted therapy.Breast Cancer Res Treat 79:S11–18, 2003.

    Article  PubMed  CAS  Google Scholar 

  25. O’Shaughnessy J, Blum J, Moiseyenko V, Jones S, Miles D, Bell D, Rosso R, Mauriac L, Osterwalder B, Burger H, Laws S: Randomized, open-label, phase II trial of oral capecitabine (Xeloda) vs a reference arm of intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) as first-line therapy for advanced/metastatic breast cancer.Ann Oncol 12:1247–1254, 2001.

    Article  CAS  Google Scholar 

  26. O’Shaughnessy J, Miles D, Vukelja S, Moiseyenko V, Ayoub JP, Cervantes G, Fumoleau P, Jones S, Lui W, Mauriac L, Twelves C, Van Hazel G, Verma S, Leonard, R: Superior survival with capecitabine plus docetaxel combination therapy in anthracycline-pretreated patients with advanced breast cancer: phase III trial results.J Clin Oncol 20:2812–2823,2002.

    Article  PubMed  CAS  Google Scholar 

  27. Meza L, Amin B, Horsey M: A phase II study of capecitabine in combination with Paclitaxel as first or second line therapy in patients with metastatic breast cancer.Proc Am Soc Clin Onocol 21, 70b (abstract #2029), 2001.

    Google Scholar 

  28. Fujimoto-Ouchi K, Sekiguchi F, Tanaka Y: Antitumor activity of combinations of anti-HER-2 antibody trastuzumab and oral fluoropyrimidines capecitabine/ 5’-dFUrd in human breast cancer models.Cancer Chemother Pharmacol 49:211–216,2002.

    Article  PubMed  CAS  Google Scholar 

  29. Tan-Chiu E Piccart M: Moving forward: Herceptin in the adjuvant setting.Oncology 63:57–63, 2002.

    Article  PubMed  Google Scholar 

  30. Paik S, Bryant J, Tan-Chiu E, Romond E, Hiller W, Park K, Brown A, Yothers G, Anderson S, Smith R, Wickerham DL, Wolmark N: Real-world performance of HER2 testing-National Surgical Adjuvant Breast and Bowel Project experience.J Natl Cancer Inst 94:852–854, 2002.

    PubMed  Google Scholar 

  31. Roche PC, Suman VJ, Jenkins RB, Davidson NE, Martino S, Kaufman PA, Addo FK, Murphy B, Ingle JN, Perez EA: Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831.J Natl Cancer Inst 94:855–857, 2002.

    PubMed  Google Scholar 

  32. Mann M, Sheng H, Shao J, Williams CS, Pisacane PI, Sliwkowski MX, DuBois RN: Targeting cyclooxygenase 2 and HER-2/neu pathways inhibits colorectal carcinoma growth.Gastroenterology 120:1713–1719, 2001.

    Article  PubMed  CAS  Google Scholar 

  33. Lu C, Speers C, Zhang Y, Xu X, Hill J, Steinbis E, Celestino J, Shen Q, Kim H, Hilsenbeck S, Mohsin SK, Wakeling A, Osborne CK, Brown PH: Effect of epidermal growth factor receptor inhibitor on development of estrogen receptor-negative mammary tumors.J Natl Cancer Inst 95:1825–1833,2003.

    PubMed  CAS  Google Scholar 

  34. Normanno N, Campiglio M, De LA, Somenzi G, Mai-ello M, Ciardiello F, Gianni L, Salomon DS Menard S: Cooperative inhibitory effect of ZD1839 (Iressa) in combination with trastuzumab (Herceptin) on human breast cancer cell growth.Ann Oncol 13:65–72, 2002.

    Article  PubMed  CAS  Google Scholar 

  35. Mendelsohn J, Baselga J: Status of epidermal growth factor receptor antagonists in the biology and treatment of cancer.J Clin Oncol 21:2787–2799, 2003.

    Article  PubMed  CAS  Google Scholar 

  36. Burke PA, DeNardo SJ, Miers LA, Kukis DL, DeNar-do GL: Combined modality radioimmunotherapy. Promise and peril.Cancer 94:1320–1331,2002.

    Article  PubMed  CAS  Google Scholar 

  37. Baselga J, Pfister D, Cooper MR, Cohen R, Burtness B, Bos M, D’Andrea G, Seidman A, Norton L, Gunnett K, Falcey J, Anderson V, Waksal H, Mendelsohn J: Phase I studies of anti-epidermal growth factor receptor chimeric antibody C225 alone and in combination with cisplatin.J Clin Oncol 18:904–914, 2000.

