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Brain Metastases in NSCLC
Boone Goodgame, MD
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Case Report #1
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Case Report #2
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Overview
• Epidemiology & prognosis
• Standards of care and current clinical questions
• Predicting brain metastasis based on molecular mechanisms
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Epidemiology
• Lung cancer is the most common cause of cancer death, with 160,000 new cases each year.
• Lung metastases are the most common intracranial malignancy.
• 30-70% of all solitary brain mets will be from a lung primary.
Lung Cancer 2001
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Epidemiology
• 10% of NSCLC subjects have brain mets at presentation.
• 6-9% of completely resected NSCLC recur only in the brain.
• 25-40% eventually develop brain mets.
• Incidence continues to rise as systemic therapy improves.
JCO 2005
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Prognosis• Without treatment, median survival is
approximately one month.
• With treatment, median survival from time of diagnosis of brain mets is 5 months. 1 year survival is 10%.
• With resected solitary brain mets, median survival is 10 months.
Int J Radiat Oncol Biol Phys 1999
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Palliative treatment
• Glucocorticoids improve symptoms and improve survival to a median of two months.
• Whole brain irradiation (WBI) improves survival to a median of 4-7 months.
Chest 92
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Resection of single metastases
JAMA 1998
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Stereotactic Radiosurgery (RS)“Gamma-Knife”
1 Cancer 19972 Lung Cancer 2004
• Advantages: Treat multiple lesions and those inaccessible by surgery.
• Severe complications (edema or hemorrhage or necrosis) in 4%.1
• Local control rates 85–96% are equal to surgery.2
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Stereotactic Radiosurgery with WBI
JCO 1998
• 236 subjects with 1 to 3 mets randomized to RS +/- WBI
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Systemic Chemotherapy
Lung Cancer 2004
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Prevention
• Chemotherapy is ineffective in micrometastatic disease due to the intact blood brain barrier.
• 50% of locally advanced NSCLC subjects will develop brain mets, 30% as site of first failure.
Int J Radiat Oncol Biol Phys 1999
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Prophylactic Cranial Irradiation
Int J Radiat Oncol Biol Phys 2005
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Predicting brain metastasis
Cell 2000
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Proliferation and evading apoptosis: Ki-67, p53, and bcl2
• 29 subjects with NSCLC and resected brain mets matched to subjects without brain mets.
• Expression by IHC for Ki-67, p53, and bcl-2 was not increased in those with brain mets but was associated with survival.
• Expression levels between the primary and brain metastasis were similar.
Int J Radiat Oncol Biol Phys 2002
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Predicting brain metastasis
Cell 2000
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Tumor stromal interactions
Cancer 2002
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Cancer 2002
Tumor stromal interactions
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Cell-cell interactions: E-cadherin-catenin complex
Lung Cancer 2002
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Prognosis of NSCLC related to E-Cadherin
• 193 subjects with stages I-III NSCLC. • Loss of expression of E-cadherin correlated with survival
and lymph node metastasis.JCO 2002
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Resected brain mets express E-cadherin
• E-cadherin was expressed in 82% of 76 cases (51% were lung primary).1
• E-Cadherin expression was strongly positive
in 86% of 35 brain mets (71% were lung primary).2
1 Brain Tumor Pathol 20032 Clin Cancer Res 1999
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E-Cadherins and Brain Metastases
• 202 stage I NSCLC subjects.
• IHC for p53, erbB2, angiogenesis factor viii, EphA2, E-cadherin, uPA, uPA receptor
• 25 subjects had isolated brain mets, all had strong expression of E-cadherin (25/109)
• None of the 92 patients with low expression of E-cad developed brain metastases.
Ann Thorac Surg 2001
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Cancer 2002
Tumor stromal interactions
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ECM Degradation: uPA
• uPA expression was also independently associated with brain metastaes in NSCLC.
• 92% of brain mets vs. 59% of other sites. (p=.002)
• Only 4% of uPA negative subjects had brain mets compared to 15% of uPA positive.
Ann Thorac Surg 2001
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Cancer 2002
Tumor stromal interactions
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ECM Degradation: Matrix metalloproteases (MMP)
• In mice overexpressing tissue inhibitor of metalloproteinase 1 (TIMP-1), brain metastases were reduced by 75%.1
• MMP2 has been shown to have high expression rates in resected brain mets.2
1 Oncogene 19982 Clin Cancer Res 1999
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Cancer 2002
Tumor stromal interactions
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Angiogenesis: VEGF
• An animal model of brain mets with breast cancer cells showed increased VEGF expression correlated with brain metastases.1
• Another mouse model studying VEGF isoforms showed that VEGF expression was necessary but not sufficient for the production of brain metastases.2
Clin Exp Metastasis 2004 Cancer Res 2000
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VEGF in Breast Cancer
• 362 node + patients, 84% ER/PR+• VEGF in cytosols quantified by ELISA
JCO 2000
Median 2.33
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Site of first recurrence by VEGF content
JCO 2000
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Metastasis suppressor genes(MSG’s)
J Clin Pathol 2005
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Can we identify a biologicallyhigh risk group ?
