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Brain Metastases in NSCLC Boone Goodgame, MD

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  • Case Report James Schuler: 12/6/40, p/w brain met at age 60, underwent resection of brain lesion, L parietal lobe on 07-05-01 Gemcitabine/carboplatin, began 08-15-01, then right upper lobe lobectomy, 12-05-01 No evidence of recurrence at the time of this CT scan, 6/10/05, 4 years after diagnosis.
  • Harry Schuler: 3/29/34, brother of 1 st patient, 71 y/o p/w billateral lung masses and mediastinal lymphadenopathy and concurrent brain met 6/29/05, treated palliatively.
  • Resection of lesions amenable to surgery followed by WBI is currently offered to those with controlled systemic disease and good performance status (karnofsky > 70) Only 30% of mets are solitary and only half of those are amenable to surgery.
  • Resection of lesions amenable to surgery followed by WBI is currently the standard of care. Stereotactic radiosurgery “gamma-knife” is used primarily for recurrence after WBI.
  • 236 subjects with 1 to 3 metastases randomized to RS +/- WBI (75% NSCLC) Median survival is prolonged to 15.4 months compared with 8.3 months (p < 0.08) in patients without extracranial disease
  • The blood-brain barrier is not intact for metastases large enough to be visible by CT or MRI, as demonstrated by the accumulation of IV contrast. Responses to systemic chemotherapy correlate roughly with response of other sites. Cortes: 38% and 50% for paclitaxel and cisplatin with vinorelbine or gemcitabine ( Clin Stud Oncol 2003) cisplatin-containing combinations: 50% (lung ca 1998), 35% ( Clin Stud Oncol 2000) Dziadziusko, temozolomide no effect
  • Well established in SCLC
  • All of the hallmarks of cancer are necessary for the growth of metastases; however, the processes most specific for the production and progression of metastases are those by which the malignant cells interact with their environment.
  • All of the hallmarks of cancer are necessary for the growth of metastases; however, the processes most specific for the production and progression of metastases are those by which the malignant cells interact with their environment.
  • Interactions between the stromal cells at the site of metastasis and the malignant cell allow its proliferation.
  • We will look at the molecules that have been found to be associated with metastasis to the brain: Cell adhesion through the E-cadherin/catenin system, matrix degradation by the uPA plasmin system and the MMP’s
  • Cells adhere to one another by E-cadherin dimers that bind to cytoplasmic  -catenin or  -catenin, which bind to  -catenin-which links to the actin cytoskeleton .  -Catenin also binds to cytoplasmic domain of the epidermal growth factor (EGF) receptor. (Bremnes, Veve et al. 2002) Phosphorylation of catenins leads to disociation and loss of expression of cadherins.
  • 193 subjects with stages I-III NSCLC, IHC for E-cad, -, ß-, and -catenins Reduced expression of -catenin and E-cad was inversely correlated with nodal metastasis at presentation Of these, only E-cad expression was independently associated with survival
  • From Duke, 202 subjects, 108 with no rec, 25 with isolated brain, & 69 with other sites of rec. IHC for p53, erbB2, angiogenesis factor viii, EphA2, E-cadherin.
  • Plasmin is the primary mediator of ECM degradation, and activates other proteolytic enzymes, allowing tumor invasion. UPA has been associated with tumor invasion and metastasis since the early 1990’s.
  • Also from Duke study, uPA+, 23/148 (15%) had brain mets, vs uPA- where 2/54 (4%) had brain mets
  • High MMP expression has been associated with invasion, metastasis, and poor prognosis in multiple malignancies
  • -         The optimal cut-off point for VEGF content, according to the lowest P values and the highest relative risk (RR), was found at 1.75 pg/mg DNA for OS. (median was 2.33) -         VEGF content (P=.2222) was not an independent predictor of RFS. However, for OS, VEGF content (1.75 pg/mg DNA v . 1.75 pg/mg DNA; P 5 .0170) was an independent predictor of OS.
  • -         The optimal cut-off point for VEGF content, according to the lowest P values and the highest relative risk (RR), was found at 1.75 pg/mg DNA for OS. (median was 2.33) -         VEGF content (P=.2222) was not an independent predictor of RFS. However, for OS, VEGF content (1.75 pg/mg DNA v . 1.75 pg/mg DNA; P 5 .0170) was an independent predictor of OS.

Brain Metastases in NSCLC Boone Goodgame, MD Brain Metastases in NSCLC Boone Goodgame, MD Presentation Transcript

  • 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”
    • 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
    1 Cancer 1997 2 Lung Cancer 2004
  • Stereotactic Radiosurgery with WBI
    • 236 subjects with 1 to 3 mets randomized to RS +/- WBI
    JCO 1998
  • 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
  • Tumor stromal interactions Cancer 2002
  • 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 2003 2 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
  • Tumor stromal interactions Cancer 2002
  • 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
  • Tumor stromal interactions Cancer 2002
  • 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
  • Tumor stromal interactions Cancer 2002
  • 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 soft tissue visceral Bone none brain
  • Metastasis suppressor genes (MSG’s) J Clin Pathol 2005
  • Can we identify a biologically high 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.
  • 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.
  • 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.