Trastuzumab in the breast cancer treatment: efficacy and resistance mechanisms

1. Slamon DJ, Clark GM, Wong SG et al. Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987; 235: 177–182.

2. Ross JS, Fletcher JA, Bloom KJ et al. Targeted therapy in breast cancer: the HER-2/neu gene and protein. Mol Cell Proteomics 2004; 3(4): 379–398 (Review).

3. 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 USA 1987; 84(20): 7159–7163.

4. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001; 2(2): 127–137 (Review).

5. Codony-Servat J, Albanell J, Lopez-Talavera JC et al. Cleavage of the HER2 ectodomain is a pervanadate‑activable process that is inhibited by the tissue inhibitor of metalloproteases-1 in breast cancer cells. Cancer Res 1999; 59(6): 1196–1201.

6. Vivanco I, Sawyers CL. The phosphatidylinositol 3-Kinase AKT pathway in human cancer. Nat Rev Cancer 2002; 2(7): 489–501 (Review).

7. Shalaby MR, Shepard HM, Presta L et al. Development of humanized bispecific antibodies reactive with cytotoxic lymphocytes and tumor cells overexpressing the HER2 protooncogene. J Exp Med 1992; 175(1): 217–225.

8. Molina MA, Codony-Servat J, Albanell J et al. Trastuzumab (herceptin), a humanized anti‑Her2 receptor mono­clonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells. Cancer Res 2001; 61(12): 4744–4749.

9. Grell P, Petráková K, Šimíčková M et al. Serum HER-2/neu: a tumor marker for monitoring response to treatment of metastatic breast cancer with trastuzumab. 19th Meeting of European Association For Cancer Research, Budapest 2006: S207.

10. Clark AS, West K, Streicher S et al. Constitutive and inducible Akt activity promotes resistance to chemotherapy, trastuzumab, or tamoxifen in breast cancer cells. Mol Cancer Ther 2002; 1(9): 707–717.

11. Yakes FM, Chinratanalab W, Ritter CA et al. Herceptin‑induced inhibition of phosphatidylinositol-3 kinase and Akt Is required for antibody-mediated effects on p27, cyclin D1, and antitumor action. Cancer Res 2002; 62(14): 4132–4141.

12. Chen WS, Xu PZ, Gottlob K et al. Growth retardation and increased apoptosis in mice with homozygous disruption of the Akt1 gene. Genes Dev 2001; 15: 2203–2208.

13. Cho H, Thorvaldsen JL, Chu Q et al. Akt1/PKBα is required for normal growth but dispensable for maintenance of glucose homeostasis in mice. J Biol Chem 2001; 276: 38349–38352.

14. Cho H, Mu J, Kim JK et al. Insulin resistance and a diabetes mellitus‑like syndrome in mice lacking the protein kinase Akt2 (PKBß). Science 2001; 292: 1728–1731.

15. Garofalo RS, Orena SJ, Rafidi K et al. Severe diabetes, age-dependent loss of adipose tissue, and mild growth deficiency in mice lacking Akt2/PKBß. J Clin Invest 2003; 112: 197–208.

16. Easton RM, Cho H, Roovers K et al. Role for Akt3/protein kinase Bγ in attainment of normal brain size. Mol Cell Biol 2005; 25: 1869–1878.

17. Tschopp O, Yang ZZ, Brodbeck D et al. Essential role of protein kinase Bγ (PKBγ/Akt3) in postnatal brain development but not in glucose homeostasis. Development 2005; 132: 2943–2954.

18. Alessi DR, James SR, Downes CP et al. Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. Curr Biol 1997; 7(4): 261–269.

19. Troussard AA, McDonald PC, Wederell ED et al. Preferential dependence of breast cancer cells versus normal cells on integrin‑linked kinase for protein kinase B/Akt activation and cell survival. Cancer Res 2006; 66(1): 393–403.

20. Feng J, Park J, Cron P et al. Identification of a PKB/Akt hydrophobic motif Ser-473 kinase as DNA-dependent protein kinase. J Biol Chem 2004; 279(39): 41189–41196. Epub 2004 Jul 15.

21. Sarbassov DD, Guertin DA, Ali SM et al. Phosphorylation and regulation of Akt/PKB by the rictor-mTOR complex. Science 2005; 307(5712): 1098–1101.

22. Maddika S, Bay GH, Kroczak TJ et al. Akt is transferred to the nucleus of cells treated with apoptin, and it participates in apoptin‑induced cell death. Cell Prolif 2007; 40(6): 835–848.

23. Svoboda M, Grell P, Fabian P et al. Significance of Akt activation and compartmentalization for prediction of outcome in Her-2 positive breast cancer patients treated with trastuzumab (Abstrakt 4022). Breast Cancer Res Treat 2007; 106 (Suppl 1): 173.

24. Nagata Y, Lan KH, Zhou X et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell 2004; 6(2): 117–127.

25. Clynes RA, Towers TL, Presta LG et al. Inhibitory Fc receptors modulate in vivo cytoxicity against tumor targets. Nat Med 2000; 6(4): 443–446.

26. Gennari R, Menard S, Fagnoni F et al. 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): 5650–5655.

27. Izumi Y, Xu L, di Tomaso E et al. Tumour biology: herceptin acts as an anti‑angiogenic cocktail. Nature 2002; 416(6878): 279–280.

28. Sarup JC, Johnson RM, King KL et al. Characterization of an anti‑p185HER2 monoclonal antibody that stimulates receptor function and inhibits tumor cell growth. Growth Regul 1991; 1(2): 72–82.

29. Baselga J, Albanell J, Molina MA et al. Mechanism of action of trastuzumab and scientific update. Semin Oncol 2001; 28 (Suppl 16): 4–11.

