Sciencecafe Zeist 10 Dec 2009


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Behandeling kanker: boeken we echt vooruitgang? door prof. dr Emiel E. Voest hoofd Medische Oncologie UMC Utrecht

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  • Use as an example of DCE-MRI – please caveat that this case is obviously anecdotal however in the early phase I studies, positive clinical outcomes (defined as lack of progression – MR, SD) was significantly correlated with a reduction in tumor blood flow as measured by DCE MRI.
  • The EGFR intracellular signaling cascade stimulates not only cell proliferation but also protection from apoptosis, loss of differentiation, angiogenesis, cell migration and metastasis formation (ie all the key processes involved in tumorigenesis) [1]. EGFR is expressed in a high proportion of solid tumors, in particular head and neck, lung and colorectal cancer [2]. Expression has been correlated with disease progression [3]. Many studies have shown that EGFR expression can be an adverse prognostic factor for cancer treatment outcome [2]. ‘ Evidence for a role for the EGFR in the inhibition and pathogenesis of various cancers has led to the rational design and development of agents that selectively target this receptor,’ Baselga 2002 [3]. Baselga J. Eur J Cancer 2001; 37 Suppl 4:S16–S22. Nicholson RI, Gee JMW, Harper ME. Eur J Cancer 2001; 37 Suppl 4:S9–S15. Baselga J. The Oncologist 2002; 7 Suppl 4:2–8.
  • Trastuzumab, a humanized monoclonal antibody directed against the extracellular domain of the transmembrane glycoprotein HER2/ neu (c-erbB-2), provides clinicians with a valuable option in the treatment of women with HER2-positive metastatic breast cancer. HER2, a member of the EGFR family that includes HER1 (EGFR-1), HER3, and HER4, is amplified or overexpressed in the tumors of approximately 20% of all patients with metastases. Measurement of HER2 is best done using FISH techniques that accurately assesses gene amplification. IHC methods using a variety of antibodies are also useful. There is an excellent direct correlation between positivity on FISH testing and 3+ positive staining by IHC (on a scale of 0 to 3+)
  • Overexpression of VEGF by tumour cells can be targeted by antibodies against VEGF antibodies against VEGF receptors soluble VEGF receptors that bind circulating VEGF small molecule inhibitors of VEGF receptors catalytic RNA molecules (ribozymes), which cleave VEGF receptor mRNA.
  • Progression-free survival was also significantly increased by 71% in the IFL plus Avastin arm (10.6 [95% CI 9.0–11.0] vs 6.2 [95% CI 5.6–7.7] months, p<0.001). 1 The stratified hazard ratio for disease progression or death during first‑line therapy in the IFL plus Avastin arm relative to the IFL plus placebo arm was 0.54 (95% CI 0.45–0.66). It is interesting to note that the difference in overall and progression-free survival between the two treatment arms is relatively constant at 4.7 and 4.4 months. Together with the study design, in which the treatment arms differed only with the addition of Avastin to IFL, this suggests that the increase in survival is due to the addition of Avastin. Hurwitz H, Fehrenbacher L, Novotny W, et al. Avastin plus irinotecan, fluorouracil, and leucovorin for the treatment of metastatic colorectal cancer. N Engl J Med 2004;350:2335–42.
