High-risk Gastrointestinal Stromal Tumors Patients Research Articles

Development and validation of a computed tomography-based radiomics signature to predict "highest-risk" from patients with high-risk gastrointestinal stromal tumor.

Some patients with high-risk gastrointestinal stromal tumor (GIST) experience disease progression after complete resection and adjuvant therapy. It is of great significance to distinguish these patients among those with high-risk GIST. Radiomics has been demonstrated as a promising tool to predict various tumors prognosis. From January 2006 to December 2018, a total of 100 high-risk GIST patients (training cohort: 60; validation cohort: 40) from Guangdong Provincial People's Hospital with preoperative enhanced computed tomography (CT) images were enrolled. The radiomics features were extracted and a risk score was built using least absolute shrinkage and selection operator-Cox model. The clinicopathological factors were analyzed and a nomogram was established with and without radiomics risk score. The concordance index (C-index), calibration plot, and decision curve analysis (DCA) were used to evaluate the performance of the radiomics nomograms. We selected 11 radiomics features associated with recurrence or metastasis. The risk score was calculated and significantly associated with disease-free survival (DFS) in both the training and validation group. Cox regression analysis showed that Ki67 was an independent risk factor for DFS [P=0.004, hazard ratio 4.615, 95% confidence interval (CI): 1.624-13.114]. The combined radiomics nomogram, which integrated the radiomics risk score and significant clinicopathological factors, showed good performance in predicting DFS, with a C-index of 0.832 (95% CI: 0.761-0.903), which was better than the clinical nomogram (C-index 0.769, 95% CI: 0.679-0.859) in training cohort. The calibration curves and the DCA plot suggested satisfying accuracy and clinical utility of the model. The CT-based radiomics nomogram, combined with the clinicopathological factors and risk score, has good potential to assess the recurrence or metastasis of patients with high-risk GIST.

FBXW7 regulates the sensitivity of imatinib in gastrointestinal stromal tumors by targeting MCL1.

Imatinib contributes to improving prognosis of high-risk or unresectable gastrointestinal stromal tumors (GISTs). As therapeutic efficacy is limited by imatinib resistance and toxicity, the exploration of predictive markers of imatinib therapeutic efficacy that enables patients to utilize more effective therapeutic strategies remains urgent. The correlation between FBXW7 and imatinib resistance via FBXW7-MCL1 axis was evaluated in vitro and in vivo experiments. The significance of FBXW7 as a predictor of imatinib treatment efficacy was examined in 140 high-risk patients with GISTs. The ability of FBXW7 to predict therapeutic efficacy of adjuvant imatinib in high-risk GIST patients was determined through 5-year recurrence-free survival (RFS) rates analysis and multivariate analysis. FBXW7 affects imatinib sensitivity by regulating apoptosis in GIST-T1 cells. FBXW7 targets MCL1 to regulate apoptosis. MCL1 involves in the regulation of imatinib sensitivity through inhibiting apoptosis in GIST-T1 cells. FBXW7 regulates imatinib sensitivity by down-regulating MCL1 to enhance imatinib-induced apoptosis in vitro. FBXW7 regulates imatinib sensitivity of GIST cells by targeting MCL1 to predict efficacy of imatinib treatment in vivo. FBXW7 regulates imatinib sensitivity by inhibiting MCL1 to enhance imatinib-induced apoptosis in GIST, and predicts efficacy of imatinib treatment in high-risk GIST patients treated with imatinib.

Prognostic significance of hemoglobin, albumin, lymphocyte, platelet in gastrointestinal stromal tumors: A propensity matched retrospective cohort study.

