Brain Metastases in NSCLC

1
Brain Metastases in NSCLC

• Boone Goodgame, MD

2
Case Report 1
3
Case Report 2
4
Overview

• Epidemiology prognosis
• Standards of care and current clinical questions
• Predicting brain metastasis based on molecular
  mechanisms

5
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
6
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
7
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
8
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
9
Resection of single metastases
JAMA 1998
10
Stereotactic Radiosurgery (RS)Gamma-Knife

• Advantages Treat multiple lesions and those
  inaccessible by surgery.
• Severe complications (edema or hemorrhage or
  necrosis) in 4.1
• Local control rates 8596 are equal to surgery.2

1 Cancer 1997 2 Lung Cancer 2004
11
Stereotactic Radiosurgery with WBI

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

JCO 1998
12
Systemic Chemotherapy
Lung Cancer 2004
13
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
14
Prophylactic Cranial Irradiation
Int J Radiat Oncol Biol Phys 2005
15
Predicting brain metastasis
Cell 2000
16
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
17
Predicting brain metastasis
Cell 2000
18
Tumor stromal interactions
Cancer 2002
19
Tumor stromal interactions
Cancer 2002
20
Cell-cell interactions E-cadherin-catenin complex
Lung Cancer 2002
21
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
22
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 2003 2 Clin Cancer Res 1999
23
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
24
Tumor stromal interactions
Cancer 2002
25
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
26
Tumor stromal interactions
Cancer 2002
27
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 1998 2 Clin Cancer Res 1999
28
Tumor stromal interactions
Cancer 2002
29
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
30
VEGF in Breast Cancer
Median 2.33

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

JCO 2000
31
Site of first recurrence by VEGF content
Bone
none
brain
visceral
soft tissue
JCO 2000
32
Metastasis suppressor genes(MSGs)
J Clin Pathol 2005
33
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 MSGs.

34
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.

35

• Special thanks to Ramaswamy Govindan.

36
References

• 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.
• Bindal, A. K., M. Hammoud, et al. (1994).
  "Prognostic significance of proteolytic enzymes
  in human brain tumors." J Neurooncol 22(2)
  101-10.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• Knights, E. M., Jr. (1954). "Metastatic tumors of
  the brain and their relation to primary and
  secondary pulmonary cancer." Cancer 7(2) 259-65.
• 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.
• 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.

37
References

• 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.
• Nathoo, N., A. Chahlavi, et al. (2005).
  "Pathobiology of brain metastases." J Clin Pathol
  58(3) 237-42.
• 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.
• 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.
• Penel, N., A. Brichet, et al. (2001). "Pronostic
  factors of synchronous brain metastases from lung
  cancer." Lung Cancer 33(2-3) 143-54.
• Rizzi, A., M. Tondini, et al. (1990). "Lung
  cancer with a single brain metastasis
  therapeutic options." Tumori 76(6) 579-81.
• Schuette, W. (2001). "Chemotherapy as treatment
  of primary and recurrent small cell lung cancer."
  Lung Cancer 33 Suppl 1 S99-107.
• Shabani, H. K., G. Kitange, et al. (2003).
  "Immunohistochemical expression of E-cadherin in
  metastatic brain tumors." Brain Tumor Pathol
  20(1) 7-12.
• 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.
• 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.