1. 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. INTEGRATING GENOTYPE IN RISK CLASSIFICATION FOR GIST RECURRENCE. A Spanish Group for Sarcoma Research (GEIS) Study BACKGROUND 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. 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. MIETTINEN-LASOTA SIMPLIFIED RISK CLASSIFICATION Miettinen M, Lasota J. Semin Diagn Pathol. 2006 May;23(2):70-83 50 HPF= 5 mm 2 METHODS 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. 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. Low risk Intermediate risk High risk 91% 60% 34% P = 0.0001 7-YEAR RFS CURVES ACCORDING TO MIETTINEN-LASOTA 70% 38% P = 0.0001 ACTUARIAL RFS CURVES ACCORDING TO del 557 and/or 558 mutation Del 557 and/or 558 No Del 557 and/or 558 7-year ACTUARIAL RFS IN LOW RISK MIETTINEN CLASSIFICATION According to prognostic genotype PDGFRa mut Del 557/558 mut Other 93% 90% 76% P=0.35 PDGFRa mut Del 557/558 mut Other 7-year ACTUARIAL RFS IN INTERMEDIATE RISK MIETTINEN CLASSIFICATION According to prognostic genotype 80 % 64 % 26 % P=0.009 PDGFRa mut Del 557/558 mut Other 7-year ACTUARIAL RFS IN HIGH RISK MIETTINEN CLASSIFICATION According to prognostic genotype 40 % 28 % 21 % P=0.79 429 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. The 7-year RFS for low MRC were 93% in MUT-PDGFR, 76% in DEL- 5758 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. 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. RESULTS VariableHRCIP Value SIZE 1.751.04-2.900.033 LOCATION1.791.24-2.600.004 MITOSES3.42.31-5.050.0001 Del 557/5581.51.02-2.320.042 Prognostic Independent Factors In Multivariate Analyses CONCLUSIONS 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.