BACKGROUNDThe combined index of hemoglobin, albumin, lymphocyte, and platelet (HALP) can reflect systemic inflammation and nutritional status simultaneously, with some evidence revealing its prognostic value for some tumors. However, the effect of HALP on recurrence-free survival (RFS) in patients with gastrointestinal stromal tumors (GISTs) has not been reported. AIMTo investigate the prognostic value of HALP in GIST patients.METHODSData from 591 untreated patients who underwent R0 resection for primary and localized GISTs at West China Hospital between December 2008 and December 2016 were included. Clinicopathological data, preoperative albumin, blood routine information, postoperative treatment, and recurrence status were recorded. To eliminate baseline inequivalence, the propensity scores matching (PSM) method was introduced. Ultimately, the relationship between RFS and preoperative HALP was investigated.RESULTSThe optimal cutoff value for HALP was determined to be 31.5 by X-tile analysis. HALP was significantly associated with tumor site, tumor size, mitosis, Ki67, National Institutes of Health (NIH) risk category, and adjuvant therapy (all P < 0.001). Before PSM, GIST patients with an increased HALP had a significantly poor RFS (P < 0.001), and low HALP was an independent risk factor for poor RFS [hazard ratio (HR): 0.506, 95% confidence interval (95%CI): 0.291-0.879, P = 0.016]. In NIH high-risk GIST patients, GIST patients with low HALP had a worse RFS than patients with high HALP (P < 0.05). After PSM, 458 GIST patients were identified; those with an increased HALP still had significantly poor RFS after PSM (P < 0.001) and low HALP was still an independent risk factor for poor RFS (HR: 0.558, 95%CI: 0.319-0.976, P = 0.041). CONCLUSIONHALP was significantly correlated with postoperative pathology and postoperative treatment. Furthermore, HALP showed a strong ability to predict RFS in GIST patients who underwent radical resection.

Development and external validation of a nomogram for individualized adjuvant imatinib duration for high‐risk gastrointestinal stromal tumors: A multicenter retrospective cohort study

IntroductionThe main emphasis of the research about adjuvant imatinib for high‐risk gastrointestinal stromal tumors (GISTs) is prolonging the treatment duration and ignores the heterogeneous that 10‐year recurrence rates ranged from about 20%–100%. Thus, this study evaluated the effect of different durations of adjuvant imatinib on outcomes in high‐risk GISTs to explore the feasibility of individual treatment.MethodsWe analyzed 855 high‐risk GIST patients from three centers who underwent macroscopically complete resection between December 2007 and September 2020. The patients were divided into training (n =564) and two validation cohorts (n = 238 and53) based on their source. Recurrence‐free survival (RFS) was the primary point. Cox multivariate analysis was used to develop the nomogram. C‐index, time‐dependent area under the curves, and calibration plots were used to assess the performance of the nomogram.ResultsUnivariate analysis showed that longer adjuvant imatinib was significantly associated with better 5‐year RFS (p < 0.0001). Further investigation identified that the same high‐risk patients with lower tumor‐associated recurrence risk benefitted little from prolonged treatment and that the recommended adjuvant imatinib duration was insufficient for those with higher recurrence risk. A nomogram for predicting 2‐, 3‐, and 5‐year RFS based on different treatment durations and four major risk factors, namely, tumor site, size, mitotic count, and rupture status, was built and validated, with a C‐index of 0.82, 0.74, and 0.70 in training and two external validation cohorts, respectively. An online dynamic nomogram was further developed for clinical applications (https://ruolinliu666.shinyapps.io/GIST/), offering predictive recurrence rates based on different treatment durations and tumor features.ConclusionsWe developed a nomogram to predict the recurrence risk for high‐risk patients according to tumor features and treatment durations of imatinib to help physicians on decision‐making for individualized treatment duration.

