Breast Cancer

, Volume 14, Issue 2, pp 156–162 | Cite as

Does lapatinib, a small-molecule tyrosine kinase inhibitor, constitute a breakthrough in the treatment of breast cancer?

  • Yoshinori Ito
  • Nahomi Tokudome
  • Tsutomu Sugihara
  • Shunji Takahashi
  • Kiyohiko Hatake
Review Article

Abstract

ErbB/HER receptor or its signal transduction pathway is an attractive therapeutic target for breast cancer. Lapatinib, an orally administered dual inhibitor of ErbB1 (EGFR) and ErbB2 (HER2) receptor tyrosine kinases has shown promising results for metastatic breast cancer (MBC). Lapatinib exhibited activity against trastuzumab-refractory MBC and showed an acceptable adverse event profile such as tran-sient mild rash, diarrhea and nausea. The addition of lapatinib to capecitabine resulted in significantly pro-longed time to progression. Large randomized trials using lapatinib following chemotherapy and surgery are ongoing for early stage HER2-overexpressing breast cancer. Various combinations with agents such as paclitaxel, aromatase inhibitors, or other molecular targeted agents are currently being investigated in clinical trials. If these approaches overcome the limitations of trastuzumab, lapatinib will become an effec-tive treatment option for breast cancer in the near future.

