Molecular and Histopathologic Prognostic Factors in Rectal Cancer

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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

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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

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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

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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

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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?

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MDM2 amplification negatively predicts response
to neoadjuvant therapy in rectal cancer
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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

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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 20022420430.
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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)

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• 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 )

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• Peri-tumoral inflammation
• favorable prognostic factor in rectal cancer

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• 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 lt 6 weeks, while at
  least 8 weeks in Perez et al.

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

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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

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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 (lt6 weeks

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Node status and DFS
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Tumor deposits DFS
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Downstaging N
P0.03
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T downstaging DFS
P0.02
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Peri-tumoral inflammation DFS
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Now in need for more FU data from prof. Pattyn
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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-Francois Millau et al. P53 transcriptional
  activities A general overview and some thoughts.
  Mutation Research 681 (2009) 118133
• Nadia N Naski et al. The p53 mRNA-Mdm2
  interaction. Cell Cycle 81, 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