  • Sciencecafe Zeist 10 Dec 2009

    1. 1. Sciencecafé Zeist 10 December 2009 Behandeling van kanker Boeken we echt vooruitgang ? Prof Dr Emile E Voest UMC Utrecht Cancer Center
    2. 2. Wat is kanker eigenlijk precies ? <ul><li>Autonome celdeling ? </li></ul><ul><li>On-controleerbare celgroei ? </li></ul><ul><li>Kwaadaardig ? </li></ul><ul><li>Agressieve groei zonder zich aan de grenzen te houden ? </li></ul><ul><li>Zaait uit naar andere organen ? </li></ul><ul><li>Lijkt niet meer op oorspronkelijke cel waaruit de kanker is ontstaan ? </li></ul><ul><li>Verzwakt immuunsysteem ? </li></ul>
    3. 3. Wat is kanker eigenlijk precies ? <ul><li>Gehoorzame cel ? </li></ul><ul><li>Controleerbare celgroei ? </li></ul><ul><li>Lijkt nog heel veel op oorspronkelijke cel waaruit de kanker is ontstaan ? </li></ul><ul><li>Immuunsysteem functioneert goed ? </li></ul><ul><li>Seed and soil ? </li></ul>
    4. 4. Celdeling – the Movie
    5. 5. Checkpoints and Cancer DNA damage X Spindle damage X Checkpoint 1 Checkpoint 2
    6. 6. Cancer cell Checkpoints and Cancer Normal cell Mutations, deletions Chromosome translocations Chromosome instability (aneuploidy) 8 9 10 11 14 15 16 17 18 19 21 22 1 2 3 13 6 7 4 5 12 y x 20 7 8 4 9 6 1 2 3 5 10 11 12 13 14 15 16 17 18 19 20 21 22 x y
    7. 7. Kleine veranderingen kunnen grote consequenties hebben
    8. 8. Angiogenesis is involved throughout tumour formation, growth and metastasis Adapted from Poon RT-P, et al. J Clin Oncol 2001;19:1207–25 Stages at which angiogenesis plays a role in tumour progression Premalignant stage Malignant tumour Tumour growth Vascular invasion Dormant micrometastasis Overt metastasis (Avascular tumour) (Angiogenic switch) (Vascularised tumour) (Tumour cell intravasation) (Seeding in distant organs) (Secondary angiogenesis)
    9. 9. EPC contribute to tumor angiogenesis and cancer progression Lyden D. et al. Nature, 401:670-677;1999. Lyden D. et al. Nat.Med., 7: 1194-1201, 2001. Adult mice with reduced Id gene dosages cannot support neo-angiogenesis when challenged with tumor Maar de gastheer speelt ook een belangrijke rol
    10. 10. Host response to treatment Roodhart et al. BBA Reviews on Cancer, 2009
    11. 11. Chemotherapy induced release of progenitor cells home to the tumor Shaked et al. Cancer Cell 2008
    12. 12. Chemotherapy induces the release of endothelial progenitor cells DC101 is an anti-VEGFR antibody Shaked, et al. Cancer Cell 2008
    13. 13. Van begrip tot behandelen <ul><li>Targets visualiseren maakt dat we de kanker kunnen visualiseren </li></ul><ul><li>Van statische naar functionele imaging </li></ul><ul><li>Vroeg detectie nog een brug te ver ? </li></ul><ul><li>Als we snappen hoe het werkt kunnen we er wat aan doen ! </li></ul><ul><li>Het tijdperk van targeted therapy is aangebroken ! </li></ul>
    14. 14. Imaging as a predictive tool <ul><li>Dynamic contrast enhanced MRI </li></ul><ul><li>(18)F-Galacto-RGD is a positron emission tomography (PET) tracer binding to alpha(v)beta(3) integrin </li></ul><ul><li>11C-acetate PET </li></ul><ul><li>Hypoxia visualisation </li></ul><ul><li>Radiolabeled bevacizumab </li></ul><ul><li>Perfusion computed tomography </li></ul>
    15. 15. Anti-VEGF therapy regresses some existing tumour microvasculature Yuan et al. Proc Natl Acad Sci USA 1996;93:14765–70 Control Bevacizumab Colorectal cancer xenograft model
    16. 16. Abnormal vasculature normalised following anti-VEGF therapy Inai T, et al. Am J Pathol 2004;165:35 –52 Normalised size and shape Reduced permeability
    17. 17. PTK 787 induces significant reduction in tumor blood flow Baseline Reduction in tumor blood flow through liver metastases at day 2 is significantly correlated with positive clinical outcome Wood, Semin Oncol (July 2003) Day 2
