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Molecular and Histopathologic Prognostic Factors in Rectal Cancer

Molecular and Histopathologic Prognostic Factors in Rectal Cancer. Monirath Hav, MD, Ph.D. fellow (VLIR project) Pathology Department Ghent University Hospital Promoters: Prof. Dr. Piet Pattyn & Prof. Dr. Claude Cuvelier. Prognostic value of MSI : a comparative study. Cambodians : 37 cases

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Molecular and Histopathologic Prognostic Factors in Rectal Cancer

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  1. Molecular and Histopathologic Prognostic Factors in Rectal Cancer Monirath Hav, MD, Ph.D. fellow (VLIR project) Pathology Department Ghent University Hospital Promoters: Prof. Dr. Piet Pattyn & Prof. Dr. Claude Cuvelier

  2. Prognostic value of MSI : a comparative study • Cambodians : 37 cases • Belgians : 39 cases • Criteria : revised Bethesda guidelines • IHC for MMR proteins  MSI testing? • MSI status  prognosis

  3. Literature review • MSI occurs in 10-20% of colorectal cancer • MSI in rectal cancer is a rare event (2%), but if present, is strongly associated with HNPCC M. Nilbert et al. Eur. J. of Cancer, issue 6, June 1999, Pages 942-945

  4. What has been known about MSI in Belgian population ? • MSI in colon CA : 12.4% • MSI in rectal CA : 1.11% • MSI has no prognostic value in colon cancer Vanessa Deschoolmeester et al. European Journal of Cancer 44 (2008) 2288-229

  5. Hypothesis & questions • Is there a difference in MSI status between the 2 populations? • If yes, is there a difference in prognostic value of MSI? • Based on your experience, how good is the correlation between IHC for MMR proteins & MSI testing?

  6. MDM2 amplification negatively predicts response to neoadjuvant therapy in rectal cancer

  7. Current study • 71 cases  59 with neoadjuvant T. • IHC: MDM2 & p53 on biopsies & resections • p53 mutation analysis • MDM2 Fluorescent In Situ Hybridization (FISH) : on biopsies • Correlation with T downstaging and prognosis

  8. mdm2 mdm2 mdm2 mdm2 mdm2 FLIP p53 p53 The Two Major Apoptotic Pathways Pro-apoptotic ligand Cell-extrinsicpathway ChemotherapyRadiotherapy DR5 DR4 DNA damage p53 Cell-intrinsicpathway FADD PUMA, NOXA BCL2, BCLXL, MCL1 BAX, BAK Procaspase 8, 10 Mitochondria Caspase 8, 10 Cytochrome c SMAC/DIABLO APAF1 Caspase 9 IAP Caspase 3, 6, 7 Apoptosis DNA damage Ashkenazi A. Nat Rev Can 2002;2:420–430.

  9. Hypothesis • Presence of MDM2 overexpression in rectal cancer ! • MDM2 overexpression - wild-type p53 • MDM2 overexpression - absence of p53 • MDM2 overexpression / amplification no p53-dependent apoptosis no downstaging (no response to neoadjuvant)

  10. MDM2 Amplification in endoscopic biopsy • Conventional chemoradiation T. does not work • Need for combination with targeted T. (i.e Nutlins & RITA inhibit mdm2-p53 binding )

  11. Peri-tumoral inflammation : favorable prognostic factor in rectal cancer

  12. Inflammation as favourable prognostic factor in 5 studies: • EORTC study. • Leuven study. • Cetuximab study. • Shia et al. Am J Surg Pathol 2004; 28: 215. • Knutsen et al. Oncol Rep 2006. • No prognostic value: • Perez et al. J Gastrointest Surg 2007; 11: 1534. • 5 positive studies: time from end neoadjuvant treatment to surgery always < 6 weeks, while at least 8 weeks in Perez et al.

  13. Annelies Debucquoy et al. Eur. Journ. of Cancer 44 (2008) 791-797

  14. The current study • 71 patients (2005-2008 : stage I – III ; mean FU time = 18Ms ) • 59 cases with neoadjuvant • Interval neoadj-surgery : +/- 6 weeks • Peri-tumoral inflammation (PTI): cut-off 25% • T Downstaging (38 cases) DFS & N+ • PTI  tumor downstaging • PTI  DFS • Tumour deposits  DFS

  15. Response to treatment causes tumor damage and necrosis, which increases inflammatory reaction and elicits a specific immune response: • Peritumoral inflammation correlates with T downstaging, which is a measure of tumor response to treatment. • Postoperative chemo tends to be effective when inflammation is present. • Prognostic value of inflammation increases with less time between end of neoadjuvant treatment and surgery (<6 weeks

  16. 1 ,8 N - ,6 Cum. Survival N + ,4 ,2 0 0 5 10 15 20 25 30 35 40 Time Node status and DFS

  17. 1 ,8 TD - ,6 Cum. Survival TD + (<3mm) ,4 ,2 0 0 5 10 15 20 25 30 35 40 Time P=0.02 Tumor deposits & DFS

  18. 10 9 8 7 6 5 Nodes invaded 4 3 2 1 0 -1 0 1 Downstaging & N + P=0.03

  19. 1 ,8 Downstaging No downstaging ,6 Cum. Survival ,4 ,2 0 0 5 10 15 20 25 30 35 40 Time T downstaging & DFS P=0.02

  20. 1 ,8 PTI + PTI - ,6 Cum. Survival ,4 ,2 0 0 5 10 15 20 25 30 35 40 Time Peri-tumoral inflammation & DFS

  21. Now in need for more FU data from prof. Pattyn

  22. References • Vanessa Deschoolmeester et al. MSI has no prognostic value in colon cancer in Belgian population. European Journal of Cancer 44 (2008) 2288-229 • M. Nilbert et al. Microsatellite instability is rare in rectal carcinomas and signifies hereditary cancer. Eur. J. of Cancer, issue 6, June 1999, Pages 942-945 • Terry Van Dyke. P53 and tumor suppression. N Engl J Med 356; 1 (2007) • Jean-Franc¸ois Millau et al. P53 transcriptional activities: A general overview and some thoughts. Mutation Research 681 (2009) 118–133 • Nadia N Naski et al. The p53 mRNA-Mdm2 interaction. Cell Cycle 8:1, 31-34 (2009) • Christine M. Eischen and Guillermaina Lozano. P53 and MDM2: Antagonists or Partners in Crime? Cancer Cell 15, march 3, 2009 • Annelies Debucquoy et al. Morphological features and molecular markers in rectal cancer from 95 patients included in the European Organization for Research and Treatment of Cancer 22921 trial: prognostic value and effects of preoperative radiochemo therapy. Eur. Journ. of Cancer 44 (2008) 791-797

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