Molecular Biomarkers in Radiotherapy of Cervical Cancer

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Molecular Biomarkers in Radiotherapy of Cervical
Cancer
A collaboration project between Department of
Gynecologic Oncology and Department of
Radiation Biology
Project group The Radiation Therapy Team at
Dept. of Gynecologic Oncology /Gunnar B.
Kristensen, Dr. Med The Clinical Radiation
Biology Group at Dept. of Radiation Biology
/Heidi Lyng, Dr. Philos
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Need for improved treatment
more individualized therapy based on biological
information
Radiotherapy of cervical carcinomas
External irradiation Tumour region (50 Gy) and
the rest of pelvis (45 Gy) Endocavitary
brachytherapy Cervix (21 Gy)
Narrow therapeutic window ? high frequency of
side effects to pelvic organs

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Aims

• Molecular methods based on microarrays will be
  combined with MR and eventually PET techniques to
  find biomarkers that can be utilized for
  biologically optimized therapy

• Identify predictive biomarkers for the
  therapeutic outcome,
• including patient survival, locoregional tumor
  control and normal tissue side
• effects.
• Identify key radiation regulated pathways in
  tumors and possible targets for
• molecular intervention.
• Explore how the molecular findings can be
  combined with functional (MR and
• PET) and molecular imaging in treatment
  planning and response monitoring.

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Study protocol on cervical cancer, stage 2b-4a
DCE-MRI
Blood sample
Tumor biopsies
gt300 patients included
Image storage
Blood and tissue storage
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Research projects
Normal tissue side effects
CT dose plan, blood samples
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Molecular screening - gene profile associated
with clinical outcome
- basis for further molecular studies
Classification of patients with different outcome
based on gene profile
Gene profile 1
Gene profile 2
P 0.02
PhD student Malin Lando
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Molecular screening intratumor heterogeneity in
gene copy number
Genome wide screening of copy number in cervix
tumor
B
A
C024/01 DNA index 1.00 Tumor cell fraction 55
23
2
12
Frequency ()
aCGH ratio (log2)
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1
3
12
12
aCGH ratio (log2)
Chromosomal location 1pter-Xqter
Pronounced heterogeneity in copy number within
cervix tumors ?
resistent subpopulations may emerge at later
stages of the disease
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Screening ? signaling
Analysis of tumor biopsies
Characterization of signaling pathways of
importance for outcome ? mechanisms of activation
PhD student Cathinka Halle
Collaboration with Division of Pathology Ruth
Holm
Low MSN expression ? poor outcome
High MSN expression
Low MSN expression
Progression free survival
P 0.004
Time (months)
Lyng et al., BMC Genomics, 2006
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Metabolic screening by use of MR-spectroscopy
- relationship to
molecular data, imaging (MR) and clinical data
Collaboration with the MR center in
Trondheim Ingrid Gribbestad