Interb: International clinical registry of ErbB2-positive breast cancer patients treated with lapatinib

Treatment options for HER2/neu breast cancer patients: a quick overview


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HER2/neu positivity

Breast cancer is a complex disease involving the dysregulated activation of multiple intracellular signalling cascades, leading to uncontrolled proliferation, prolonged cell survival, angiogenesis, invasion and metastasis [1]. 20- 30% of breast carcinomas overexpress the HER2/neu receptor (HER2) on cell surface. The overexpression of HER2/neu is associated with a higher tumor aggressiveness and significantly shorter overall survival [2]. The HER2/neu receptor belongs to the epidermal growth factor receptors family that have a variety of growth factors as physiological ligands. However, HER2/neu is the only member of the ErbB family that has no known natural or physiological ligand. Instead, it is held in conformation similar to ErbB monomers that have already bounded ligand, allowing to form homodimers or heterodimers with other ligand-bound ErbB receptors (mainly ErbB3) to stimulate intracellular signalling [3]. Stimulation of the receptors leads to tyrosine kinases phosphorylation, which activate pathways for cell survival (phosphatidyl-inositol-3 kinase) and proliferation (mitogen-activated protein kinase). The activated signal pathway and cellular process are determined by the homodimer or heterodimer composition.

Although tumorigenesis is a result of several mutations and/or epigenetic events, some solid tumors, including HER2/neu-positive breast cancer, are highly dependent on just one oncogene [1]. For example, in vitro experiments focused on downregulation of the HER2/neu gene expression showed up to 60% reduction of HER2/neu -positive cancer cells proliferation [4]. Further, ErB2 is a preferred heterodimeric partner in the generation of heterodimeric signalling complexes. Thus, a high attention is given to HER2/neu inhibitors in the development of successful HER2/neu -positive cancer therapies.

Breast cancer therapy: current approaches

Trastuzumab (Herceptin®), a monoclonal antibody that binds to the extracellular domain of the HER2/neu protein, has been recently used in the treatment of metastatic and early-stage HER2/neu -positive cancer, usually in combination with other chemoterapeutic agent. Nevertheless, some carcinomas develop resistance to trastuzumab and the therapy may fail [5,6]. The proposed mechanisms of resistance include expression of redundant survival signalling pathways, deficient expression of the PTEN suppressor gene, expression of a highly active truncated form of HER2/neu (p95HER-2) lacking the extracellular domain – the recognition site for trastazumab, and downregulation of the cyclin-dependent kinase inhibitor p27kip1 [7].

Lapatinib is a small molecule, which is able to penetrate the cell and block the inside part of the HER2/neu receptor. The molecule competes with ATP for binding at the HER2/neu catalytic kinase domain block, preventing the tyrosine kinase enzyme from being activated. The inhibition is reversible.

Thus, the principle of action is different from trastuzumab and other types of therapies. An international Phase III trial (EGF100151) confirmed a high efficacy of the lapatinib treatment in combination with capecitabine in HER2/neu -positive patients in comparison to capecitabine monotherapy [8,9]. In the ITT population, as determined by an independent review, the combination of lapatinib and capecitabine prolonged the median time to progression to 27.1 weeks versus 18.6 weeks (HR= 0.57, p < 0.001) with capecitabine monotherapy in women pretreated with an anthracycline, a taxane, and trastuzumab. The overall response rate (CR+PR) was 23.7% vs 13.9% (p = 0.017), partial response 23% vs. 14%, clinical benefit (CR+PR+SD ≥ 6 months) 29.3% vs. 17.4% (p =0.008) [8,9]. Combination of lapatinib and paclitaxel as a first-line treatment was tested in a Phase III clinical trial [10]. Initial clinical studies also indicate a lapatinib potency in the treatment of the most aggressive form of the disease – inflammatory breast cancer [11]. With the prolonged survival of HER2/neu-positive patients, number of brain metastases increases. Large molecules do not effectively cross the blood-brain barrier. A Phase II study by Lin et al. [12] demonstrated that the small lapatinib molecule effectively crosses this barrier, has a biologic effect in brain tumors, and exhibits clinical activity.

