04 Biologia molecular en Cáncer de Pulmón

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Autor/a Dra. Eloisa Jantús
V Jornada de Revisión del Congreso Mundial de Cáncer de Pulmón.
ARCO MEDITERRANEO. Valencia 8-Nov-2013

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04 Biologia molecular en Cáncer de Pulmón

  1. 1. Molecular Biology: diagnostic, prognostic and predictive biomarkers Dra. Eloisa Jantus Lewintre Laboratorio de Oncología Molecular Fundación para la investigación del Hospital General Universitario de Valencia
  2. 2. Biomarkers for LUNG CANCER BLOOD sample Evolve Locoregional Mestastatic Modified from Wistuba et al, Nat Rev Clin Oncol 2011
  3. 3. Biomarkers for LUNG CANCER Tissue SAMPLE/ MATRIX ISSUES Blood (Serum/Plasma) CNB BAL, Sputum Place of sample ? How many ? Diagnostic TYPE OF BIOMARKER Prognostic Predictive Diagnosis WHEN? Response evaluation Progression What methodology should be used ?
  4. 4. Biomarkers for LUNG CANCER Fresh/ frozen Tissue FFPE CNB SAMPLE/ MATRIX ISSUES Blood BAL, Sputum Place of sample ? How many ? HETEROGENEITY
  5. 5. Biomarkers for LUNG CANCER SAMPLE/ MATRIX ISSUES Tissue Fresh/ frozen FFPE Biobank
  6. 6. Biomarkers for LUNG CANCER Types of tumor specimens in lung cancer TUMOR CELLS ARE NEEDED !!
  7. 7. Biomarkers for LUNG CANCER SAMPLE/ MATRIX ISSUES Blood Biobannk
  8. 8. Biomarkers for LUNG CANCER MATRIX CTCs Cell free DNA Serum Plasma (EDTA) Proteins Metabolites
  9. 9. Biomarkers for LUNG CANCER
  10. 10. T. Mok PLASMA TUMOR PLASMA C3
  11. 11. Biomarkers for LUNG CANCER Diagnostic TYPE OF BIOMARKER Prognostic Predictive
  12. 12. Biomarkers for LUNG CANCER RESPONSE RISK P. Massion DIAGNOSTIC PROGNOSIS
  13. 13. Biomarkers for LUNG CANCER Complement system: Innate immunity Ajona, JNCI 2013
  14. 14. Biomarkers for LUNG CANCER
  15. 15. • Caucasic • Three discovery studies -> plasma patients with benign and stage IA lung cancer (n=147) • The classifier was validated on an independent set of plasma samples (n = 104) • The classifier proteins are modulated by transcription regulators (NF2L2, AHR, MYC, and FOS) associated with lung cancer, lung inflammation, and oxidative stress networks
  16. 16. Biomarkers for LUNG CANCER Sozzi, G JCO in press 2013 1000 controls 85 lung cancer miRNA signature: 24 miRNAS (high, intermediate, low) Blood samples Diagnostic value: NPV: 99% Prognostic biomarker and Predictive of response Superior diagnostic performance of LDCT if combined with miRNA tests
  17. 17. Biomarkers for LUNG CANCER Diagnostic TYPE OF BIOMARKER Prognostic Predictive
  18. 18. Ca de pulmón Biomarkers for LUNG CANCER Ferté, C. et al. Nat. Rev. Clin. Oncol. 7, 367–380 (2010)
  19. 19. Biomarkers for LUNG CANCER Table 2 . KRAS mutations: correlation with Histology KRAS WT Mutated SCC ADC* Others Total 67 51 16 134 98.5% 79.7% 88.9% 89.3% 1 13 2 16 1.5% 20.3% 11.1% 10.7% p Table 3. KRAS mutations: correlation with Smoking Status 0.002 KRAS Non Smoker Former Smoker Current Smoker Total WT 13 54 67 134 6 4 6 16 37.5% 25% 37.5% 100% Mutated p 0.007
  20. 20. Biomarkers for LUNG CANCER Table 2 . KRAS mutations: correlation with Histology KRAS WT Mutated SCC ADC* Others Total p 67 51 16 134 98.5% 79.7% 88.9% 89.3% 1 13 2 16 1.5% 20.3% 11.1% 10.7% Table 3. KRAS mutations: correlation with Smoking Status 0.002 KRAS Non Smoker Former Smoker Current Smoker Total WT 13 54 67 134 6 4 6 16 37.5% 25% 37.5% 100% Mutated 23 mese s 81.2 mese s p 0.007
