Challenges of Brain Metastasis in ErbB2 (HER-2-positive) Breast Cancer and the Potential of Small Molecules

Challenges of Brain Metastasis in ErbB2 (HER-2-positive) Breast Cancer and the Potential of Small Molecules

Alexandra dos Santos Zimmer, David Cameron
European Oncological Disease 2007
Published: October 2008
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Brain Metastasis in Breast Cancer
The incidence of central nervous system (CNS) metastatic disease in breast cancer patients depends on the stage at initial diagnosis. Approximately 2.5% of those patients who initially presented with localised disease, 7.6% of those with regional disease at presentation and 13.4% of patients presenting with stage IV disease are suffering from CNS metastatic disease.1–3 However, there are no prospective screening studies of serial computed tomography (CT) or magnetic resonance imaging (MRI) to evaluate the rate of occult CNS metastasis in patients with breast cancer over time.4 Where more extensive studies have been performed, higher rates have been reported. For example, Miller et al. reported an incidence of 14.8% of occult CNS involvement in heavily pre-treated breast cancer patients,5 and autopsy studies have found clinically unsuspected brain metastasis in 30% of patients with advanced breast cancer.6,7

The median time to diagnosis of CNS metastatic disease is two years after the initial diagnosis of breast cancer, and it is unusual for it to be the only site of metastatic disease.8,9 Systemic disease used to be the leading cause of morbidity and mortality in these patients.2 There is only limited knowledge of the factors that predict for the development of CNS metastasis, but the main ones reported include young age, African ethnicity, oestrogen receptor (OR)-negativity, HER2-positivity, high tumour grade and BRCA1 phenotype.1,2,5,9–12

Clinical Presentation and Consequences of Brain Metastasis Headache is the most common manifestation of parenchymal brain metastasis, occurring in between quarter and half of all patients. In addition, changes in mental status and cognitive function occur in a similar number of patients. Other manifestations that can also occur are motor deficits, seizures, ataxia and nausea or vomiting. The presence of hemiparesis, hemisensory loss and aphasia are not common, but are usually related to parenchymal metastasis.2

Leptomeningeal metastasis can present with the same clinical picture as parenchymal lesions, but more frequently the symptoms involve pain or headache. Cranial neuropathies may occur, with cranial nerves 3, 4, 6, 7 and 8 the most often affected.2

The negative impact of brain metastasis on the quality of life for both patients and their families is clear. There will be obvious limitations in daily tasks and activities and, even for those without any functional loss, in many countries there is an immediate prohibition on driving a vehicle.