30. Slamon DJ, Leyland-Jones B, Shak S et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001; 344(11): 783–792.

31. Pegram MD, Lipton A, Hayes DF et al. 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): 2659–2671.

32. Lôrincz T, Tóth J, Badalian G et al. HER-2/neu genotype of breast cancer may change in bone metastasis. Pathol Oncol Res 2006; 12(3): 149–152.

33. Gancberg D, Di Leo A, Cardoso F et al. Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites. Ann Oncol 2002; 13(7): 1036–1043.

34. Gong Y, Booser DJ, Sneige N. Comparison of HER-2 status determined by fluorescence in situ hybridization in primary and metastatic breast carcinoma. Cancer 2005; 103(9): 1763–1769.

35. Price-Schiavi SA, Jepson S, Li P et al. 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): 783–791.

36. Nagy P, Friedländer E, Tanner M et al. 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): 473–482.

37. Christianson TA, Doherty JK, Lin YJ et al. NH2‑terminally truncated HER-2/neu protein: relationship with shedding of the extracellular domain and with prognostic factors in breast cancer. Cancer Res 1998; 58(22): 5123–5129.

38. Molina MA, Sáez R, Ramsey EE et al. NH(2)‑terminal truncated HER-2 protein but not full-length receptor is associated with nodal metastasis in human breast cancer. Clin Cancer Res 2002; 8(2): 347–353.

39. Anido J, Scaltriti M, Bech Serra, JJ et al. Biosynthesis of tumorigenic HER2 C‑terminal fragments by alternative initiation of translation. EMBO J 2006; 25(13): 3234–3244. Epub 2006 Jun 22.

40. Scaltriti M, Rojo F, Ocaña A et al. 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): 628–638.

41. Sáez R, Molina MA, Ramsey EE et al. p95HER-2 predicts worse outcome in patients with HER-2-positive breast cancer. Clin Cancer Res 2006; 12(2): 424–431.

42. Cameron D, Casey M, Press M et al. A phase III randomized comparison of lapatinib plus capecitabine versus capecitabine alone in women with advanced breast cancer that has progressed on trastuzumab: updated efficacy and biomarker analyses. Breast Cancer Res Treat 2008: Jan 11 [Epub ahead of print].

43. Lin NU, Paul D, Dieras V et al. Lapatinib and capecitabine for the treatment of brain metastases in patients with HER2+ breast cancer – an updated analysis from EGF105084. (Abstract 6076). Breast Cancer Res Treat 2007; 106 (Suppl 1).

44. Lee JW, Soung YH, Seo SH et al. Somatic mutations of ERBB2 kinase domain in gastric, colorectal, and breast carcinomas. Clin Cancer Res 2006; 12(1): 57–61.

45. Nahta R, Hung MC, Esteva FJ. The HER-2-targeting antibodies trastuzumab and pertuzumab synergistically inhibit the survival of breast cancer cells. Cancer Res 2004; 64(7): 2343–2346.

46. Nahta R, Yuan LX, Zhang B et al. 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): 11118–11128.

47. Baselga J, Cameron D, Miles D et al. Objective response rate in a phase II multicenter trial of pertuzumab (P), a HER2 dimerization inhibiting monoclonal antibody, in combination with trastuzumab (T) in patients (pts) with HER2-positive metastatic breast cancer (MBC) which has progressed during treatment with T (Abstract 1004). Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings. Part I. Vol 25, No. 18S (June 20, Suppl).

48. Allen LF, Eiseman IA, Fry DW et al. CI-1033, an irreversible pan-erbB receptor inhibitor and its potential application for the treatment of breast cancer. Semin Oncol 2003; 30 (5 Suppl 16): 65–78.

49. Burstein H, Awada A, Badwe R et al. HKI-272, an irreversible pan erbB receptor tyrosine kinase inhibitor: preliminary phase 2 results in patients with advanced breast cancor (Abstract 6061). Breast Cancer Res Treat 2007; 106 (Suppl 1).

50. Fujita T, Doihara H, Kawasaki K et al. PTEN activity could be a predictive marker of trastuzumab efficacy in the treatment of ErbB2-overexpressing breast cancer. Br J Cancer 2006; 94(2): 247–252.

51. Fujita T, Doihara H, Washio K et al. Proteasome inhibitor bortezomib increases PTEN expression and enhances trastuzumab‑induced growth inhibition in trastuzumab‑resistant cells. Anticancer Drugs 2006; 17(4): 455–462.

52. Lu CH, Wyszomierski SL, Tseng LM et al. Preclinical testing of clinically applicable strategies for overcoming trastuzumab resistance caused by PTEN deficiency. Clin Cancer Res 2007; 13(19): 5883–5888.

53. Resnicoff M, Baserga R. The role of the insulin‑like growth factor I receptor in transformation and apoptosis. Ann N Y Acad Sci 1998; 842: 76–81.

54. Khandwala HM, McCutcheon IE, Flyvbjerg A et al. The effects of insulin‑like growth factors on tumorigenesis and neoplastic growth. Endocr Rev 2000; 21: 215–244.

55. O’Connor R, Fennelly C, Krause D. Regulation of survival signals from the insulin‑like growth factor-I receptor. Biochem Soc Trans 2000; 28: 47–51.

56. Samani AA, Yakar S, LeRoith D et al. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev 2007; 28(1): 20–47. Epub 2006 Aug 24 (Review).

57. Köstler WJ, Hudelist G, Rabitsch W et al. Insulin‑like growth factor-1 receptor (IGF‑1R) expression does not predict for resistance to trastuzumab‑based treatment in patients with Her-2/neu overexpressing metastatic breast cancer. J Cancer Res Clin Oncol 2006; 132(1): 9–18. Epub 2005 Sep 24.