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Biomarkers and personalized Therapy for CRC T. Thomaidis

Biomarkers and personalized Therapy for CRC T. Thomaidis. Colorectal cancer: Distribution. Worldwide around 1.4 mm new cases and 694.000 deaths per year. Metastasized colorectal cancer. 5-Fluorouracil & Derivate. Oxaliplatin. Irinotecan. Bevacizumab Cetuximab Panitumumab Ramucirumab.

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Biomarkers and personalized Therapy for CRC T. Thomaidis

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  1. Biomarkers and personalized Therapy for CRC T. Thomaidis

  2. Colorectal cancer: Distribution Worldwide around 1.4 mm new cases and 694.000 deaths per year

  3. Metastasized colorectal cancer 5-Fluorouracil & Derivate Oxaliplatin Irinotecan Bevacizumab Cetuximab Panitumumab Ramucirumab TAS 102 Aflibercept Regorafenib

  4. Treatment Traditional Oncology ParadigmTrial & Error“One Drug Fits All” Personalized Therapy Responder Personalized HealthcarePatient Stratification“The Right Drug for the Right Patient” Non-Responder

  5. Biomarkers • Prognostic Biomarkers: Parameters that show the progression of the disease regardless of the type of treatment. • Predictive Biomarkers: Parameter that assess the most likely response to a particular treatment type

  6. Normal Tumour cell Biomarkers

  7. Biomarkers JNCI 101:1310, 2009

  8. EGFR-Pathway

  9. EGFR-Pathway

  10. Timeline of mOS in patients with mCRC 5-FU/LV Bolus Saltz, 2000 12,6 5-FU/LV Infusion Douillard, 2000 14,1 IFL Saltz, 2000 14,8 FOLFIRI (de Gramontoder AIO) Douillard, 2000 17,4 Goldberg, 2004 FOLFOX 19,5 IFL + Bevacizumab Hurwitz, 2004 20,3 XELOX/FOLFOX + Bevacizumab Saltz, 2008 21,3 FOLFOXIRI Falcone, 2007 22,6 FOLFOX + Cetuximab Bokemeyer, 2011 22,8* FOLFIRI + Cetuximab Van Cutsem, 2011 23,5* FOLFOX + Panitumumab Douillard, 2011 23,9* FOLFIRI+ Cetuximab Heinemann, 2014 33,1* Thomaidis, Möhler 2014 CTX + EGFR-AK >36* 5 0 10 15 20 25 Overall Survival (Months) *KRAS-wt-Population

  11. Mutations in CRC • Why 40-60 % K-ras wt do not respond to a treatment with EGFR-Ab?

  12. Molecular mCRC-Subgroups

  13. NRAS-mut n=50 (4%) KRAS-mut n=565 (43%) “All-wt” n=581 (44%) BRAF-mut n=102 (8%) 39 11 102 554 Total n=1316 (81%) Mutations in CRC Maughan, The Lancet 2011

  14. Ras-Mutations and EGFR-therapy Sorich, Ann Oncol. 2015

  15. Ras wt: anti- EGFR or anti-VEGF? • Fire 3: Folfiri + Cetuximab vs Folfiri + Bevacizumab • mOS: 33,1 vs 25 months p=0.00059 • PEAK: Folfox + Panitumumab vs Folfox + Bevacizumab • mOS: 41,3 vs 28,9 Mo (p= 0.058) mPFS: 13 vs 9,5 Mo (p= 0.029) • CALGB/SWOG-80405:Ctx+Cetuximab vs Ctx+Bevac • ORR in Cetuximab-Arm (69% vs 54%, p<0.01)

  16. BRAF • V600E mutations 8-12 % in patients with mCRC • Female, older patients • 2/3 right Colon • Mucinous differentiation • High rate on lymphnodes and peritoneal carcinomatosis • Worse prognosis, mPFS < 6 Mo mOs< 1 year

  17. BRAF: Prognostic ? Saridaki Z, Plos One 2013

  18. BRAF: Predictive ? Seymour, Lancet Oncol 2013

  19. TRIBE: FOLFOXIRI+Bevacizumab Folfiri+ Bev. Folfoxiri+ Bev. ITT = Intent-to-treat, OS = Overall Survival Cremolini et al. WCGC 2014; O–007.