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References:
  1. Barnholtz-Sloan JS, et al., Incidence proportions of brain metastases in patients diagnosed (1973 to 2001) in the Metropolitan Detroit Cancer Surveillance System, J Clin Oncol, 2004;22:2865–72.
  2. Lin NU, Bellon JR, Winer, EP, CNS metastases in breast cancer, J Clin Oncol, 2004;22:3608–17.
  3. Tsukada Y, Fouad A, Pickren JW, Lane WW, Central nervous system metastasis from breast carcinoma. Autopsy study, Cancer, 1983;52:2349–54.
  4. Lin NU, Winer EP, Brain metastases: the HER2 paradigm, Clin Cancer Res, 2007;13:1648–55.
  5. Miller KD, et al., Occult central nervous system involvement in patients with metastatic breast cancer: prevalence, predictive factors and impact on overall survival, Ann Oncol, 2003;14: 1072–7.
  6. Cho SY, Choi HY, Causes of death and metastatic patterns in patients with mammary cancer. Ten-year autopsy study, Am J Clin Pathol, 1980;73:232–4.
  7. Lee YT, Breast carcinoma: pattern of metastasis at autopsy, J Surg Oncol, 1983;23:175–80.
  8. Carey LA, et al., Central nervous system metastases in women after multimodality therapy for high risk breast cancer, Breast Cancer Res Treat, 2004;88:273–80.
  9. Gonzalez-Angulo AM, et al., Central nervous system metastases in patients with high-risk breast carcinoma after multimodality treatment, Cancer, 2004;101:1760–66.
  10. Hicks DG, et al., Breast cancers with brain metastases are more likely to be estrogen receptor negative, express the basal cytokeratin CK5/6, and overexpress HER2 or EGFR, Am J Surg Pathol, 2006;30:1097–1104.
  11. Ryberg M, et al., Predictors of central nervous system metastasis in patients with metastatic breast cancer. A competing risk analysis of 579 patients treated with epirubicin-based chemotherapy, Breast Cancer Res Treat, 2005;91:217–25.
  12. Souglakos J, et al., Central nervous system relapse in patients with breast cancer is associated with advanced stages, with the presence of circulating occult tumour cells and with the HER2/neu status, Breast Cancer Res, 2006;8:R36.
  13. Slamon DJ, et al., Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene, Science, 1987;235:177–82.
  14. Slamon DJ, et al., Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer, Science, 1989;244:707–12.
  15. Slamon DJ, 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.
  16. Clayton AJ, et al., Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer, Br J Cancer, 2004;91:639–43.
  17. Stemmler HJ, et al., Characteristics of patients with brain metastases receiving trastuzumab for HER2 overexpressing metastatic breast cancer, Breast, 2006;15:219–25.
  18. Yau T, et al., Incidence, pattern and timing of brain metastases among patients with advanced breast cancer treated with trastuzumab, Acta Oncol, 2006;45:196–201.
  19. Moy B, Goss PE, Lapatinib: current status and future directions in breast cancer, Oncologist, 2006;11:1047–57.
  20. Doolittle ND, et al., Delivery of chemotherapy and antibodies across the blood-brain barrier and the role of chemoprotection, in primary and metastatic brain tumours: report of the Eleventh Annual Blood-Brain Barrier Consortium meeting, J Neurooncol, 2007;81:81–91.
  21. Pestalozzi BC, et al., Identifying breast cancer patients at risk for Central Nervous System (CNS) metastases in trials of the International Breast Cancer Study Group (IBCSG), Ann Oncol, 2006;17:935–44.
  22. Bendell JC, et al., Central nervous system metastases in women who receive trastuzumab-based therapy for metastatic breast carcinoma, Cancer, 2003;97:2972–7.
  23. Lai R, Dang CT, Malkin MG, Abrey LE, The risk of central nervous system metastases after trastuzumab therapy in patients with breast carcinoma, Cancer, 2004;101:810–16.
  24. Burstein HJ, Lieberman G, Slamon DJ, et al., Isolated central nervous system metastases in patients with HER2- overexpressing advanced breast cancer treated with first-line trastuzumab-based therapy, Ann Oncol, 2005;16:1772–7.
  25. Gabos Z, et al., Prognostic significance of human epidermal growth factor receptor positivity for the development of brain metastasis after newly diagnosed breast cancer, J Clin Oncol, 2006;24:5658–63.
  26. Smith I, et al., 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial, Lancet, 2007;369:29–36.
  27. Romond EH, et al., Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer, N Engl J Med, 2005;353:1673–84.
  28. Patel RR, Mehta MP, Targeted therapy for brain metastases: improving the therapeutic ratio, Clin Cancer Res, 2007;13: 1675–83.
  29. Boogerd W, Dalesio O, Bais EM, van der Sande JJ, Response of brain metastases from breast cancer to systemic chemotherapy, Cancer, 1992;69:972–80.
  30. Rosner D, Nemoto T, Lane WW, Chemotherapy induces regression of brain metastases in breast carcinoma, Cancer, 1986;58:832–9.
  31. Fleming DR, Goldsmith GC, Stevens DA, Herzig RH, Doseintensive chemotherapy for breast cancer with brain metastases: a case series, Am J Clin Oncol, 1999;22:371–4.
  32. Rivera E, et al., Phase I study of capecitabine in combination with temozolomide in the treatment of patients with brain metastases from breast carcinoma, Cancer, 2006;107: 1348–54.
  33. Jayson GC, Howell A, Carcinomatous meningitis in solid tumours, Ann Oncol, 1996;7:773–86.
  34. Grossman SA, Krabak MJ, Leptomeningeal carcinomatosis, Cancer Treat Rev, 1999;25:103–19.
  35. Tetef ML, et al., Pharmacokinetics and toxicity of high-dose intravenous methotrexate in the treatment of leptomeningeal carcinomatosis, Cancer Chemother Pharmacol, 2006;46:19–26.