Keywords

Breast cancer ErbB HER Lapatinib 

Abbreviations

MBC

Metastatic breast cancer

EGFR

Epidermal growth factor receptor

MAPK

Mitogen-activated protein kinase

PI3K

Phatidylinositol 3 kinase

IGF-IR

Insulin-like growth factor-l receptor

Cdk

Cyclin-dependent kinase

ER

Estrogen receptor

Al

Aromatase inhibitor

TAM

Tamoxifen

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References

  1. 1).
    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 344:783–792, 2001.PubMedCrossRefGoogle Scholar
  2. 2).
    Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, Tan-Chiu E, Martino S, Paik S, Kaufman PA, Swain SM, Pisansky TM, Fehrenbacher L, Kutteh LA, Vogel VG, Visscher DW, Yothers G, Jenkins RB, Brown AM, Dakhil SR, Mamounas EP, Lingle WL, Klein PM, Ingle JN, Wolmark N: (Tras-tuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer).N Engl J Med 353:1673–1684, 2005.PubMedCrossRefGoogle Scholar
  3. 3).
    Piccart-Gebhart MJ, Procter M, Leyland-Jones B, Goldhirsch A, Untch M, Smith I, Gianni L, Baselga J, Bell R, Jackisch C, Cameron D, Dowsett M, Barrios CH, Steger G, Huang CS, Andersson M, Inbar M, Lichinitser M, Lang I, Nitz U, Iwata H, Thomssen C, Lohrisch C, Suter TM, Ruschoff J, Suto T, Greatorex V, Ward C, Straehle C, McFadden E, Dolci MS, Gel-ber RD; Herceptin Adjuvant (HERA) Trial Study Team: (Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer).N Engl J Med 353:1659–1672, 2005.PubMedCrossRefGoogle Scholar
  4. 4).
    Savona M, Talpaz M: (Chronic myeloid leukemia: changing the treatment paradigms).Oncology 20:707–711, 2006.PubMedGoogle Scholar
  5. 5).
    Held G, Poschel V, Pfreundschuh M: Monoclonal antibody therapy for B-cell malignancies.Semin Oncol 2:s2–14, 2006.Google Scholar
  6. 6).
    Herbst RS, Fukuoka M, Baselga J: (Gefitinib-a novel targeted approach to treating cancer).Nat Rev Cancer 4:956–965, 2004.PubMedCrossRefGoogle Scholar
  7. 7).
    Nygren P, Sorbye H, Osterlund P, Pfeiffer P: (Targeted drugs in metastatic colorectal cancer with special emphasis on guidelines for the use of bevacizumab and cetuximab: an Acta Oncologica expert report).Acta Oncol 44:203–217, 2005.PubMedCrossRefGoogle Scholar
  8. 8).
    Olayioye MA, Neve RM, Lane HA, Hynes NE: (The ErbB signaling network: receptor heterodimerization in development and cancer).EMBO J 19:3159–3167, 2000.PubMedCrossRefGoogle Scholar
  9. 9).
    Lin NU, Winer EP: (New targets for therapy in breast cancer: small molecule tyrosine kinase inhibitors).Breast Cancer Res 6:204–210, 2004.PubMedCrossRefGoogle Scholar
  10. 10).
    Burris HA 3rd: (Dual kinase inhibition in the treatment of breast cancer: initial experience with the EGFR/ ErbB-2 inhibitor lapatinib).Oncologist 9:10–15, 2004.PubMedCrossRefGoogle Scholar
  11. 11).
    Hung MC, Lau YK: (Basic science of HER-2/neu: a review).Semin Oncol 26:51–59, 1999.PubMedGoogle Scholar
  12. 12).
    Rowinsky EK The ErbB family: (targets for therapeutic development against cancer and therapeutic strategies using monoclonal antibodies and tyrosine kinase inhibitors).Annu Rev Med 55:433–457, 2004.CrossRefGoogle Scholar
  13. 13).
    Karen E. Lackey: (Lessons from the drug discovery of lapatinib, a dual ErbBl/2 tyrosine kinase inhibitor).Current Topics in Medicinal Chemistry 6:435–460, 2006.PubMedCrossRefGoogle Scholar
  14. 14).
    Wood ER, Truesdale AT, McDonald OB, Yuan D, Hassell A, Dickerson SH, Ellis B, Pennisi C, Horne E, Lackey K, Alligood KJ, Rusnak DW, Gilmer TM, She-wchuk L: (A unique structure for epidermal growth receptor bound to GW572016 (lapatinib): Relationships among protein conformation, Inhibitor off-rate, and receptor activity in tumor cells).Cancer Res 64:6652–6659, 2004.PubMedCrossRefGoogle Scholar
  15. 15).
    Xia W, Bisi J, Strum J, Liu L, Carrick K, Graham KM, Treece AL, Hardwicke MA, Dush M, Liao Q, West-lund RE, Zhao S, Bacus S, Spector NL: (Regulation of survivin by ErbB2 signaling: therapeutic implications for ErbB2-overexpressing breast cancers).Cancer Res 66:1640–1647, 2006.PubMedCrossRefGoogle Scholar
  16. 16).
    Burris HA 3rd, Hurwitz HI, Dees EC, Dowlati A, Blackwell KL, O’Neil B, Marcom PK, Ellis MJ, Over-moyer B, Jones SF, Harris JL, Smith DA, Koch KM, Stead A, Mangum S, Spector NL: (Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas).J Clin Oncol 23:5305–5313, 2005.PubMedCrossRefGoogle Scholar
