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. Prognostic value of MSI : a comparative study. Cambodians : 37 cases - PowerPoint PPT PresentationTRANSCRIPT
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
• Belgians : 39 cases
• Criteria : revised Bethesda guidelines
• IHC for MMR proteins MSI testing?
• MSI status prognosis
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
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
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?
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
The Two Major Apoptotic Pathways
Ashkenazi A. Nat Rev Can 2002;2:420–430.
Caspase 3, 6, 7
Apoptosis
Pro-apoptotic ligand
FADD
FLIP
DR5
DR4
Cell-extrinsicpathway
Procaspase 8, 10
p53p53
Caspase 9
Caspase 8, 10
p53
BAX, BAK
Mitochondria
SMAC/DIABLO
ChemotherapyRadiotherapy
DNA damage
PUMA, NOXA
APAF1
Cytochrome c
DNA damage
IAP
Cell-intrinsicpathway
BCL2, BCLXL,
MCL1
mdm2
mdm2
mdm2mdm2
mdm2
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)
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 )
• 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.
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
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
Tumor deposits & DFS
P=0.02
0
,2
,4
,6
,8
1
Cu
m.
Su
rviv
al
0 5 10 15 20 25 30 35 40Time
TD +(<3mm)
TD -
T downstaging & DFS
P=0.02
0
,2
,4
,6
,8
1
Cum
. S
urvi
val
0 5 10 15 20 25 30 35 40Time
Downstaging
No downstaging
Peri-tumoral inflammation & DFS
0
,2
,4
,6
,8
1
Cum
. S
urvi
val
0 5 10 15 20 25 30 35 40
Time
PTI +
PTI -
References
1. Vanessa Deschoolmeester et al. MSI has no prognostic value in colon cancer in Belgian population. European Journal of Cancer 44 (2008) 2288-229
2. 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
3. Terry Van Dyke. P53 and tumor suppression. N Engl J Med 356; 1 (2007)4. Jean-Franc¸ois Millau et al. P53 transcriptional activities: A general overview and
some thoughts. Mutation Research 681 (2009) 118–1335. Nadia N Naski et al. The p53 mRNA-Mdm2 interaction. Cell Cycle 8:1, 31-34 (2009)6. Christine M. Eischen and Guillermaina Lozano. P53 and MDM2: Antagonists or
Partners in Crime? Cancer Cell 15, march 3, 20097. 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