Brain Metastases in NSCLC

Boone Goodgame, MD

Case Report #1

Case Report #2

Overview

• Epidemiology & prognosis

• Standards of care and current clinical questions

• Predicting brain metastasis based on molecular mechanisms

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

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

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

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

Resection of single metastases

JAMA 1998

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

Stereotactic Radiosurgery with WBI

JCO 1998

• 236 subjects with 1 to 3 mets randomized to RS +/- WBI

Systemic Chemotherapy

Lung Cancer 2004

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

Prophylactic Cranial Irradiation

Int J Radiat Oncol Biol Phys 2005

Predicting brain metastasis

Cell 2000

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

Predicting brain metastasis

Cell 2000

Tumor stromal interactions

Cancer 2002

Cancer 2002

Tumor stromal interactions

Cell-cell interactions: E-cadherin-catenin complex

Lung Cancer 2002

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

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

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

Cancer 2002

Tumor stromal interactions

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

Cancer 2002

Tumor stromal interactions

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

Cancer 2002

Tumor stromal interactions

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

VEGF in Breast Cancer

• 362 node + patients, 84% ER/PR+• VEGF in cytosols quantified by ELISA

JCO 2000

Median 2.33

Site of first recurrence by VEGF content

JCO 2000

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Metastasis suppressor genes(MSG’s)

J Clin Pathol 2005

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.

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.

• Special thanks to Ramaswamy Govindan.

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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.

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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.

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metastases in patients undergoing radical treatment for non-small-cell lung cancer: A cochrane review." Int J Radiat Oncol Biol Phys.

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17. Rizzi, A., M. Tondini, et al. (1990). "Lung cancer with a single brain metastasis: therapeutic options." Tumori 76(6): 579-81.

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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.