HER2/neu targeted therapies are more effective when they are combined with other agents [7]. Trastuzumab is commonly used in combination with cytotoxic drugs. A combination of trastuzumab and lapatinib was also tested in a Phase I trial with encouraging results [13]. Preclinical studies indicate that lapatinib and trastuzumab have synergistic effect and, furthermore, lapatinib showed activity against cells, which were resistant to trastuzumab, and, therefore, there is no cross-resistance between lapatinib and trastuzumab [14]. Crosstalk between estrogen and ErbB receptors provides a rationale for combining HER2/neu therapies with antiestrogens [7].

Adverse side effects include e.g. diarrhea [15], skin rash, nausea, vomiting, tiredness etc. Nevertheless, the clinical studies confirmed that the lapatinib therapy (alone or in combination with other drugs) is generally well tolerated, adverse affects of grade 3 and 4 occur very rarely, and the incidence of the most frequent events can be easily managed by adopting safety guidelines [16]. Clinical trials also showed that the lapatinib use is associated with a low risk of cardiac adverse effects [17], which, however, appears to be lower than in the use of trastazumab [8].

References

  1. Baselga J (2008) Evolving options and future challenges for targeted therapies in ErbB2 (HER2)-positive breast cancer. EJC Suppl 6(5): 1-6.
  2. Slamon DJ, Clark GM,Wong SG, et al. (1987) Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235(4785): 177−82.
  3. Jackisch C (2008) Challenges in the treatment of ErbB2 (HER2)-positive breast cancer. EJC Suppl 6(5): 7-14.
  4. Colomer R, Lupu R, Bacus SS, Gelmann EP (1994) ErbB-2 antisense oligonucleotides inhibit the proliferation of breast carcinoma cells with erbB-2 oncogene amplification. Br J Cancer 70(5): 819−25.
  5. Smith IE (2001) Efficacy and safety of Herceptin in women with metastatic breast cancer: results from pivotal clinical studies. Anti-cancer Drug 12(Suppl 4): S3−10.
  6. Hsieh AC, Moasser MM (2007) Targeting HER proteins in cancer therapy and the role of the non-target HER3. Br J Cancer 97(4): 453−7.
  7. Spector N, Xia W, El-Hariry I, et al. (2007) Small molecule HER-2 tyrosine kinase inhibitors. Breast Cancer Res 9(2): 205
  8. Geyer CE, Forster J, Lindquist D, et al. (2006) Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 355(26): 2733−43.
  9. Cameron D, Casey M, Press M, et al. (2008) 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.
  10. Di Leo A, Gomez H, Aziz Z, et al. (2007) Lapatinib (L) with paclitaxel compared to paclitaxel as first-line treatment for patients with metastatic breast cancer: A phase III randomized, double-blind study of 580 patients. J Clin Oncol ASCO Annual Meeting Proceedings 25(Suppl 18): Abstract #1011.
  11. Cristofanilli M, Boussen H, Baselga J, et al (2006) 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 Treat 100(Suppl 1): Abstract #1.
  12. Lin NU, Carey LA, Liu MC, et al (2006) Phase II trial of lapatinib for brain metastases in patients with HER2+ breast cancer. J Clin Oncol 24(Suppl 18): Abstract #503.
  13. Storniolo A, Burris H, Pegram M et al (2005) A phase I, openlabel study of lapatinib (GW572016) plus trastuzumab; a clinically active regimen. J Clin Oncol 23(Suppl 16): Abstract #559.
  14. Konecny GE, Pegram MD, Venkatesan N, et al. (2006) Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumabtreated breast cancer cells. Cancer Res 66(3): 1630–1639.
  15. Crown JP, Burris HA, Jones S, et al. (2007) Safety and tolerability of lapatinib in combination with taxanes (T) in patients with breast cancer (BC). J Clin Oncol 25(18S): Abstract #1027.
  16. Cameron D (2008) Promises borne out in clinical studies. EJC Suppl 6(5): 15-24.
  17. Perez EA, Byrne JA, Hammond IW, et al. (2006) Cardiac safety experience in 3127 patients (pts) treated with lapatinib. Ann Oncol 17(Suppl 9): Abstract #1420.