  21. 21. Biomarkers for LUNG CANCER Diagnostic TYPE OF BIOMARKER Prognostic Predictive
  22. 22. Ca de pulmón Biomarkers for LUNG CANCER De-selection Ferté, C. et al. Nat. Rev. Clin. Oncol. 7, 367–380 (2010)
  23. 23. Biomarkers for LUNG CANCER ADC SCC Li et al, J Clin Oncol 2013
  24. 24. Biomarkers for LUNG CANCER ADC CUALES DEBEN SER EVALUADOS COMO BIOMARCADORES PREDICTIVOS????
  25. 25. Biomarkers for LUNG CANCER •EGFR •ALK •KRAS •HER2 •BRAF •ROS1 •RET mut and amplif BRAF RET Sensitive to Vemurafenib / Dabrafenib/ MEK inh Sensitive to RET kinase inh
  26. 26. Biomarkers for LUNG CANCER
  27. 27. Biomarkers for LUNG CANCER Drilon, 2013 Stahel, 2013
  28. 28. Biomarkers for LUNG CANCER
  29. 29. NGS, Foundation Medicine In total, 3 of 91 tumor samples which had no other sign of cancer-causing genetic abnormalities, had fusions involving NTRK1.
  30. 30. Asian population!!
  31. 31. Biomarkers for LUNG CANCER Diagnostic TYPE OF BIOMARKER Prognostic Predictive What methodology should be used ?
  32. 32. Biomarkers for LUNG CANCER EGFR mutation testing methodology Test sensitivity Mutations detected
  33. 33. Biomarkers for LUNG CANCER ALK ALK fusion variants in NSCLC Peters et al., 2013 Lung Cancer
  34. 34. Biomarkers for LUNG CANCER FISH IHC RNAseq
  35. 35. Biomarkers for LUNG CANCER Tissue should be priorized for EGFR and ALK testing. EGFR and ALK results should be available within 2 weeks (10 working days) •In resection specimens, testing is not recommended in lung cancer that lack morphological or IHC evidence of adenocarcinoma differentiation •In limited specimens (biopsies, cytology), testing may be performed in SCC or small cell histology + clinical criteria Lindenman, JTO 2013
  36. 36. Biomarkers for LUNG CANCER BUT….. Biomarkers can be determined in BLOOD samples MULTIPLEX ANALYSIS (NGS) are more informative …. Same amount of sample
  37. 37. Biomarkers for LUNG CANCER
  38. 38. Biomarkers for LUNG CANCER Diagnostic TYPE OF BIOMARKER Prognostic Predictive REBIOPSIES What we should do after resistance to targeted therapies?
  39. 39. Biomarkers for LUNG CANCER Consider liquid biopsies!!
  40. 40. RESISTANCE TO EGFR TKI P. Giannikopoulos, WCLC 2013
  41. 41. N=16 sample sample P. Giannikopoulos, WCLC 2013 AXL overexpression in 2
  42. 42. R. Thomas, WCLC 2013
  43. 43. HGF (circulating levels) in SCLC is prognostic  may be predictive? E. Arriola,2013
  44. 44. Biomarkers for LUNG CANCER Rebiopsies … why?
  45. 45. Biomarkers for LUNG CANCER Squamous cell carcinoma
  46. 46. Biomarkers for LUNG CANCER Squamous cell carcinoma : FGFR
  47. 47. Squamous cell carcinoma: FGFR
  48. 48. Biomarkers for LUNG CANCER Squamous cell carcinoma
  49. 49. Biomarkers for LUNG CANCER Squamous cell carcinoma : HLA-A
  50. 50. Biomarkers for LUNG CANCER BIOMARKERS TESTS
  51. 51. Li T, et al, J Clin Oncol 2013
  52. 52. Biomarkers for LUNG CANCER
  53. 53. Li T, et al, J Clin Oncol 2013
  54. 54. Biomarkers for LUNG CANCER
  55. 55. Biomarkers for LUNG CANCER
  56. 56. Take a Biomarkers for LUNG CANCER home message ...
  57. 57. Take a Biomarkers for LUNG CANCER home message ...
  58. 58. 3rd and 4th generation sequencing for mutation analysis Transcriptomic miRNAs Epigenetics Proteomics and Metabolomics Validation of the new methodologies: standardization, CLIA References laboratories: networks organized by contries

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