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Clinical variables, pathological factors, and molecular markers for enhanced soft tissue sarcoma prognostication. G. Lahat, B. Wang, D. Tuvin, DA. Anaya, C. Wei, B. Bekele, KD. Smith, AJ. Lazar, PW. Pisters, RE. Pollock, D. Lev Sarcoma Research Center UT MD Anderson Cancer Center - PowerPoint PPT Presentation
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Clinical variables, pathological factors, and molecular markers for enhanced soft tissue sarcoma prognostication
G. Lahat, B. Wang, D. Tuvin, DA. Anaya, C. Wei, B. Bekele, KD. Smith, AJ. Lazar, PW. Pisters,
RE. Pollock, D. Lev
Sarcoma Research Center
UT MD Anderson Cancer Center
Houston, TX U.S.A.
Current STS staging systems have several important shortcomings
• The TNM and grade criteria do not reflect the heterogeneity of STS
• Available nomograms are not universally applicable
• No current STS staging system includes molecular predictors of outcome
• Patient I- 6cm high grade extremity UPS
• Patient II- 25cm retroperitoneal dedifferentiated LPS
Both are AJCC Stage III patients!
Purpose
To identify clinical, pathological, and molecular descriptors of STS clinical behavior for inclusion in revised staging systems
Methods
• UTMDACC STS prospective database
• Univariate and multivariate statistical analyses
• Clinically annotated STS tissue microarray
Local recurrence only 474Primary & Metastatic 435Metastatic disease only 350
UTMDACC STS Database1996-2007
6,702 patients
Definitive treatment3,717
Primary disease only2,458
Surgical treatment of primary tumor
1,442
Study cohort1,091
Second opinion2,985
R2 resection and non-specific histologies
351
Non- surgical treatment
1,016
Patient and tumor characteristics
Male: 52%; Female: 48%
Median age (range): 54.5 years (15-91)
Median follow-up: 53.3 months
Extremity 58%
Intra thoracic
6%
Intra abdominal
26%
Superficial trunk 6%
Head and neck 2.5%
Non-extremity location is associated with increased STS-specific mortality
Non-extremity (n= 464; 42%)
Extremity (n= 627; 58%)
p<0.0001
A T3 category may be added to the AJCC STS staging system
p<0.0001
Tumor size>15cm (n= 230; 21%)
Tumor size 5-10cm (n=336; 31%)
Tumor size 10-15cm (n= 202; 19%)
Tumor size< 5cm (n= 309; 29%)
High grade is associated with increased STS-specific mortality
p<0.0001
High grade (n=737; 67.6%)
Low/intermediate grade (n=354; 32.2%)
Interaction between variables: tumor size and grade effects on STS-specific
mortality
p<0.0001
High grade, size>15cm
High grade, size 5-15cm
High grade, size<5cm
Low/intermediate grade
Low /intermediate grade, negative margins
Low/intermediate grade, positive margins
High grade, negative margins
High grade, positive margins
Interaction between variables: margin positivity and grade effects on STS-
specific mortality
p<0.0001
Multivariate Cox Proportional Hazard Models for STS-specific mortality
Variable Levels HR P value
Microscopic margins Positive vs. negative 5.9 <0.0001
Primary site Non-extremity vs. extremity 3.19 <0.0001
Tumor size 5-15cm vs. <5cm >15cm vs. <5cm
2.987.45
<0.0001<0.0001
Disease grade High grade vs. low/intermediate grade 2.06 <0.0001
Histology UPS vs. WDDedifferentiated liposarcoma vs. WDOthers vs. WD
8.074.022.98
0.0010.005<0.0001
Multivariate Cox Proportional Hazard Models for STS local recurrence free
survival
Variable Levels HR P value
Age Continuous in 10 years increment 1.26 <0.0001
Primary site Non-extremity vs. extremity 1.84 <0.0001
Margin positivity Positive vs. negative margins 2.39 <0.0001
Disease grade High grade vs. low/intermediate grade 1.90 0.001
Gender Male vs. female 1.54 0.01
ConclusionsAnn Surg Oncol 2008; 15:2739-48
STS size, site, grade, histology, and microscopic margin status should be included in a revised staging system
Can we further improve and individualize prognostication?
Every STS is “unique”
CureDistant
metastasis followed by
death
6cm, extremity, HG, UPS,
R0 resection
6cm, extremity, HG, UPS,
R0 resection
Patient A Patient B
Clinical and pathological prognostic factors are not enough!
Molecular markers are important potential prognostic factors
• High throughput assays
• Detection of DNA, RNA, and protein targets
• Simultaneous analysis of large tumor sets
• Correlation with clinical data
TMA (n=205)TMA (n=205)Growth and metastasis
Ki-67
Apoptosis/survival
P53
MDM2
Bcl2
Bcl-x
Cytokines/receptors/signaling
EGFR
VEGF
β-Catenin
Extracellular matrix
MMP2
MMP9
High MMP2 expression correlates with decreased STS-specific survival
Overall Survival time (month)
Pro
po
rtio
n S
urv
ivin
g
0 12 24 36 48 60 72 84 96 108 120 132 144 156
0.0
0.2
0.4
0.6
0.8
1.0
P-value= 0.004
Percent of area mmp2 positive <=10% ( E / N = 23/101 )Percent of area mmp2 positive >10% ( E/N =35/67)
72%
46%
Disease specific survival time (months)
Percent MMP2 pos ≤ 10%
Percent MMP2 pos > 10%
Multivariate Cox Proportional Hazard Models for disease specific survival
(TMA cohort)
Variable Levels HR P value
Primary site Non-extremity vs. extremity 2.95 0.001
Disease grade High grade vs. low/intermediate grade 2.5 0.02
Age Continuous in 10 years increment 1.62 <0.0001
MMP2 expression > 10% vs. ≤ 10% 1.74 0.04
Multivariate Cox Proportional Hazard Models for local recurrence
(TMA cohort)
Variable Levels HR P value
Age Continuous in 10 years increment
1.51 0.008
Primary site Non-extremity vs. extremity 4.09 0.005
MMP2 expression > 10% vs. ≤ 10% 6.28 0.006
Matrix metalloproteinases(MMP2) and STS
Number of patients Correlation with outcome
Maguire PD, et al (Oncology, 2000) 12 Negative
Benassi MS, et al (Ann Oncol, 2001) 73 Positive; grade, DFS
Previous series
Conclusions
• High MMP2 expression may be an adverse independent predictor of outcome in STS
• Inclusion as a molecular prognostic factor in future STS staging systems, pending large scale validation
• Individualized therapeutic strategy
• Should be further studied as potential targets for therapy
Acknowledgments
Vision and direction: Insights and teamwork:
Sarcoma Research CenterUniversity of Texas
MD Anderson Cancer Center
Dina Lev, MD Daniel Tuvin, MD
Raphael Pollock, MD, PhD Daniel Anaya, MD
Peter Pisters, MD Kerrington Smith, MD
Alex Lazar, MD, PhD
Nebiyou Bekele, PhD
Kevin Coombs, PhD
Caimiao Wei, PhD
Thank you for your attention!
TMA Tumor characteristics
Extremity 86%
Size> 5cm (76%)
HG (75%)
UPS
78%
Negative margins (70%)