[67] Gastrointestinal Stromal Tumors (GISTs): Molecular Analysis of KIT/PDGFRA/BRAF Genes Refines Risk Assessment (Register Study)

Sabrina Rossi, Rosalba Miceli, Luisa Toffolatti, Daniela Gasparotto, Giovanna Gallina, Alessandra Marzotto, Enrico Scaramel, Luca Messerini, Italo Bearzi, Guido Mazzoleni, Carlo Capella, Gianluigi Arrigoni, Aurelio Sonzogni, Angelo Sidoni, Luigi Mariani, Chiara Gnocchi, Roberta Valenti, Roberta Maestro, Alessandro Gronchi, Paolo G Casali, Angelo P Dei Tos. General Hospital, Treviso, Italy; Istituto Nazionale Tumori, Milano, Italy; CRO, Aviano, Italy; Firenze University School of Medicine, Firenze, Italy; University of Marche, Ancona, Italy; General Hospital, Bolzano, Italy; Macchi Fondation, Varese, Italy; San Raffaele Hospital, Milano, Italy; General Hospital, Bergamo, Italy; Medical School, Perugia, Italy; Novartis Farma, Origgio, Italy

Background: We analyzed a subset of naive GISTs from the REGISTER series, to assess whether KIT/PDGFRA/BRAF mutations are relevant to prognosis.
Design: DNA was analyzed in 451/526 GISTs previously evaluated to generate a OS nomogram, based on age, tumor site, as well as mitotic index (MI) and size both considered as continuous variables. Univariable and multivariable analyses were performed. A backward selection procedure was applied to the multivariable model to automatically generate prognostically homogeneous groups.
Results:

GeneExon (ex)Cases(%)
KIT932(7,1)
KIT11253(56,1)
KIT134(0,9)
KIT173(0,6)
PDGFRA1210(2,2)
PDGFRA147(1,6)
PDGFRA1878(17,3)
BRAF155(1,1)
WT cases-59(13,1)


KIT ex 11 mutations included 21 557-558 deletions. PDGFRA ex 18 mutations comprised 60 Asp842Val substitutions. Median MI was more than 2,6-fold and 4-fold higher in 557-558 del group compared to the all series and Asp842Val group, respectively (8 vs 3 and 2 mitoses/50HPF, respectively, p=0,02). Proportion of 557-558 del cases was higher in colorectal GISTs (16%) compared to other sites (5,9% in stomach and 0 in small intestine). The poorest OS at 120 months was observed among KIT-mutated patients (46.3%), whereas PDGFRA-mutated and WT patients had similar OS (67.5% and 62.5%, respectively). In the final model all the nomogram variables retained their independent value. The molecular variable defined 3 prognostic groups (p=0.001) with improvement of model discriminative ability as compared with nomogram variables only (C=0.732 vs 0.725). The most indolent group consisted of PDGFRA ex 12, BRAF and KIT ex 13 mutated cases. The intermediate group included WT cases, KIT ex 17 and PDGFRA ex 14-mutated cases as well as Asp842Val cases (group 2 vs group 1 HR 3.06, CI 1.09, 8.58). The most aggressive group comprised KIT ex 9 and 11 as well as PDGFRA ex 18 mutated cases except for Asp842Val cases (group 3 vs group 1 HR 4.52, CI 1.65, 12.37). There was no difference in outcome between del557-558 and other ex 11 mutations, a datum probably related to 557-558 del association with colorectal site and high MI.
Conclusions: We identified 3 molecular groups with distinct prognosis, refining risk assessment.
Category: Bone & Soft Tissue

Tuesday, March 5, 2013 1:00 PM

Poster Session IV # 29, Tuesday Afternoon

 

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