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DNA diagnosis of lung cancer Patrick Willems GENDIA Antwerp, Belgium

DNA diagnosis of lung cancer Patrick Willems GENDIA Antwerp, Belgium. Treatment of Lung Cancer. Small Cell Lung Cancer (SCLC) chemotherapy radiation Non-Small Cell Lung Cancer (NSCLC) surgery radiation chemotherapy targeted treatment immunotherapy.

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DNA diagnosis of lung cancer Patrick Willems GENDIA Antwerp, Belgium

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  1. DNA diagnosis of lung cancer Patrick Willems GENDIA • Antwerp, Belgium

  2. Treatment of Lung Cancer • Small Cell Lung Cancer (SCLC) • chemotherapy • radiation • Non-Small Cell Lung Cancer (NSCLC) • surgery • radiation • chemotherapy • targeted treatment • immunotherapy

  3. Personalized cancer treatment • Immunotherapy to stimulate immune response to cancer PD-1 inhibitors PD-L1 inhibitors CTLA-4 inhibitors • Targeted therapy with designer drugs that target the genetic cause of the tumor mAB: Herceptin TKI: Gleevec

  4. Problems in personalized cancer treatment • Immunotherapy Extremely expensive (100-300.000 Euro/year) Few biomarkers (companion diagnostics) • Targeted therapy with designer drugs Very expensive (50-100.000 Euro/year) Biomarkers (companion diagnostics)

  5. Problems in personalized cancer treatment The very high cost of personalised treatment makes companion diagnostics (cancer biomarkers) necessary

  6. Cancer biomarkers tumor material (biopsy) blood (liquid biopsy)

  7. Market for tumor biomarkers in Liquid biopsies TARGETS DRUGS SEQUENCING Liquid biopsy market for tumor biomarkers: 40 Billion USD per year (Illumina estimate)

  8. Current paradigm PATIENT general treatment visit PHYSICIAN Result Pathological studies sample PATHOLOGIST Lab

  9. Future paradigm PATIENT Personalised treatment visit PHYSICIAN PHARMA Result Molecular testing sample LAB Pathologist

  10. Mortality UK, 2009-2011

  11. Cancer Morbidity and Mortality Canada, 2007

  12. New cancers per year in Belgium • Lung : 7.100 • Colon : 6.500 • Prostate : 8.800 • Breast : 9.700 TOTAAL : 65.000

  13. 14 % of all cancer • 80 % is non–small cell lung cancer (NSCLC) • Belgium : 7.100 new cases per year • Worldwide : 10 million new cases per year • Worldwide : 8 million fatalities per year • The main cause (20-30%) of cancer-related death in both men and women : • More women die of lung ca than breast, cervical and uterine ca combined. • More men die of lung ca than prostate and colorectal ca combined. Lung cancer

  14. Treatment of Lung Cancer • Small Cell Lung Cancer (SCLC) • chemotherapy • Radiation • Non-Small Cell Lung Cancer (NSCLC) • surgery • radiation • chemotherapy • immunotherapy • personalised targeted treatment

  15. Immunotherapy for NSCLC • CTLA-4 (cytotoxic T-lymphocyte–associated antigen 4) : ipilimumab • PD-1 (programmed death-1) : nivolumab, pembrolizumab • PD-L1 (programmed death-1 ligand) BMS-935559, MPDL3280A

  16. Inhibition immune checkpoints

  17. Biomarkers for immunotherapy for Lung Ca Few biomarkers for immunotherapy First real biomarker : Tumor load (amount of mutations-driver and passenger) Response to pembrolizumab (PD-1 inhibitor) better if high mutation load Science, April 3, 2015 (Rizvi et al)

  18. MSI as Biomarker for immunotherapy MMR deficiency Genomic instability Large mutation load in tumor (driver and passenger) Many mutant proteins - neoantgens Immune response

  19. Immunotherapy for NSCLC • Extremely expensive (100-300.000 Euro/year) • No biomarkers to select patients

  20. Targetedtherapywith designer drugs • Receptor antibodies (---- ab) • HER2 : Trastuzumab (Herceptin) • EGFR : Cetuximab, Pertuzumab • MET : AMG102 • VEGF : Befacizumab • Tyrosine Kinase Inhibitors : TKI (---- ib) • BRC-ABL : Imatinib (Gleevec) • KRAS : Tipifarnib • BRAF : Sorafenib • MEK • ERK • mTOR : Everolimus

  21. inhibit receptor kinases by interfering with ligand-receptor binding Preventing intracellularsignaling Receptor antibodies

  22. Herceptin (Trastuzumab) Inhibits HER2 dimerisation / activation and the downstream signaling pathways MAPK and AKT/mTOR Active whenthere is HER2 overexpression • Breast ca (25 %) • Gastric ca (20 %) Herceptin