  17. 17).
    Lin NU, Carey LA, Liu MC, Younger J, Come SE, Bullitt E, Van Den Abbeele AD, Li X, Hochberg FH, Winer EP: (Phase II trial of lapatinib for brain metastases in patients with HER2+ breast cancer).Proc Am Soc Clin Oncol 24:18S, 2006.Google Scholar
  18. 18).
    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 65:11118–11128, 2005.PubMedCrossRefGoogle Scholar
  19. 19).
    Nahta R, Takahashi T, Ueno NT, Hung MC, Esteva FJ: (P27 (kipl) down-regulation is associated with trastuzumab resistance in breast cancer cells).Cancer Res 64:3981–3986, 2004.PubMedCrossRefGoogle Scholar
  20. 20).
    Lu Y, Zi X, Pollak M: (Molecular mechanisms underlying IGF-I-induced attenuation of the growth-inhibitory activity of trastuzumab (Herceptin) on SKBR3 breast cancer cells).Int J Cancer 108:334–341, 2004.PubMedCrossRefGoogle Scholar
  21. 21).
    Nagata Y, Lan KH, Zhou X, Tan M, Esteva FJ, Sahin AA, Klos KS, Li P, Monia BP, Nguyen NT, Horto-bagyi GN, Hung MC, Yu D: (PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients).Cancer Cell 6:103–104, 2004.CrossRefGoogle Scholar
  22. 22).
    Nagy P, Friedlander E, Tanner M, Kapanen AI, Car-raway KL, Isola J, Jovin TM: (Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a Her-ceptin-resistant, MUC4-expressing breast cancer cell line).Cancer Res 65:473–482, 2005.PubMedGoogle Scholar
  23. 23).
    Burris HA 3rd, Hurwitz HI, Dees EC, Dowlati A, Bla-ckwell KL, O’Neil B, Marcom PK, Ellis MJ, Overmoy-er B, Jones SF, Harris JL, Smith DA, Koch KM, Stead A, Mangum S, Spector NL: (Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pretreated patients with metastatic carcinomas).J Clin Oncol 23:5305–5313, 2005.PubMedCrossRefGoogle Scholar
  24. 24).
    Versola M, Burris HA, Jones S, Wilding G, Taylor C, Pandite L, Smith DA, Stead A, Spector NL: (Clinical activity of GW572016 in EGF10003 in patients with solid tumors).Proc Am Soc Clin Oncol 22:14S, 2004.Google Scholar
  25. 25).
    Blackwell KL, Kaplan EH, Franco SX, Marcom PK, Maleski JE, Sorensen MJ, Berger MS: (A phase II, open-label, multicenter study of GW572016 in patients with trastuzumab-refractory metastatic breast cancer).Proc Am Soc Clin Oncol 22:14S, 2004.Google Scholar
  26. 26).
    Gomez HL, Chavez MA, Doval DC, Nag S, Chow LW, Chang PC, Ahmad NM, Berger M, Arbushites M, Westlund R, Stanislaus M, Zaks T, Stein S: Results from a phase II randomized study of lapatinib as first-line treatment for patients with ErbB2-amplified advanced or metastatic breast cancer.Breast Cancer Res and Treat 100:S68, 2006.Google Scholar
  27. 27).
    Spector NL, Blackwell K, Hurley J, Harris JL, Lom-bardi D, Bacus S, Ahmed SB, Boussen H, Frikha M, Ayed FB: (EGF103009, a phase II trial of lapatinib monotherapy in patients with relapsed/refractory inflammatory breast cancer (IBC): Clinical activity and biologic predictors of response).Proc Am Soc Clin Oncol24:18S, 2006.Google Scholar
  28. 28).
    Perez EA, Byrne JA, Hammond I.W, Rafi R, Martin AM, Berger MS, Zaks TZ, Oliva CR, Roychowdhury DF, Stein SH: (Results of an analysis of cardiac function in 2,812 patients treated with lapatinib).Proc Am Soc Clin Oncol 24:18S, 2006.Google Scholar
  29. 29).
    Minami H, Nakagawa K, Kawada K, Mukai H, Tahara M, Kurata T, Uejima H, Nogami T, Sasaki Y, Fukuoka M: (A phase I study of GW572016 in patients with solid tumors).Proc Am Soc Clin Oncol 22:14S, 2004.Google Scholar
  30. 30).
    Iwata H, Toi M, Fujiwara Y, Ito Y, Fujii H, Nakamura S, Aogi K, Zaks T, Sasaki Y, Takashima S: Phase II clinical study of lapatinib (GW572016) in patients with advanced or metastatic breast cancer.Breast Cancer Res and Treat 100:S68, 2006.Google Scholar
  31. 31).
    Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D: (Lapatinib plus capecitabine for HER2-positive advanced breast cancer).N Engl J Med 355:2733–2743, 2006.PubMedCrossRefGoogle Scholar
  32. 32).
    Cristofanilli M, Boussen H, Baselga J, Lluch A, Ben Ayed F, Friaha M, Ben Ahmed S, Hurley J, Johnston S, Kaufman B, Findlay M, Olopade O, Shannon C, Harris J, Stein S, Spector N: A phase II combination study of lapatinib and paclitaxel as a neoadjuvant therapy in patients with newly diagnosed inflammatory breast cancer (IBC).Breast Cancer Res and Treat 100:S5, 2006.Google Scholar
  33. 33).