  36. Chamberlain MC, Kormanik PR, Carcinomatous meningitis secondary to breast cancer: predictors of response to combined modality therapy, J Neurooncol, 1997;35:55–64.
  37. Orlando L, et al., Intrathecal chemotherapy in carcinomatous meningitis from breast cancer, Anticancer Res, 2002;22: 3057–9.
  38. Aragon-Ching JB, Zujewski JA, CNS metastasis: an old problem in a new guise, Clin Cancer Res, 2007;13:1644–7.
  39. Reid A, Vidal L, Shaw H, de Bono J, Dual inhibition of ErbB1 (EGFR/HER1) and ErbB2 (HER2/neu), Eur J Cancer, 2007;43: 481–9.
  40. Baselga J, Arteaga CL, Critical update and emerging trends in epidermal growth factor receptor targeting in cancer, J Clin Oncol, 2005;23:2445–59.
  41. Britten CD, Targeting ErbB receptor signalling: a pan-ErbB approach to cancer, Mol Cancer Ther, 2004;3:1335–42.
  42. Xia W, et al., Combination of EGFR, HER-2/neu, and HER-3 is a stronger predictor for the outcome of oral squamous cell carcinoma than any individual family members, Clin Cancer Res, 1999;5:4164–74.
  43. Tateishi M, et al., Prognostic influence of the co-expression of epidermal growth factor receptor and c-erbB-2 protein in human lung adenocarcinoma, Surg Oncol, 1994;3:109–13.
  44. Rusnak DW, et al., The effects of the novel, reversible epidermal growth factor receptor/ErbB-2 tyrosine kinase inhibitor, GW2016, on the growth of human normal and tumour-derived cell lines in vitro and in vivo, Mol Cancer Ther, 2001;1:85–94.
  45. Burris HA 3rd, et al., Phase I safety, pharmacokinetics, and clinical activity study of lapatinib (GW572016), a reversible dual inhibitor of epidermal growth factor receptor tyrosine kinases, in heavily pre-treated patients with metastatic carcinomas, J Clin Oncol, 2005;23:5305–13.
  46. Blackwell KL, Burstein H, Pegram M, et al., Determining relevant biomarkers from tissue and serum that may predict response to single agent lapatinib in trastuzumab refractory metastatic breast cancer, in ASCO Vol. 23 3004 (J Clin Oncol, 2005).
  47. Gomez HL, Chavez MA, Doval DC, Randomised study of lapatinib as first-line treatment for patients with HER2- amplified advanced or metastatic breast cancer, in San Antonio Breast Cancer Symposium (San Antonio-USA, 2006).
  48. Lin NUC, Lin LA, Younger J, et al., Phase II trial of lapatinib for brain metastases in patients with HER2+ breast cancer, in ASCO Vol. 24 503 (J Clin Oncol, 2006).
  49. www.clinicaltrials.gov. Clinical Trials. Vol. 2007.
  50. Geyer CE, et al., Lapatinib plus capecitabine for HER2- positive advanced breast cancer, N Engl J Med, 2006;355:2733–43.
  51. Namba Y, et al., Gefitinib in patients with brain metastases from non-small-cell lung cancer: review of 15 clinical cases, Clin Lung Cancer, 2004;6:123–8.
  52. Shaw H, A phase I dose escalation study of BIBW 2992, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in patients with advanced solid tumours, in ASCO Vol. 18S (J Clin Oncol, 2006).
  53. Rabindran SK, et al., Antitumour activity of HKI-272, an orally active, irreversible inhibitor of the HER-2 tyrosine kinase, Cancer Res, 2004;64:3958–65.
  54. Allen LF, Eiseman IA, Fry DW, Lenehan PF, CI-1033, an irreversible pan-erbB receptor inhibitor and its potential application for the treatment of breast cancer, Semin Oncol, 2003;30:65–78.
  55. Izzedine H, Buhaescu I, Rixe O, Deray G, Sunitinib malate, Cancer Chemother Pharmacol, 2006.
  56. Abrams TJ, et al., Pre-clinical evaluation of the tyrosine kinase inhibitor SU11248 as a single agent and in combination with ‘standard of care’ therapeutic agents for the treatment of breast cancer, Mol Cancer Ther, 2003;2:1011- –21.
  57. Murray LJ, et al., SU11248 inhibits tumour growth and CSF- 1R-dependent osteolysis in an experimental breast cancer bone metastasis model, Clin Exp Metastasis, 2003;20:757–66.
  58. Miller KDB, Rugo AD, et al., Phase II study of SU11248, a multitargeted receptor tyrosine kinase inhibitor (TKI), in patients with previously treated metastatic breast cancer, in ASCO Vol. 23 563, 2005.
  59. Patyna SP, Distribution of sunitinib and its active metabolite in brain and spinal cord tissue following oral or intravenous administrations in rodents and monkeys, in ENA Vol. 4 21 (Eur J Cancer, Prague, 2006).
  60. Wachsberger P, Burd R, Dicker AP, Improving tumour response to radiotherapy by targeting angiogenesis signalling pathways, Hematol Oncol Clin North Am, 2004;18:1039–57, viii.
  61. Schueneman AJ, et al., SU11248 maintenance therapy prevents tumour regrowth after fractionated irradiation of murine tumour models, Cancer Res, 2003;63:4009–16.
  62. Zingg D, et al., Differential activation of the phosphatidylinositol 3’-kinase/Akt survival pathway by ionising radiation in tumour and primary endothelial cells, Cancer Res, 2004;64:5398–5406.
  63. Tan J, Hallahan DE, Growth factor-independent activation of protein kinase B contributes to the inherent resistance of vascular endothelium to radiation-induced apoptotic response, Cancer Res, 2003;63:7663–7.
  64. Boehm T, Folkman J, Browder T, O’Reilly MS, Antiangiogenic therapy of experimental cancer does not induce acquired drug resistance, Nature, 1997;390:404–7.
  65. Kim DW, Huamani J, Fu A, Hallahan DE, Molecular strategies targeting the host component of cancer to enhance tumour response to radiation therapy, Int J Radiat Oncol Biol Phys, 2006;64:38–46.
  66. Wong TZ, van der Westhuizen GJ, Coleman RE, Positron emission tomography imaging of brain tumours, Neuroimaging Clin N Am, 2002;12:615–26.

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