Clinicopathological features and prognosis of gastrointestinal stromal tumors with KIT/PDGFRA gene "homozygous mutation": a multicenter retrospective cohort study

Objective: To investigate the clinicopathological features of gastrointestinal stromal tumor (GIST) with KIT/PDGFRA "homozygous mutation", the efficacy of targeted therapy and the prognosis. Methods: A retrospective cohort study and propensity score matching were used. "Homozygous mutation" was defined as the detection of KIT/PDGFRA gene status of GIST by Sanger sequencing, which showed that there was only mutant gene sequence in the sequencing map, lack of wild-type sequence or the peak height of mutant gene sequence was much higher than that of wild-type gene sequence (> 3 times). "Heterozygous mutation" was defined as the mutant gene sequences coexisted with wild type gene sequences, and the peak height was similar (3 times or less). The clinicopathological data and follow-up information of 92 GIST patients with KIT/PDGFRA "homozygous mutation" were collected from 4 hospitals in Shanghai from January 2008 to May 2021 (Renji Hospital, Shanghai Jiaotong University School of Medicine: 70 cases; Zhongshan Hospital, Fudan University: 14 cases; Changhai Hospital, Naval Military Medical University: 6 cases and Ruijin Hospital, Shanghai Jiaotong University School of Medicine: 2 cases). Patients with perioperative death, other malignancies, and incomplete clinicopathological information were excluded. The clinicopathological features of the patients and the efficacy of targeted drug therapy were observed and analyzed. The efficacy was evaluated using Choi criteria, which were divided into complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). In addition, a total of 230 patients with high-risk GIST with "heterozygous mutation" in exon 11 of KIT gene and 117 patients with recurrent or metastatic GIST with "heterozygous mutation" in exon 11 of KIT gene were included. The propensity score matching method was used to match GIST patients with "heterozygous" and "homozygous" mutations in exon 11 of KIT gene (1∶1) for survival analysis. The disease-free survival (DFS) between two groups of high-risk GIST patients who underwent complete surgical resection were compared. And progression-free survival (PFS) in patients with recurrent or metastatic GIST were compared. Results: Of the 92 GIST cases with KIT/PDGFRA "homozygous mutation", 58 were males and 34 were females, with a median onset age of 62 (31-91) years. Primary GIST 83 cases. Primary high-risk GIST (53 cases), metastatic GIST (21 cases) and recurrent GIST (9 cases) accounted for 90.2% (83/92). There were 90 cases of KIT gene"homozygous mutation" (exon 11 for 88 cases, exon 13 for 1 case, exon 17 for 1 case), and 2 cases of PDGFRA gene "homozygous mutation" (exon 12 for 1 case, exon 18 for 1 case). The median follow-up time was 49 (8-181) months. Among the 61 cases of primary localized GIST undergoing complete surgical resection, 2 cases were intermediate-risk GIST, 5 cases were low-risk GIST, and 1 case was very low-risk GIST, of whom 1 case of intermediate-risk GIST received 1-year adjuvant imatinib mesylate (IM) therapy after operation, and no tumor recurrence developed during the follow-up period. The remaining 53 cases were high-risk GIST, and follow-up data were obtained from 50 cases, of whom 22 developed tumor recurrence during follow-up. Of 9 patients directly receiving neoadjuvant targeted therapy (IM or avapritinib), 5 had complete imaging follow-up data, and the evaluation of efficacy achieved PR. Of all the 92 GIST cases with KIT/PDGFRA "homozygous mutation", 50 (54.4%) had tumor metastasis or tumor recurrence or progression during follow-up, and 12 (13.0%) died of the tumor. Survival analysis combined with propensity score showed that in 100 cases of high-risk GISTs with complete resection, GISTs with "homozygous mutation" in exon 11 of KIT gene had shorter disease-free survival (DFS) than GISTs with "heterozygous mutation" in exon 11 of KIT gene (median DFS: 72 months vs. 148 months, P=0.015). In 60 cases of recurrent or metastatic GISTs with KIT gene exon 11 mutation, IM was used as the first-line treatment, and the progression-free survival (PFS) of GISTs with "homozygous mutation" was shorter compared to GISTs with "heterozygous mutation" (median PFS: 38 months vs. 69 months, P=0.044). The differences were statistically significant. Conclusions: "Homozygous mutation" in KIT/PDGFRA gene is associated with the progression of GIST. The corresponding targeted therapeutic drugs are still effective for GIST with KIT/PDGFRA gene "homozygous mutation". Compared with GIST patients with "heterozygous mutation" in KIT exon 11, GIST patients with "homozygous mutation" in KIT exon 11 are more likely to relapse after surgery and to develop resistance to IM. Therefore, it is still necessary to seek more effective treatment methods for this subset of cases.