    18. 18. Radiolabeled bevacizumab Nagengast et al. J Nuclear Med 2007 Day 1 Day 3 Day 7
    19. 19. Targeted therapy <ul><li>Waar staan we nu ? </li></ul><ul><li>Welke doelwitten ? </li></ul><ul><li>Hoe specifiek is specifiek ? </li></ul><ul><li>Moeten we de manier waarop we klinische studies doen aanpassen ? </li></ul><ul><li>Behandeling op maat ? </li></ul>
    20. 20. De HER receptoren HER 1 EGFR ErbB1 HER 2 ErbB2 Neu Her 3 and 4 ErbB3 ErbB4 EGF TGFalpha Amphiregulin Betacellulin Epiregulin Epiregulin Neuregulins No known ligand
    21. 21. The importance of EGFR as a target
    22. 22. EGFR expression in human cancer However, levels of expression do not correlate with response to therapy <ul><li>40-91% </li></ul><ul><li>Lung cancer (NSCLC) </li></ul><ul><li>90-100% </li></ul><ul><li>Head & neck cancer </li></ul><ul><li>35-70% </li></ul><ul><li>Ovarian cancer </li></ul><ul><li>33-74% </li></ul><ul><li>Gastric cancer </li></ul><ul><li>75-82% </li></ul><ul><li>Colorectal cancer </li></ul>
    23. 23. EGFR inhibitors in the clinic <ul><li>Cetuximab (Erbitux) approved for colorectal cancer refractory to irinotecan (intravenous) </li></ul><ul><li>Erlotinib (Tarceva) approved for lung cancer after failure of one line of chemotherapy (oral) </li></ul><ul><li>Lapatinib (Tycerb) approved for breast cancer, dual inhibitor of Her1 and Her2 </li></ul>Note: mechanism of action of antibodies (cetuximab) and small molecules (e.g., erlotinib) is different
    24. 24. Twee negatieve studies ?? 1073 and 1039 patients were entered in both trials, respectively <ul><ul><li>Gefitinib in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 2. Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A, Johnson DH </li></ul></ul><ul><li>J Clin Oncol. 2004 Mar 1;22(5):785-94 </li></ul><ul><ul><li>Gefitinib in combination with gemcitabine and cisplatin in advanced non-small-cell lung cancer: a phase III trial--INTACT 1. Giaccone G, Herbst RS, Manegold C, Scagliotti G, Rosell R, Miller V, Natale RB, Schiller JH, Von Pawel J, Pluzanska A, Gatzemeier U, Grous J, Ochs JS, Averbuch SD, Wolf MK, Rennie P, Fandi A, Johnson DH. </li></ul></ul><ul><ul><li>J Clin Oncol. 2004 Mar 1;22(5):777-84 </li></ul></ul>
    25. 25. Paez et al. Science 2004; 304:1458-1461 Also Lynch et al. NEJM 2004;350: 2129-2139 <ul><ul><li>Adenocarcinoma: 21% of patients had a mutation in EGFR </li></ul></ul><ul><li>Other NSCLC: 2% of patients had a mutation in EGFR </li></ul><ul><li>In patients with mutations EGFR inhibitors perform better than chemotherapy </li></ul><ul><li>Selection is the key!! </li></ul>Mutations predict response to EGFR antagonists in lung cancer
    26. 26. HER-2 Inhibition: proof of concept for targeted therapy in HER-2+ BC Patients <ul><li>Over expression of HER-2/neu receptors translates into poor prognosis </li></ul><ul><li>~25% of mBC patients over-express HER-2/neu </li></ul><ul><li>2 approved treatments for HER2/neu+ tumors: </li></ul><ul><ul><li>Trastuzumab </li></ul></ul><ul><ul><li>Lapatinib </li></ul></ul>
    27. 27. Pivotal Herceptin combination therapy trial (H0648g) Time to progression – HER2 3+ patients 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 Time (months) Probability of survival Herceptin ® + CT = 7.8 m CT alone = 4.6 m p<0.05
    28. 28. Agents targeting the VEGF pathway VEGF VEGF receptor-2 Cation channel  Permeability Antibodies inhibiting VEGF (e.g. bevacizumab (Avastin TM ) Antibodies inhibiting VEGF receptors Soluble VEGF receptors (VEGF-TRAP) Small-molecules inhibiting VEGF receptors (TKIs) (e.g. PTK-787) Ribozymes (Angiozyme) – P – P P– P– – P – P P– P– – P – P P– P– Migration, permeability, DNA synthesis, survival Lymphangiogenesis Angiogenesis TKI = tyrosine kinase inhibitor