  20. SWOG S1406: BRAF mut. mCRC Kopetz et al., ASCO GI 2017 and ASCO 2017

  21. SWOG S1406: BRAF mut. mCRC- PFS Disease-control 67 vs 22% Kopetz et al., ASCO GI 2017 and ASCO 2017 075

  22. Tumorbiology: right vs left colon cancer • RCC show frequently hypermethylation 2 • LCRC show higher levels of Epiregulin and Amphiregulin, chromosomal Aberrations,liver metastases and CEA levels • Better clinical outcome for LCRC vs RCC (1)Missiaglia et al; ASCO 2013 (2) Nature. 2012;487(7407):330–337; (3) J Clin Oncol. 2012;30(Suppl): Abstr 3516.

  23. Holch, Eur J Cancer. 2017

  24. Immune Checkpoint Molecule: PD-1 ① Suppresses the over-activated T cell ② Inhibits the T-cell attack IFNγ IFNγR MHC TCR TCR MHC + + - CD28 - B7 PD-L1 CTLA-4 SHP2 PD-L1 PD-L2 PD-1 PD-L2 PD-1 Antigen presenting cells (APC) Activated T cell Cancer cell

  25. Immune Checkpoint Inhibitor: Anti-PD-1 antibody ① Augments the T-cell activation ② Restores the T-cell attack IFNγ Perforin Granzyme IFNγR MHC TCR TCR MHC + + CD28 - - B7 PD-L1 CTLA-4 PD-L1 PD-L2 PD-1 PD-L2 PD-1 Anti-PD-1 antibody Antigen presenting cells (APC) Activated T cell Cancer cell

  26. Microsatellite Instability Kloor et al. 2014 • MSI-h >30%, MSI-L: 10-30%, MSS: <10%

  27. Pembrolizumab in MSI high mCRC PFSOS Le DT et al. N Engl J Med. 2015

  28. Worse response to 5-FU Microsatellite Instability: adj. Setting 500 Pat with St. II&III CRC Sargent et al JCO 2010

  29. AREG- AREG+ 600 Patients Locally advanced CRCSt. IIb und III(n = 281) Hif-1α- Hif-1α+ R VEGFR-3- VEGFR-3+ 5-FU + LV (n= 133) 5-FU + LV + Irinotecan (n = 136) PTEN- PTEN+ FOGT-4 p<0.05 Thomaidis et al. J Exp Clinical Cancer Res 2014

  30. HER2 neu  Trastuzumab+Lapatinib ? Mutations in PIK3CA, exon 20 Evaluation of PTEN loss by IHC Evaluation of the levels of the EGFR ligands amphiregulin, epiregulin and TGF-α EGFR protein expression EGFR amplification and copy number EGFR ectodomain mutations Evaluation of HER3, and MET receptor overexpression Future molecules

  31. Personalized Factors Expansion of the tumor Local expansion? Lymph nodes? Metastases? Patient wish General Condition Comorbidity

  32. Interdisciplinary approach

  33. Treatment of mCRC All-RAS & BRAF WT (left colon) RAS or BRAF Mutation or right colon FOLFOX – Cetuximab FOLFOX – Panitumumab FOLFIRI – Cetuximab FOLFIRI – Panitumumab FOLFOXIRI +/- Bev XELOX/FOLFOX – XELIRI/FOLFIRI + Bev TMLorFOLFIRI Aflibercept or FOLFIRI RAM after Oxaliplatin / Beva FOLFIRI Aflibercept orBeva FOLFOX – Beva BRAF MUT Cetuxi / Irino / Vemurafenib Regorafenib / TAS 102 Regorafenib / TAS 102 Checkpoint-Inhibitor (CI) in MSI Regorafenib/ TAS-102 CI bei MSI / TL in HER2+ Trastuzumab / Lapatinib (TL) in HER2+

  34. Thank you for your attention

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