Final analysis of the randomized trial on imatinib as an adjuvant in localized gastrointestinal stromal tumors (GIST) from the EORTC Soft Tissue and Bone Sarcoma Group (STBSG), the Australasian Gastro-Intestinal Trials Group (AGITG), UNICANCER, French Sarcoma Group (FSG), Italian Sarcoma Group (ISG), and Spanish Group for Research on Sarcomas (GEIS)☆

In 2004, we started an intergroup randomized trial of adjuvant imatinib versus no further therapy after R0-R1 surgery in localized, high/intermediate-risk gastrointestinal stromal tumors (GIST) patients. Interim analysis results were published in 2015 upon recommendation from an independent data review committee. We report the final outcome of the study. This was a randomized, open-label, multicenter phase III trial carried out at 112 hospitals in 12 countries. Patients were randomized to 2 years of imatinib, 400 mg daily, or no further therapy after surgery. The primary endpoint was imatinib failure-free survival (IFFS), while relapse-free survival (RFS), relapse-free interval (RFI), overall survival (OS) and toxicity were secondary endpoints. Adjusting for the interim analyses, results on IFFS were assessed on a 4.3% significance level; for the other endpoints, 5% was used. Nine hundred and eight patients were randomized between January 2005 and October 2008: 454 to imatinib and 454 to observation; 835 patients were eligible. With a median follow-up of 9.1 years, 5 (10)-year IFFS was 87% (75%) in the imatinib arm versus 83% (74%) in the control arm [hazard ratio (HR)= 0.87, 95.7% confidence interval (CI) (0.65; 1.15), P= 0.31]; RFS was 70% versus 63% at 5 years and 63% versus 61% at 10 years, [HR= 0.71, 95% CI (0.57; 0.89), P= 0.002]; OS was 93% versus 92% at 5 years and 80% versus 78% at 10 years [HR= 0.88, 95% CI (0.65; 1.21), P= 0.43]. Among 526 patients with high-risk GIST by local pathology, 10-year IFFS and RFS were 69% versus 61%, and 48% versus 43%, respectively. With 9.1 years of follow-up, a trend toward better long-term IFFS in imatinib-treated patients was observed in the high-risk subgroup. Although the difference was not statistically significant and the surrogacy value of such an endpoint is not validated, this may be seen as supporting the results reported by the Scandinavian/German trial, showing a sustained small but significant long-term OS benefit in high-risk GIST patients treated with 3 years of adjuvant imatinib.

A model to predict the recurrence of middle-high risk gastrointestinal stromal tumors based on preoperative fibrinogen and peripheral blood inflammatory indexes

