Frequency, biological behaviour and survival nomograms discrimination in non-KIT mutated gastrointestinal stromal tumors

Background Non-KIT mutated gastrointestinal stromal tumors (GIST) are infrequent, accounting for less than 25% of all cases. Validated recurrence risk scores do not include genetic evaluation and uncommon mutations were not included in the development of prognostic nomograms. The aim of this study was to characterize the subpopulation of patients with non-KIT mutated GIST, evaluating the survival discrimination of the nomograms. Methods Retrospective evaluation of non-mutated exon 9/11-KIT GIST patients treated in a comprehensive cancer centre, between October 2009-March 2021, with a median follow-up of 4 years was performed. Sociodemographic, clinical and treatment data were extracted. For prognostic evaluation, there were defined 3 groups according to Miettinen-Lasota (2006) classification and the discriminative potential of Gold nomogram (2009) in survival prediction was evaluated. Results Of the 280 patients treated, 57 (20.4%) were included: 31 (54.4%) had the exon 18-PDGFRA mutation (74% D842V mutation); 17 (29.8%) were considered wild-type for KIT/PDGFRA; 4 (7.3%) presented with exon 12- or 14- PDGFRA mutations and 2 patients (3.6%) revealed exon 13- or 17- KIT mutations. The majority were male (n=37, 65%), with a mean diagnosis age of 61 years old [33-87], with localized disease (n=51, 89%), in the stomach (n=44, 77%) with a median diameter of 5.3 cm [1.2-26] and a low mitotic index (n=46, 81%). According to Miettinen-Lasota classification, 67% (n=38) revealed low risk, 16% (n=9) intermediate risk and 12% (n=7) high risk of recurrence. 8% (n=4) performed adjuvant imatinib. Compared to others, D842V exon 18-PDGFRA mutated patients (n=23) had the same average age at diagnosis (63 in mutated vs 62 years; p=0.14), were predominantly male (78%, n=18 vs 58%, n=18; p=0.12), with gastric tumours (100%, n=23 vs 65%, n=20; p=0.001) and with mixed morphology (48%, n=11 vs 16%, n=5; p=0.001). Most presented with low risk of recurrence (87%, n=20 vs 59%, n=17; p = 0.16) and they also had a lower risk of recurrence estimated by the nomogram used at 2 years (4% vs 10%, p<0.001) and 5 years (8.5% vs 19%, p=0.001). During follow-up, there were 3 relapses (probability of recurrence of these patients between 15-99% by Gold nomogram); only one patient died without evidence of disease. Conclusions Non-KIT mutated GIST are a heterogeneous molecular group, composed mostly of exon 18-PDGFRA mutation, and revealed a non-aggressive biological behaviour, discriminated by risk scores. Given the low number of relapses, validation of conventional prognostic nomograms will require a multicentric collaborative effort. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure All authors have declared no conflicts of interest.