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Published on 1 September 2007

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The emerging role of tyrosine kinase inhibitors in HER2-positive breast cancer

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Filippo Montemurro
MD

Senior consultant

Unit of Medical Oncology and Haematology
Institute for Cancer Research and Treatment
Candiolo
Turin
Italy

E: filippo.montemurro@ircc.it

Aberrant signalling through tyrosine kinase receptors (TKRs) is critically implicated in cancerogenesis and tumour progression. These receptors, which can be grouped into 20 subfamilies on the basis of structural ­characteristics, share common features: they have an extra‑cellular domain, which interacts with ligands, a trans‑membrane domain and an intracellular domain, which includes a highly conserved catalytic portion. This ­latter component contains the ATP-binding site, which is responsible for receptor ­autophosphorylation and downstream signalling initiation.(1)

The EGFR family of TKRs
The epidermal growth ­factor receptor (EGFR) ­family of TKRs, comprising four type I ­tyrosine kinase transmembrane receptors: EGFR/HER1, HER2, HER3 and HER4, plays an important role is played in human cancers.(2) These receptors are activated by ligand-induced homo- and heterodimerisation. Exceptions to this rule are represented by HER2, which has no known ligand and is believed to act by hetero‑dimerisation with the other members in the ­presence of their specific ligands, and by HER3, which has no intrinsic tyrosine kinase activity. Inhibition of ­aberrant signalling mediated by TKRs of the EGFR family may be achieved by ­targeting the receptor’s ­extracellular portion using, for ­example, monoclonal ­antibodies, or by interfering with the catalytic domain on the intracellular portion of the receptor with small-­molecule tyrosine kinase ­inhibitors (TKIs).

Targeting the HER2 abnormality
A subset of some 20–30% of breast cancers ­occurring in humans is characterised by ­amplification of the HER2 gene, which results in overexpression of the HER2 receptor.(3,4)

HER2 targeting with the monoclonal antibody trastuzumab has represented a major step forward in treating this subset of patients.(5–9) However, despite radical changes in prognosis, tumour progression during treatment is common. Optimal treatment of patients failing on trastuzumab treatment has been a dilemma until recently.(10) In fact, despite elegant preclinical models, mechanisms of resistance to this monoclonal antibody have not been ­convincingly elucidated in vivo, providing no solid grounds for designing rational salvage strategies.(11)

Among these mechanisms, cooperation of EGFR and HER2 has been correlated with ­resistance to trastuzumab. For example, our group has shown that overexpression of transforming growth ­factor alpha (TGFa), a natural ligand of EGFR, may ­characterise the acquisition of a trastuzumab-resistant phenotype.(12) This would suggest a ­possible role for combined EGFR and HER2 targeting as a strategy potentially resulting in overcoming and/or delaying trastuzumab resistance. Gefitinib and ­erlotinib are specific EGFR-TKIs which have been associated with clinical activity in lung cancer and in other “EGFR-driven neoplasms”.(13)

Unfortunately, a phase II trial of gefitinib and ­trastuzumab in HER2-positive advanced breast cancer patients suggested a possible antagonistic action, discouraging further developments in this direction.(14) Recently however lapatinib, a novel TKI, has provided promising data for patients with HER2-positive advanced breast cancer whose ­disease is not sensitive to trastuzumab. Lapatinib is an orally available 4-anilinoquinoline derivative that is able to reversibly inhibit the tyrosine kinase activity of EGFR and HER2. Like other small-molecule TKIs, lapatinib mimics ATP and competes with ATP for its binding site on the tyrosine kinase domain. Phase II trials showed that this compound is clinically active in patients with HER2-positive advanced breast ­cancer who have failed several previous lines of chemo‑therapy, including trastuzumab-based treatments.(15)