Objective: At present, the modified NIH classification commonly used in clinical practice is still insufficient for assessing the risk of postoperative recurrence in some patients with intermediate-high risk gastrointestinal stromal tumors (GIST). Through exploring risk factors for recurrence of intermediate-high risk GIST, this study establishes a predictive model for recurrence with more convenience and more precision in order to guide adjuvant therapy for intermediate-high risk GIST patients. Methods: A retrospective case-control study was carried out. Clinical and pathological data of 432 GIST patients who did not receive preoperative targeted treatment, underwent complete resection in the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology from January 2005 to June 2018, and were diagnosed as intermediate- or high-risk based on modified NIH classification by postopertive pathology, were retrospectively analyzed. Cox regression model was used to idenitify independent risk factors of recurrence, and a recurrence risk scoring model was established. The receiver operating characteristic curve (ROC curve), consistency index (C-index) and calibration curve were used to evaluate the accuracy of the scoring model in predicting the recurrence of moderate-risk and high-risk GIST patients. Results: Among 432 GIST patients, 332 were diagnosed as high-risk and 100 as moderate-risk; 237 were males and 195 females with average age of (57.4±12.4) years. Of 432 patients, 211 cases (48.8%) had fibrinogen (FIB) >3.5 g/L; 85 cases (19.7%) had platelet to lymphocyte ratio (PLR)>272.5; 122 cases (28.2%) had neutrophil to lymphocyte ratio (NLR) > 4.2; 102 cases (23.6%) had systemic inflammatory reaction index (SIRI)> 2.7; 198 cases (45.8%) had tumor long diameter >8 cm and 108 cases (25.0%) had mitotic counts > 8/50 HPF. Cox multivariable analysis showed that FIB (HR=1.789, 95% CI: 1.058-3.027, P=0.030), PLR (HR=1.862, 95% CI: 1.067-3.249, P=0.029), SIRI (HR=1.790, 95% CI: 1.039-3.084, P=0.036), tumor long diameter (HR=1.970, 95% CI: 1.105-2.925, P=0.017) and mitotic counts (HR=2.187, 95% CI:1.211-3.950, P=0.009) were independent risk factors for recurrence in patients with middle-risk and high-risk GIST. These 5 factors were included in the risk scoring model, which was given a weight score of 58 points, 62 points, 58 points, 63 points, and 78 points, respectively. Patients with a total score of ≤ 78 points were classified as moderate-risk recurrence (group I), those of 78 to 136 points as high-risk recurrence (group II) and those of >136 points as very high-risk recurrence (group III). ROC curve showed that the area under the curve (AUC) of the scoring model was 0.730 and the C-index was 0.724 (95% CI:0.687-0.787). The calibration curves and the Kaplan-Meier curves of patients in the three groups revealed that this model had a good predictive accuracy. Conclusions: For intermediate-risk and high-risk GIST patients, the preoperative FIB >3.5 g/L, PLR > 272.5 and SIRI > 2.7 are independent risk factors of recurrence after surgery. The recurrence risk scoring model established by combining tumor long diameter, mitotic counts, FIB, PLR and SIRI can effectively predict the risk of postoperative recurrence and metastasis in moderate-risk and high-risk GIST patients.

Clinicopathological features and prognosis of gastrointestinal stromal tumor with PDGFRA-D842V mutation

Objective: Platelet-derived growth factor alpha (PDGFRA) mutations are respectively rare in gastrointestinal stromal tumors (GIST). Most GIST with PDGFRA exon 18 mutations including D842V mutation are highly resistant to imatinib. The treatment of GIST harboring PDGFRA primary drug-resistant mutation is a major challenge. This article aims to investigate clinicopathologic features of GIST with PDGFRA-D842V mutation and the efficacy of comprehensive treatment, providing a reference for clinical practice. Methods: A retrospective cohort study was conducted to collect the clinicopathological and follow-up data of patients with GIST harboring PDGFRA mutation who were diagnosed and treated in the GIST Clinic of Renji Hospital from January 2005 to May 2020. According to the mutation site, the enrolled patients were divided into D842V mutation group and non-D842V mutation group. The differences of clinicopathologic characteristics between the two groups were compared. Furthermore, overall survival and prognostic factors were analyzed. Results: A total of 71 patients with PDGFRA-mutant GIST were included in this study, including 47 cases of D842V mutation (66.2%) and 24 cases of non-D842V mutation (33.8%). There were 28 male patients and 19 female patients in D842V mutation group, with a median age of 60 (36-82) years. There were 16 male patients and 8 female patients in non-D842V mutation group, with a median age of 62 (30-81) years. There were no significant differences in age, gender, primary location, surgical procedure, tumor size, mitotic count, expression of CD117 and DOG1, Ki-67 proliferation index and modified NIH grade between the two groups (all P>0.05). The positive rate of CD34 was 89.4% (42/47) and 62.5% (15/24) in the D842V mutation group and the non-D842V mutation group, respectively, with a statistically significant difference (χ(2)=5.644, P=0.018). Among all the cases, 66 cases underwent R0 resection without preoperative treatment; two cases underwent emergency operation with R1 resection because of tumor rupture; 2 cases were not operated after the pathological and mutation types were confirmed by biopsy (one case received avapritinib treatment and obtain partial remission). One case was diagnosed as wild-type GIST per needle biopsy in another institute, and underwent R0 resection after preoperative imatinib treatment for 6 months. After surgery, 5 high-risk GIST patients with D842V mutation and 5 high-risk GIST patients with non-D842V mutation were treated with imatinib for more than one year. The median follow-up time was 37 (1-153) months. As of the last follow-up among the patients who received R0 resection, 4 patients with D842V mutation had relapse, of whom 1 was in the period of imatinib administration, and the 3-year relapse-free survival rate was 94.2%; none of the patients with non-D842V mutation had relapse. There was no statistically significant difference in relapse-free surivval between two groups (P=0.233). Univariate analysis revealed that mitotic count (P=0.002), Ki-67 proliferation index (P<0.001) and modified NIH grade (P=0.025) were the factors associated with relapse-free survival of patients with D842V mutation after R0 resection (all P<0.05). However, the above factros were not testified as independant prognostic facors in multivariate Cox analysis (all P<0.05). Conclusion: Clinicopathologic features and the efficacy of radical resection in patients with PDGFRA-D842V mutation are similar to those in patients with non-D842V mutation.

