Brain Metastases in NSCLC Boone Goodgame, MD Case Report #

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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

• 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
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Stereotactic Radiosurgery with WBI

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

JCO 1998
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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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Tumor stromal interactions
Cancer 2002
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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 2003 2 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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Tumor stromal interactions
Cancer 2002
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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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Tumor stromal interactions
Cancer 2002
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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 1998 2 Clin Cancer Res 1999
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Tumor stromal interactions
Cancer 2002
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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
Median 2.33

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

JCO 2000
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Site of first recurrence by VEGF content
Bone
none
brain
visceral
soft tissue
JCO 2000
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Metastasis suppressor genes(MSGs)
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 MSGs.

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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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