This prompted evaluation of this agent in a phase III trial, where heavily pretreated HER2-positive advanced breast cancer patients who had progressed during at least one previous ­trastuzumab-based programme were randomised to capecitabine (2,500 mg/m2/day administered orally for 14 consecutive days, with one week’s rest) or capecitabine (2,000 mg/m2/day administered orally for 14 consecutive days, with one week’s rest) plus lapatinib (1,250 mg/day continuously).(16) The study was shut down after the first interim analysis of efficacy and safety, triggered by the occurrence of 114 breast cancer events in 321 randomised patients. The intent-to-treat analysis of time to ­progression (TTP), which was the primary endpoint of the study, showed clear-cut superiority for the lapatinib-containing arm (hazard ratio 0.51, p = 0.00016). ­Interestingly, the authors reported a numerical advantage for the combined treatment in terms of less central nervous system progression in patients receiving lapatinib (4/160 vs 11/161 cases). This ­suggests that lapatinib, like other small-­molecule TKIs, may act beyond the blood/brain barrier. Both treatment arms were well tolerated, as testified by similar discontinuation rates in the absence of tumour progression (14% vs 11% in the combined and capecitabine-alone arms, respectively).

The main difference in the toxicity profile was an increase in grade 1 and 2 diarrhoea in the combined arm (45% vs 28%). A phase II trial of single-agent lapatinib in previously untreated HER2-positive advanced breast cancer patients showed that its clinical activity is in the range of that reported with single-agent trastuzumab in the same setting.(17)

Conclusion
Results obtained with the TKI lapatinib have been acclaimed as practice-changing and as offering a ­further weapon in the fight against HER2-­positive breast cancer. Several questions, which have ­implications for the rational use of these forms of targeted therapies, remain open. One is whether responders to trastuzumab or lapatinib share ­common biological features or if they are two ­distinct subgroups, where the choice of one or other ­compound may make a difference in terms of ­clinical efficacy. Another ­question is whether ­lapatinib is active, because of its nature of simultaneous EGFR and HER2 TKI, or just because targeting HER2 by tyrosine kinase inhibition is a more efficient way to interfere with the signalling mediated by this ­receptor. Despite these and other open questions forming the basis for ­ongoing research, the clinically valuable results obtained with lapatinib encourage further efforts at ­developing other HER2-directed TKIs, some of which have already been tested in clinical trials.(18)

References
1. Yarden Y, Ullrich A. Growth factor receptor tyrosine kinases. Annu Rev Biochem 1988;57:443-78.
2. Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol 2001;2:127-37.
3. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 1989;244:707-12.
4. 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;235:177-82.
5. Montemurro F, Valabrega G, Aglietta M. Trastuzumab-based combination therapy for breast cancer. Expert Opin Pharmacother 2004;5:81-96.
6. 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;344:783-92.
7. Marty M, Cognetti F, Maraninchi D, et al. 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. J Clin Oncol 2005;23:4265-74.
8. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353:1659-72.
9. Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353:1673-84.
10. Montemurro F, Donadio M, Clavarezza M, et al. Outcome of patients with HER2-positive advanced breast cancer progressing during trastuzumab-based therapy. Oncologist 2006;11:318-24.
11. Valabrega G, Montemurro F, Aglietta M. Trastuzumab: mechanism of action, resistance and future perspectives in HER2 overexpressing breast cancer. Ann Oncol 2007:18:977-84.
12. Valabrega G, Montemurro F, Sarotto I, et al. TGFalpha expression impairs trastuzumab-induced HER2 downregulation. Oncogene 2005;24:3002-10.
13. Baselga J, Arteaga CL. Critical update and emerging trends in epidermal growth factor receptor targeting in cancer. J Clin Oncol 2005;23:2445-59.
14. Arteaga CL, O’Neil A, Moulder SL, et al. ECOG1100: a phase I–II study of combined blockade of the erbB receptor network with trastuzumab and gefitinib ([Isquo]Iressa) in patients (pts) with HER2-overexpressing metastatic breast cancer (met br ca). Breast Cancer Res Treat 2004;88:S15. Abstract 25.
15. Montemurro F, Valabrega G, Aglietta M. Lapatinib: a dual inhibitor of EGFR and HER2 tyrosine kinase activity. Expert Opin Biol Ther 2007;7:257-68.
16. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med 2006;355:2733-43.
17. Gomez HL, Chavez MA, Doval DG, et al. Updated biomarker 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 Treat 2006; 100: S68. Abstract 1090.
18. Munster PN, Britten CD, Mita M, et al. First study of the safety, tolerability, and pharmacokinetics of CP-724,714 in patients with advanced malignant solid HER-2 expressing tumors. Clin Cancer Res 2007;13:1238-45.



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