    Schiff R, Massarweh SA, Shou J, Bharwani L, Mohsin SK, Osborne CK: (Cross-talk between estrogen receptor and growth factor pathways as a molecular target for overcoming endocrine resistance).Clin Cancer Res 10:331S-336S, 2004.PubMedCrossRefGoogle Scholar
  34. 34).
    Bjornstrom L, Sjoberg M: (Mechanisms of estrogen receptor signaling: convergence of genomic and nongenomic actions on target genes).Mol Endocrinol 19:833–842, 2005.PubMedCrossRefGoogle Scholar
  35. 35).
    Albain K, Elledge R, Gradishar WJ, Hayes DF, Rowin-bsky E, Hudis C, Pusztai L, Treipathy D, Modi S, Rubi S: Open-label, phase II, multicenter trial of ZD1839 (Iressa) in patients with advanced breast cancer.Breast Cancer Res and Treat 76:S33, 2002.Google Scholar
  36. 36).
    Baselga J, Albanell J, Ruiz A, Lluch A, Gascon P, Guillem V, Gonzalez S, Sauleda S, Marimon I, Tabe-rnero JM, Koehler MT, Rojo F: (Phase II and tumor pharmacodynamic study of gefitinib in patients with advanced breast cancer).J Clin Oncol 23:5323–5333, 2005.PubMedCrossRefGoogle Scholar
  37. 37).
    Robertson JFR, Gutteridge E, Cheung KL, Owers R, Koehler M, Hamilton L, Gee J, Nicholson RI: Gefitinib (ZD1839) is active in acquired tamoxifen (TAM)-resistant oestrogen receptor (ER)-positive and ER-negative breast cancer: Results from a phase II study. Proc Am Soc Clin Oncol 22:2003.Google Scholar
  38. 38).
    Ellis MJ, Coop A, Singh B, Mauriac L, Llombert-Cus-sac A, Janicke F, Miller WR, Evans DB, Dugan M, Brady C, Quebe-Fehling E, Borgs M: (Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase HI randomized trial).J Clin Oncol 19:3808–3816, 2001.PubMedGoogle Scholar
  39. 39).
    Konecny GE, Pegram MD, Venkatesan N, Finn R, Yang G, Rahmeh M, Untch M, Rusnak DW, Spehar G, Mullin RJ, Keith BR, Gilmer TM, Berger M, Pod-ratz KC, Slamon DJ: Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overex-pressing and trastuzumab-treated breast cancer cells.Cancer Res 66:1630–1639, 2006.PubMedCrossRefGoogle Scholar
  40. 40).
    Xia W, Gerard CM, Liu L, Baudson NM, Ory TL, Spector NL: (Combining lapatinib (GW572016), a small molecule inhibitor of ErbB1 and ErbB2 tyrosine kinases, with therapeutic anti-ErbB2 antibodies enhances apoptosis of ErbB2-overexpressing breast cancer cells).Oncogene 24:6213–6221, 2005.PubMedCrossRefGoogle Scholar
  41. 41).
    Storniolo A, Burris H, Pegram M, Overmoyer B, Miller K, Jones S, Silverman P, Paul E, Loftiss J, Pandite L: (A phase I, open-label study of lapatinib (GW 572016) plus trastuzumab; a clinically active regimen).Proc Am Soc Clin Oncol 23:16S, 2005.Google Scholar
  42. 42).
    Dejonge M, Savage S, Verweij J, Collins TS, Eskens F, Whitehead B, Suttle AB, Pandite LB, Ho PT, Hurwitz H: (A Phase I, open-label study of the safety and pharmacokinetics of pazopanib and lapatinib administered concurrently).Proc Am Soc Clin Oncol 24:18S, 2006.Google Scholar
  43. 43).
    Witters L, Witkoski A, Planas-Silva M, Viallet J, Berger M, Lipton A: (Synergistic inhibition of breast cancer cell lines with the combination of a dual inhibitor of EGFR/HER-2/neu and a Bcl-2 inhibitor Journal of Clinical Oncology).Proc Am Soc Clin Oncol 24:18S, 2006.Google Scholar
  44. 44).
    Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, Thorsen T, Quist H, Matese JC, Brown PO, Botstein D, Eystein Lonning P, Borresen-Dale AL: (Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications).Proc Natl Acad Set USA 98:10869–10874, 2001.CrossRefGoogle Scholar
  45. 45).
    Spector NL, Xia W, Burris H 3rd, Hurwitz H, Dees EC, Dowlati A, O’Neil B, Overmoyer B, Marcom PK, Blackwell KL, Smith DA, Koch KM, Stead A, Man-gum S, Ellis MJ, Liu L, Man AK, Bremer TM, Harris J, Bacus S: (Study of the biologic effects of lapatinib, a reversible inhibitor of ErbB1 and ErbB2 tyrosine kinases, on tumor growth and survival pathways in patients with advanced malignancies).J Clin Oncol 23:2502–2512, 2005.PubMedCrossRefGoogle Scholar

Copyright information

© The Japanese Breast Cancer Society 2007

Authors and Affiliations

  • Yoshinori Ito
    • 1
  • Nahomi Tokudome
    • 1
  • Tsutomu Sugihara
    • 1
  • Shunji Takahashi
    • 1
  • Kiyohiko Hatake
    • 1
  1. 1.Department of Medical OncologyCancer Institute Hospital, Japanese Foundation for Cancer ResearchJapan

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