Prognostic Value of Fibrinogen and Lymphocyte Count in Intermediate and High Risk Gastrointestinal Stromal Tumors.

PurposeData about the prognostic value of fibrinogen concentration and absolute lymphocyte count for the prognosis of gastrointestinal stromal tumors (GISTs) were limited. Thus, the aim of the present study was to investigate the predictive value of preoperative fibrinogen concentration and absolute lymphocyte count in GISTs.Patients and MethodsFrom March 2002 to December 2017, 143 intermediate and high risk GIST patients treated with R0 resection were enrolled in the present study. Clinicopathological characteristics were recorded. The optimal cut-off values of patients were calculated by X-tile software. Categorical variables were analyzed using Chi-square test or Fisher’s exact test. Disease-free survival was analyzed by the Kaplan–Meier method and compared by a Log rank test.ResultsThere were 71 males (49.65%) and 72 females. The median age was 56 years (range 19–86). The optimal cut-off value was 4.5 g/L for fibrinogen concentration (P=0.000) and 1.0×109/L for lymphocyte count (P=0.002). No significant association was found between lymphocyte level and clinicopathological features. However, elevated fibrinogen level was correlated with tumor location, tumor size and NIH risk category. Tumor size, fibrinogen concentration and lymphocyte count were independent risk factors for the prognosis of patients according to the multivariate analysis. The prognosis of patients with high fibrinogen concentration or low lymphocyte count was significantly worse than that with low fibrinogen concentration or high lymphocyte count. Further, combination of fibrinogen concentration and lymphocyte count could increase the prognostic value for GIST patients.ConclusionFibrinogen concentration and absolute lymphocyte count were independent prognostic factors for intermediate and high risk GIST patients. The combination of fibrinogen concentration and absolute lymphocyte count could further increase the predictive value for the prognosis of GIST patients.