• High expression of E-cadherin.
• High expression of uPA and MMP.
• High expression of VEGF.
• More studies needed for MSG’s.
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Conclusions• Brain mets are increasingly responsible for a
large part of the morbidity and mortality from NSCLC.
• Prophylactic cranial radiation is effective but the appropriate population is not defined.
• High E-cadherin and uPA expression are strongly associated with isolated brain metastases.
• VEGF and the metastasis suppressor genes are strong candidates for further investigation.
• Biologic risk stratification would allow the design of better trials of prevention strategies.
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• Special thanks to Ramaswamy Govindan.
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References1. Arnold, S. M., A. B. Young, et al. (1999). "Expression of p53, bcl-2, E-cadherin, matrix
metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 in paired primary tumors and brain metastasis." Clin Cancer Res 5(12): 4028-33.
2. Bindal, A. K., M. Hammoud, et al. (1994). "Prognostic significance of proteolytic enzymes in human brain tumors." J Neurooncol 22(2): 101-10.
3. Bremnes, R. M., R. Veve, et al. (2002). "High-throughput tissue microarray analysis used to evaluate biology and prognostic significance of the E-cadherin pathway in non-small-cell lung cancer." J Clin Oncol 20(10): 2417-28.
4. Bremnes, R. M., R. Veve, et al. (2002). "The E-cadherin cell-cell adhesion complex and lung cancer invasion, metastasis, and prognosis." Lung Cancer 36(2): 115-24.
5. Chang, D. B., P. C. Yang, et al. (1992). "Late survival of non-small cell lung cancer patients with brain metastases. Influence of treatment." Chest 101(5): 1293-7.
6. D'Amico, T. A., T. A. Aloia, et al. (2001). "Predicting the sites of metastases from lung cancer using molecular biologic markers." Ann Thorac Surg 72(4): 1144-8.
7. Figlin, R. A., S. Piantadosi, et al. (1988). "Intracranial recurrence of carcinoma after complete surgical resection of stage I, II, and III non-small-cell lung cancer." N Engl J Med 318(20): 1300-5.
8. Kim, L. S., S. Huang, et al. (2004). "Vascular endothelial growth factor expression promotes the growth of breast cancer brain metastases in nude mice." Clin Exp Metastasis 21(2): 107-18.
9. Knights, E. M., Jr. (1954). "Metastatic tumors of the brain and their relation to primary and secondary pulmonary cancer." Cancer 7(2): 259-65.
10. Kruger, A., O. H. Sanchez-Sweatman, et al. (1998). "Host TIMP-1 overexpression confers resistance to experimental brain metastasis of a fibrosarcoma cell line." Oncogene 16(18): 2419-23.
11. Lagerwaard, F. J., P. C. Levendag, et al. (1999). "Identification of prognostic factors in patients with brain metastases: a review of 1292 patients." Int J Radiat Oncol Biol Phys 43(4): 795-803.
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References12. Lester, J. F., F. R. Macbeth, et al. (2005). "Prophylactic cranial irradiation for preventing brain
metastases in patients undergoing radical treatment for non-small-cell lung cancer: A cochrane review." Int J Radiat Oncol Biol Phys.
13. Nathoo, N., A. Chahlavi, et al. (2005). "Pathobiology of brain metastases." J Clin Pathol 58(3): 237-42.
14. Noordijk, E. M., C. J. Vecht, et al. (1994). "The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age." Int J Radiat Oncol Biol Phys 29(4): 711-7.
15. Patchell, R. A., P. A. Tibbs, et al. (1990). "A randomized trial of surgery in the treatment of single metastases to the brain." N Engl J Med 322(8): 494-500.
16. Penel, N., A. Brichet, et al. (2001). "Pronostic factors of synchronous brain metastases from lung cancer." Lung Cancer 33(2-3): 143-54.
17. Rizzi, A., M. Tondini, et al. (1990). "Lung cancer with a single brain metastasis: therapeutic options." Tumori 76(6): 579-81.
18. Schuette, W. (2001). "Chemotherapy as treatment of primary and recurrent small cell lung cancer." Lung Cancer 33 Suppl 1: S99-107.
19. Shabani, H. K., G. Kitange, et al. (2003). "Immunohistochemical expression of E-cadherin in metastatic brain tumors." Brain Tumor Pathol 20(1): 7-12.
20. Sulzer, M. A., M. P. Leers, et al. (1998). "Reduced E-cadherin expression is associated with increased lymph node metastasis and unfavorable prognosis in non-small cell lung cancer." Am J Respir Crit Care Med 157(4 Pt 1): 1319-23.
21. Yano, S., H. Shinohara, et al. (2000). "Expression of vascular endothelial growth factor is necessary but not sufficient for production and growth of brain metastasis." Cancer Res 60(17): 4959-67.