1. New Proposals for Lung Cancer Staging Akif Turna, MD, PhD, FETCS Yedikule Teaching Hospital for Chest Diseases and Thoracic Surgery, Istanbul, Turkey

2. Presentation Scheme - Conventional Staging of Lung Cancer - New Staging Proposals - Non-anatomical staging - Histopathological Staging - Molecular Staging - Pathologically tailored surgical therapy - Genotypically tailored surgical therapy - Future directions

3. Lung Cancer - The Number one cause of cancer deaths worldwide - 162 460 deaths from NSCLC occured in 2006 in US - M1 and N2-3 indicated poorer survival, futile surgery

4. Conventional Staging (6th)

5. Survival Rates in Resected Non-Small Cell Lung Cancer

6. Survival Curves of Patients with Thyroid Carcinoma According to Stages

7. Text Survivals in Melanoma Patients

8. Text Staging in Melanoma

9. New Staging Proposal

11. Text n=100869

12. Text New T Definitions (T1)

13. Text New T Definitions (T2-T4)

15. Recursive Partitioning

16. Text Sample Size in 7th Staging Proposal

17. Text 7th Staging Proposal- Lymph Nodes: WHY IS THAT NOT DIFFERENT?

18. Text Survival According to N1 type

19. Text Multiple N1 and Multiple N2 Involvement

20. Anatomical Proposals

21. Text

22. New Proposals for Lymph Node Locations

23. Text New Proposals for Lymph Node Locations

24. Histopathological Staging

25. Histopathological Factors ‣ Histological type ‣ Grade ‣ Lymphatic Invasion ‣ Blood vessel invasion ‣ Necrosis ‣ Cytokeratin expression

26. Text

29. Poncelet et al., 2008, EJCTS

32. Molecular Staging

34. Role of p53 ✦ TP53 gene alterations are present in about 50% of NSCLC and their prognostic implications have been evluated in diverse clinical studies. ✦ Tumor response to anticancer therapies has been recognized to be largely based on apoptosis induction ✦ Active p53 has emerged as an important modulator of DNA-damage-induced apoptosis.

35. EGFR

37. Molecular Markers of Prognosis - p53 - EGFR - erbB2 - ERCC1 - RRM1 - PTEN - ErbB-1 - cyclin A - PCNA -p16 -RASS1A -FHIT -k-ras -DNA methylation

38. Molecular Markers of Prognosis - Volm and colleagues found that diminished expression of fas, ERbB-1, cyclin A and PCNA coincided with long term survival - Two multi-institutional trials (ACOSOG 20030 and CALGB 9761) indicate that DNA methylation profiles are associated with tumor histology and stage, as well as response to therapy and overall survival in lung cancer patients.

39. Excision Repair Cross Complemantation Group 1 (ERCC1) ✦ Protein component of nucleotide excision repair complex ✦ This complex reognizes and repairs cisplatin- induced DNA adducts ✦ Therefore it is thought to be important for resistance to platinum agents.

41. Olaussen et. al, NEJM, 2006

42. Chen HY, et al. NEJM, 2007

43. Survival Based on ERCC1 expression ERCC1+, median: 86 months p=0.01 ERCC1-, median: 44 months

44. Zheng et. al, NEJM

45. Pathologically Tailored Surgical Therapy?

49. Neadjuvant Therapy: Routine or Selective?

50. Text Kandioler-Eckerberger D, et al. J Thorac Cardiovasc Surg;1999

51. Molecularly Tailored Surgical Therapy? Lee et al., Lung Cancer, 2007

52. Genotypically Tailored Surgical Therapy?

53. Genotypically Tailored Therapy ✦ Fas-1377 A/G polymorphism was investigated ✦ There was no relationship between Fas-1377 G-A polymorphism and lung cancer, but smoking seemed to increase the possibility of inducing lung cancer in AG genotypes more than other genotypes.

54. Genotypically Tailored Surgical Therapy ?

55. Relationship between polymorphisims of gene encoding microsomal epoxide hydrolase and lung cancer

58. Text NCCN- Guideline-2009

59. Survival According to ERCC1 expression in Neoadjuvant Chemotherapy Administered Patients Text

60. Postoperative Complications and Survival Song et al., Annals of Thoracic Surgery, 2007

61. Future Studies ✦ Molecular mechanisms associated with ERCC1 ✦ Randomized studies regarding molecularly tailored surgical therapies. ✦ Clinical studies based on genomics and proteomics ✦ Large studies with molecular PET markers.

62. Acknowledgements Nur Ürer, Nur Büyükpınarbaşılı, Ilhan Yaylım, Zelal Erkisi, Ali Kılıçgün Turgay Isbir