    29. 29. Phase III trial of IFL ± Avastin in metastatic CRC (AVF2107g): progression-free survival Hurwitz H, et al. N Engl J Med 2004;350:2335–42 Median progression-free survival (months) IFL + placebo: 6.2 (95% CI: 5.6 – 7.7) IFL + Avastin: 10.6 (95% CI: 9.0–11.0) HR=0.54 (95% CI: 0.45–0.66) p<0.001 Probability of being progression-free 1.0 0.8 0.6 0.4 0.2 0 0 10 20 30 Time (months) 6.2 10.6 IFL + Avastin IFL + placebo CRC = colorectal cancer CI = confidence interval
    30. 30. <ul><li>Stratify: </li></ul><ul><ul><li>DFI < 24 mos. vs. > 24 mos. </li></ul></ul><ul><ul><li>< 3 vs. > 3 metastatic sites </li></ul></ul><ul><ul><li>Adjuvant chemotherapy yes vs. no </li></ul></ul><ul><ul><li>ER+ vs. ER- vs. ER unknown </li></ul></ul>RANDOMI ZE Paclitaxel + Bevacizumab Paclitaxel E2100: A Randomized Phase III Trial of Paclitaxel versus Paclitaxel plus Bevacizumab as First-Line Therapy for Locally Recurrent or Metastatic Breast Cancer 28-day cycle: Paclitaxel 90 mg/m 2 D1, 8 and 15 Bevacizumab 10 mg/kg D1 and 15
    31. 31. Progression Free Survival 0.0 0.2 0.4 0.6 0.8 1.0 Months PFS Probability 0 6 12 18 24 30 HR = 0.51 (0.43-0.62) Log Rank Test p<0.0001 Pac. + Bev. 11.4 months Paclitaxel 6.11 months 484 events reported
    32. 32. <ul><li>Maar het gaat niet altijd goed !! </li></ul>
    33. 34. CAIRO2 Arm A Arm B Randomisatie Capecitabine Oxaliplatin Bevacizumab Capecitabine Oxaliplatin Bevacizumab Cetuximab
    34. 35. Hazard ratio= 1,22 (1,04-1,43) p= 0,01 Mediaan (95% CI) CT + bev 10.7 (9.7-12.3) CT + bev + cetuximab 9.4 (8.4-10.5)
    35. 36. Dit staat niet op zichzelf <ul><li>Kras mutaties predict response to treatment with cetuximab </li></ul><ul><li>EGFR mutations predict response to treatment with gefitinib and erlotinib </li></ul><ul><li>PI3K mutations predict resistance to trastuzumab </li></ul><ul><li>BRCA1 mutations predict sensitivity to cisplatin </li></ul><ul><li>KIT and PDGFR mutations predict response to imatinib </li></ul>
    36. 37. Welk les kunnen we hieruit leren? <ul><li>Selectie van patienten op één factor met kanker geeft reeds verbetering van de behandelingsresultaten </li></ul><ul><li>Ondanks grootste stap voorwaarts in decennia is de overlevingswinst van de behandeling nog steeds beperkt </li></ul>
    37. 38. Onze visie <ul><li>Iedere patient met kanker heeft op ieder moment een unieke ziekte </li></ul><ul><li>De “vingerafdruk” van een kanker bepaalt de optimale behandeling </li></ul><ul><li>Individualiseren van behandeling geeft grotere winst dan veralgemeniseren van kanker </li></ul><ul><li>Inzicht in de biologie van kanker is de basis </li></ul><ul><li>De sleutel is het DNA </li></ul>
    38. 39. Patienten met kanker Behandeling Medicijn A Medicijn B Medicijn C Medicijn D Kanker soort Huidige situatie: simplistische indeling op orgaan borst prostaat darm long
    39. 40. Patienten met kanker Behandeling Medicijn A Medicijn B Medicijn C Medicijn D Kanker soort Realiteit: kanker is een unieke ziekte, uniforme behandeling is beperkt succesvol borst long darm prostaat
    40. 41. Patienten met borstkanker Behandeling Herceptin Kanker soort Huidige situatie: iets minder simplistisch Her2 positief Her2 negatief
    41. 42. Patienten met kanker Behandeling Medicijn A Medicijn B Medicijn C Medicijn D Unieke kanker per patient Gewenste situatie Medicijn A+D Medicijn B+D etc
    42. 43. Cancer: past, present and future Past Present Future
    43. 44. Een droom Patient with cancer Biopsy Mutational analysis tumor genome Selection of appropriated therapy Prolong survival