    PubMed  CAS  Google Scholar 

  38. Shin DM, Donate NJ, Perez-Soler R, Shin HJ, Wu JY, Zhang P, Lawhom K, Khuri FR, Glisson BS, Myers J, Clayman G, Pfister D, Falcey J, Waksal H, Mendelsohn J, Hong WK: Epidermal growth factor receptor-targeted therapy with C225 and cisplatin in patients with head and neck cancer.Clin Cancer Res 7:1204–1213, 2001.

    PubMed  CAS  Google Scholar 

  39. Kelland LR, Smith V, Valenti M, Patterson L, Clarke PA, Detre S, End D, Howes AJ, Dowsett M, Workman P, Johnston SR: Preclinical antitumor activity and pharmacodynamic studies with the farnesyl protein transferase inhibitor R115777 in human breast cancer.Clin Cancer Res 7:3544–3550, 2001.

    PubMed  CAS  Google Scholar 

  40. Johnston SR, Hickish T, Ellis P, Houston S, Kelland L, Dowsett M, Salter J, Michiels B, Perez-Ruixo JJ, Palmer P, Howes A: Phase II study of the efficacy and tolerability of two dosing regimens of the farnesyl transferase inhibitor, R115777, in advanced breast cancer.J Clin Oncol 21:2492–2499, 2003.

    Article  PubMed  CAS  Google Scholar 

  41. Hidalgo M, Rowinsky EK: Rapamycin-sensitive signal transduction pathway as a target for cancer therapy.Oncogene 19:6680–6686, 2000.

    Article  PubMed  CAS  Google Scholar 

  42. Mita MM, Mita A, Rowinsky EK: Mammalian target of rapamycin: a new molecular target for breast cancer.Clin Breast Cancer 4:126–137, 2003.

    Article  PubMed  CAS  Google Scholar 

  43. 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 2:127–137, 2002.

    Article  PubMed  CAS  Google Scholar 

  44. Albanell J, Codony J, Rovira A, Mellado B, Gascon, P: Mechanism of action of anti-HER2 monoclonal antibodies: scientific update on trastuzumab and 2C4.Adv Exp Med Biol 532:253–268, 2003.

    PubMed  CAS  Google Scholar 

  45. Rusnak DW, Affleck K, Cockerill SG, Stubberfield C, Harris R, Page M, Smith KJ, Guntrip SB, Carter MC, Shaw RJ, Jowett A, Stables J, Topley P, Wood ER, Brignola PS, Kadwell SH, Reep BR, Mullin RJ, Alli-good KJ, Keith BR, Crosby RM, Murray DM, Knight WB, Gilmer TM, Lackey K: The characterization of novel, dual ErbB-2/EGFR, tyrosine kinase inhibitors: potential therapy for cancer.Cancer Res 61:7196–7203, 2001.

    PubMed  CAS  Google Scholar 

  46. Xia W, Mullin RJ, Keith BR, Liu LH, Ma H, Rusnak DW, Owens G, Alligood KJ, Spector NL: Anti-tumor activity of GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of EGFR/erbB2 and downstream Erkl/2 and AKT pathways.Oncogene 21:6255–6263,2002.

    Article  PubMed  CAS  Google Scholar 

  47. Allen LF, Lenehan PF, Eiseman IA, Elliott WL, Fry DW: Potential benefits of the irreversible pan-erbB inhibitor, CI-1033, in the treatment of breast cancer.Semin Oncol 29:11–21, 2002.

    PubMed  CAS  Google Scholar 

  48. Stathopoulos GP: characterization as a target for cancer therapy in relation to orphan status disorders.Oncol Rep 9:1257–1259, 2002.

    PubMed  CAS  Google Scholar 

  49. Nahta R, Esteva FJ, Trent S, Yang C, Schmidt EV, Hortobagyi GN, Iglehart JD, Kempkes B: In vitro effects of trastuzumab and vinorelbine in trastuzum-ab-resistant breast cancer cells.Cancer Chemother Pharmacol 53:186–190, 2004.

    Article  PubMed  CAS  Google Scholar 

  50. Burstein HJ, Harris LN, Gelman R, Lester SC, Nunes RA, Kaelin CM, Parker LM, Ellisen LW, Kuter I, Gadd MA, Christian RL, Kennedy PR, Borges VF, Bunnell CA, Younger J, Smith BL, Winer EP: Preop-erative therapy with trastuzumab and paclitaxel followed by sequential adjuvant doxorubicin/cyclophos-phamide for HER2 overexpressing stage II or I breast cancer: a pilot study.J Clin Oncol 21:46–53, 2003.

    Article  PubMed  CAS  Google Scholar 

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Kataoka, A., Ishida, M., Murakami, S. et al. Sensitization of chemotherapy by anti-HER. Breast Cancer 11, 105–115 (2004). https://doi.org/10.1007/BF02968288

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