The analysis of 3-year adjuvant therapy with imatinib in patients with high-risk molecular profiled gastrointestinal stromal tumors (GIST) treated in routine practice

IntroductionThe real-world data on adjuvant imatinib therapy in high-risk primary GIST are scarce. MethodsWe have analysed the data of 107 consecutive patients with gastrointestinal stromal tumour (GIST) after resection treated with adjuvant imatinib (for planned 3 years with initial dose 400 mg daily, started not later than 4 months after operation) in 6 oncological centres in 2013–2018. All patients were required to have high risk of recurrence (at least 50% according to NCCN/AFIP criteria), known mutational status to exclude PDGFRA D842V mutants and KIT/PDGFRA-wild type cases from therapy without any further selection. Median follow-up time was 27 months. ResultsThe most common primary localization of GIST was small bowel (63 patients; 59%), followed by the stomach (40 patients; 37%). The majority of GIST cases harboured exon 11 KIT mutations (88 cases, 82%), 11 cases had exon 9 KIT mutations (10%), 8 had other KIT/PDGFRA mutations potentially sensitive to imatinib. Forty patients (37%) finished 3-year adjuvant imatinib therapy as planned, 48 (45%) still continue therapy, 5 (4.5%) patients had finished adjuvant therapy prematurely due to toxicity, 6 (6%) due to disease progression on treatment and 8 (7.5%) due to other reasons. The disease relapse was detected in 19 patients, of them in 5 cases in exon 9 KIT mutants (45%), and 14 cases in patients with exon 11 KIT mutations (11%) [p < 0.01]. Estimated 4-year relapse-free survival (RFS) rate is 78%. ConclusionsThe early results of adjuvant therapy with imatinib in routine practice outside clinical trials in high-risk mutation-driven GIST patients only confirm high efficacy of this therapy with better tolerability than in clinical trials. We found overrepresentation of exon 9 KIT mutants and ruptured tumors in a group of patients with disease relapse.

The real world outcomes of 3-year adjuvant therapy with imatinib in patients with high-risk molecular profiled gastrointestinal stromal tumors (GIST).

e23524 Background: The real-world data on outcomes of adjuvant therapy in high-risk gastrointestinal stromal tumors (GIST) are very limited. Methods: We have analyzed the data of 107 consecutive patients (52 male, 56 female) with GIST after resection treated with adjuvant imatinib (for planned 3 years with initial dose 400 mg daily, started not later than 4 months after operation) in 6 oncological centers in 2013-2018. All patients were required to have high risk of recurrence (at least 50% according to NCCN/AFIP criteria), known mutational status to exclude PDGFRA D842V mutants and KIT/PDGFRA-wild type cases from therapy. Median follow-up time was 24 months. Results: The most common primary localization of GIST was small bowel (63 patients; 59%), followed by the stomach (40 patients; 37%). The majority of GIST cases harbored exon 11 KIT mutations (88 cases, 82%), 11 cases had exon 9 KIT mutations (10%), 8 had other KIT/PDGFRA mutations potentially sensitive to imatinib. Thirty three patients (31%) finished 3-year adjuvant imatinib therapy as planned, 59 (55%) still continue therapy, 4 (4%) patients had finished adjuvant therapy prematurely due to toxicity, 6 (6%) due to disease progression on treatment and 5 (4%) due to other reasons. The disease relapse was detected in 16 patients, of them in 4 cases in exon 9 KIT mutants (36%), and 10 cases in patients with exon 11 KIT mutations (11%) [p &lt; 0.05]. Estimated 4-year relapse-free survival (RFS) rate is 78%. Conclusions: The early results of adjuvant therapy with imatinib in routine practice outside clinical trials in high-risk mutation-drive GIST patients only confirm high efficacy of this therapy with better tolerability than in clinical trials. Moreover, overrepresentation of exon 9 KIT mutants in a group of patients with disease relapse may indicate that standard 400 mg dose in adjuvant treatment is not sufficient for prevention of disease relapse.

