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INTEGRATING GENOTYPE IN RISK CLASSIFICATION FOR GIST RECURRENCE. A Spanish Group for Sarcoma Research (GEIS) Study
Javier Martin-Broto, Silvia Calabuig, Jordi Rubió, Antonio Gutierrez, José Duran, Florencia García, Javier Martinez Trufero, Joan Maurel, Xavier García del Muro, Josefina Cruz, Ricardo Cubedo, Andrés Poveda, Claudia Valverde,
Jose L Gonzalez de Sande, Ana de Juan, Jose A López-Guerrero.
RESULTS
BACKGROUND
7-YEAR RFS CURVES ACCORDING TO
MIETTINEN-LASOTA
Relevant prognostic factors for relapse free survival (RFS) in GIST rely
on clinical and pathologic variables such as size, mitoses, location or
tumor rupture. However, being GIST a solid tumor model for molecular
research and targeted therapies, it seems legitimate to explore the
integration of relevant molecular prognostic factors into the risk
classification.
Low risk
429 patients were identified according to the inclusion criteria, 35 of
them had insufficient data, thus 394 patients entered into the analysis.
Median size was 7 cm and with a median follow-up of 84 months there
were 137 recurrences (37%). DEL-5758 and MUT-PDGFR were
present in 65 and 25 cases respectively.
91%
Intermediate risk
The 7-year RFS for low MRC were 93% in MUT-PDGFR, 76% in DEL5758 and 90% in the remainder (p=0.35), for Intermediate MRC were
80%, 26% and 64% (p=0-009) respectively and for high MRC were
40%, 21% and 28% (p=0.79) respectively.
60%
High risk
Several authors have pointed out the detrimental prognostic role of
deletion type mutations involving 557/558 (DEL-5758) codons of exon
11 in KIT gene in localized GIST. On the other hand, mutations of
PDGFR (MUT-PDGFR) gene have been associated with lower risk of
recurrence. We will analyze the influence of these genotype factors for
each Miettinen risk category.
34%
P = 0.0001
7-year ACTUARIAL RFS IN LOW RISK MIETTINEN
CLASSIFICATION
According to prognostic genotype
ACTUARIAL RFS CURVES ACCORDING TO del 557
and/or 558 mutation
MIETTINEN-LASOTA SIMPLIFIED RISK CLASSIFICATION
93%
No Del 557 and/or 558
90%
50 HPF= 5 mm2
Size
Mitotic count (50 hpf)
Very Low Risk
2- 5 cm
≤ 5 mitoses
gastric
Low Risk
>5 ≤ 10 cm
2- 5 cm
≤ 5 mitoses
≤ 5 mitoses
gastric
intestinal
Intermediate Risk
>10 cm
>5 y ≤ 10 cm
2- 5 cm
≤ 5 mitoses
≤ 5 mitoses
> 5 mitoses
gastric
intestinal
gastric
2- 5 cm
> 10 cm
> 5 mitoses
≤ 5 mitoses
intestinal
intestinal
>5 y ≤ 10 cm
> 10 cm
> 5 mitoses
> 5 mitoses
gastric
gastric
>5 y ≤ 10 cm
> 10 cm
> 5 mitoses
> 5 mitoses
intestinal
intestinal
High Risk
Miettinen M, Lasota J. Semin Diagn Pathol. 2006 May;23(2):70-83
PDGFRa mut
Other
Del 557/558 mut
Prognostic Independent Factors In Multivariate Analyses
Variable
Del 557 and/or 558
38%
P=0.35
HR
CI
P Value
SIZE
1.75
1.04-2.90
0.033
LOCATION
1.79
1.24-2.60
0.004
MITOSES
3.4
2.31-5.05
0.0001
Del 557/558
1.5
1.02-2.32
0.042
P = 0.0001
7-year ACTUARIAL RFS IN HIGH RISK
MIETTINEN CLASSIFICATION
According to prognostic genotype
7-year ACTUARIAL RFS IN INTERMEDIATE RISK
MIETTINEN CLASSIFICATION
According to prognostic genotype
METHODS
PDGFRa mut
Other
Del 557/558 mut
80 %
Clinical data, therapeutic and follow-up procedures stemmed from the
GIST Registry of GEIS. Main inclusion criteria were: localized GIST,
adequate surgery, size > 2 cm, complete genotype for KIT and PDGFR
genes, no adjuvant imatinib and minimum follow-up of 3 years. RFS
was measured by Kaplan-Meier method.
CONCLUSIONS
PDGFRa mut
Other
Del 557/558 mut
64 %
40 %
28 %
26 %
21 %
P=0.009
For each Miettinen Risk Category, RFS was estimated for those
harboring DEL-5758 or MUT-PDGFR. Univariate and multivariate
analyses were performed using log-rank test and Cox regression.
76%
70%
Location
On univariate analysis: mitoses, size, location (gastric vs non gastric)
and genotype were found to be significantly correlated with RFS.
Multivariate analyses revealed that size (HR 1.75; CI 1.04-2.90),
location (HR 1.79; CI 1.24-2.60), mitoses (RR 3.4; CI 2.31-5.05) and
DEL-5758 (RR 1.5; CI 1.02-2.32) were independent prognostic factors
for RFS.
P=0.79
Genotype significantly affects prognosis in localized GIST and
therefore should be integrated into the risk classification especially in
intermediate MCR.
Deletion type mutations involving 557 and/or 558 codons of KIT gene
carries a significant worse prognosis in localized intermediate risk
according to Miettinen. Therefore, these patients should be advised for
adjuvant imatinib.
PDGFRa mutants showed a trend toward lower risk of recurrence, but
did not reach statistical significance. Maybe because of the
unexpected low number of PDGFRa mutatnts in our series.