  23. Tyrosine kinase inhibitors (TKI) TKI inhibits a Tyrosine kinase by binding to its kinase domain Preventing phosphorylation (activation) of target

  24. Gleevec Gleevec (Imatinib) inhibitsTyrosinekinases by binding to its kinase domain Thereby preventing phosphorylation (activation) of targets : • BCR-ABL (CML) • cKIT (GIST, Mastocytosis) • PDGFR (GIST)

  25. Targeted treatment • Non-Small Cell Lung Cancer (NSCLC) • surgery • radiation • chemotherapy • personalised targeted treatment • immunotherapy • Small Cell Lung Cancer (SCLC) • chemotherapy • radiation

  26. Targeted treatment of NSCLC Expensive, but many biomarkers to select patient Personalised targeted treatment targets specific somatic mutations that cause NSCLC These mutations are patient-specific These mutations can be detected by molecular studies of : tumor (biopsy) blood (liquid biopsy)

  27. Progress in lung ca treatment

  28. Problems in targeted cancer treatment The very high cost of personalised treatment makes companion diagnostics (cancer biomarkers) necessary The mutations leading to lung ca are the biomarkers to guide targeted therapy

  29. Inheritance of cancer • Majority of cancers are caused by genetic anomalies in the tumor (somatic mutations) • Minority of cancers is inherited (germline mutations) : • Breast Cancer : 10 % • Colon cancer : 5-10 % • Prostate cancer : low • Lung cancer : very low

  30. Inheritance of lung cancer • NO germline mutations • MANY somatic mutations

  31. Driver and passenger gene mutations Vogelstein et al, Science Aug 22, 2013 NEJM May 30, 2015

  32. Somatic mutations in cancer P

  33. Somatic mutations in adeno ca NSCLC TP53 : 34 % EGFR : 10-30 % KRAS : 15-25 % MLL3 : 10 % STK11 : 9 % CDKN2A : 8 % ALK fusions : 5 % HER 2 : 2% BRAF : 1-2 % Ros fusions : 2 % PTEN : 25 % (loss) P

  34. Somatic mutations in adeno ca NSCLC

  35. Cell growth and survival pathway

  36. Genetic testing for lung cancer • EGFR: deletions in exon 19 L858R mutation in exon 21 T790M mutation in exon 20 • KRAS: mutations of codons 12 and 13 • BRAF: V600E, G469A and D594G mutations • ALK-EML4 fusion

  37. EGFR Mutations in lung cancer EGFR mutations : 10 % (Europe) 30 % (Asia) women, non-smokers, adenocarcinoma (NSCLC) 90% of EGFR mutations : L858R in exon 21 (Sensitivity to TKIs) Small deletions in exon 19 (Sensitivity to TKIs) T790M in exon 20 (Resistance to TKIs) First-generation EGFR tyrosine-kinase inhibitors : Erlotinib (Tarceva) Gefitinib (Iressa) Second-generation EGFR tyrosine-kinase inhibitors : Dacomitinib Afatinib (Gilotrif) P

  38. EGFR mutations

  39. EGFR Resistance : T790M mutation Inhibitors of EGFR with the T790M mutation : AZD9291 CO-1831

  40. EGFR resistance : KRAS and BRAF mutations TREATMENT RELAPSE

  41. KRAS Mutations in lung cancer KRAS mutations : 15-25 % in NSCLC smokers 90% of KRAS mutations : codon 12 (90 %) codon 13 (5-10 %) KRAS Mutations are contraindications for EGFR TKI

  42. BRAF Mutations in lung cancer BRAF mutations : 1-4 % in NSCLC 55 % of KRAS mutations : V600E BRAF Mutations are contraindications for EGFR TKI

  43. ALK Mutations in lung cancer • ALK mutations : 5 % in NSCLC • ALK activation is caused by EML4-ALK fusion generated by inv(2)(p21p23) • ALK mutations are sensitive to ALK inhibitors : Crizotinib (Xalkori) Ceritinib (Zykadia)

  44. ROS1 Mutations in lung cancer ROS1 mutations : 2 % ROS1 activation is caused by ROS1 fusion to different partners ROS1 mutations are sensitive to Crizotinib (Xalkori) P

  45. Why perform genetic studies on tumor DNA ? • Initial diagnosis and prognosis Initial therapy • Monitoring recurrence – metastasis Secundary therapy

  46. Prognosis according to EGFR mutations

  47. Prognosis according to BRAF mutations

  48. Why perform genetic studies on tumor DNA ? • Initial diagnosis and prognosis Initial therapy • Monitoring recurrence – metastasis Secundary therapy

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