Immune-Infiltration Based Signature As a Novel Prognostic Biomarker in Gastrointestinal Stromal Tumor

Background: Accumulating evidence showed that tumor-infiltrating lymphocytes (TILs) are dominant determinants of survival outcomes in various kinds of tumors. Thus, we sought to investigate the distribution and density of TILs in gastrointestinal stromal tumors (GISTs), and develop an immune-infiltration (II) based signature to predict prognosis. Methods: The expression of 7 immune features was investigated by immunohistochemistry from 435 GIST patients in tumor center (TC) and margin (TM), respectively. Then, a 4-feature-based II-GIST signature was constructed using the LASSO Cox regression model in the training cohort and validated in another two validation cohorts. The II-GIST signature integrated CD3+ TC, CD3 + TM, CD8+ TM and CD45RO+ TM. Results: High CD3+, CD8+, CD45RO+, NKp46+ and CD20+ infiltrations, in TC or TM correlated with improved recurrence-free survival (RFS) and overall survival (OS). Kaplan-Meier analysis and the log rank test suggested that high II-GIST patients experience better RFS and OS. Multivariate analyses demonstrated that II-GIST signature is an independent prognostic factor. When stratified by tumor size, mitotic index, National Institutes of Health (NIH) risk categories and primary tumor location, II-GIST remained to be an efficient prognostic model. The receiver operator characteristic (ROC) curve demonstrated that the prognostic accuracy of II-GIST signature is superior to that of NIH risk categories. Further analysis demonstrated that moderate and high risk GIST patients with high II-GIST could gain survival benefits from adjuvant imatinib therapy. Conclusion: The novel II-GIST signature could accurately predict the survival outcomes of GIST patients. In addition, the II-GIST signature was a useful predictor for survival benefit from imatinib therapy among moderate and high risk GISTs. Funding Statement: This study was supported by National Natural Science Foundation of China, No. 81702325; Natural Science Foundation of Guangdong Province, No. 2017A030310565; 3&3 Project of the First Affiliated Hospital of Sun Yat-sen University. Declaration of Interests: The authors declare that they have no conflict of interest. Ethics Approval Statement: This study was reviewed and approved by the Ethics Committee of the First Affiliated Hospital of Sun Yat-sen University and the Second Affiliated Hospital of Guangzhou University of Chinese Medicine.

Evidence for improvements to risk stratification in high-risk gastrointestinal stromal tumor patients

Evidence for improvements to risk stratification in high-risk gastrointestinal stromal tumor patients

A Novel Pathological Prognostic Score (PPS) to Identify “Very High-Risk” Patients: a Multicenter Retrospective Analysis of 506 Patients with High Risk Gastrointestinal Stromal Tumor (GIST)

BackgroundTo determine the better risk stratification based on surgical pathology and to assess the clinical outcomes after curative resection with a new scoring system in high risk gastrointestinal stromal tumor (GIST) patients. MethodsWe retrospectively evaluated 506 high-risk GIST patients who underwent curative resection as initial treatment at four centers from 2001 to 2015. ResultsMultivariate analysis revealed that only Ki-67 labeling index (LI) and mitotic index were independent prognostic factors of overall survival (OS). For the two tumor-related pathological factors, Ki-67 LI > 7% and mitotic index ≥ 7/50 high power fields were allocated 1 point each. The total score was defined as the Pathological Prognostic Score (PPS). When Ki-67 LI and mitotic index were replaced by PPS, a multivariate analysis still identified PPS as an independent predictor of OS (HR 2.719; 95% CI 1.309–5.650; P = 0.007). Patients with a PPS of 0, 1, or 2 had a 5-year survival of 91.8, 79.8, and 51.0%, respectively (P = 0.001). Furthermore, an elevated PPS (PPS = 2) was associated with larger tumor size, non-stomach tumor, and open resection (all P < 0.05). ConclusionThe PPS independently predicted postoperative survival in high-risk GIST, and it might facilitate the selection of appropriate treatment strategy for these patients.

Image analysis is an excellent tool for quantifying Ki-67 to predict the prognosis of gastrointestinal stromal tumor patients.

We investigated the quantification of Ki-67 staining using digital image analysis (IA) as a complementary prognostic factor to the modified National Institutes of Health (NIH) classification in patients with gastrointestinal stromal tumor (GIST). We examined 92 patients, focusing on the correlation between age, sex, primary tumor site, tumor size, predominant histologic type, mitotic index, modified NIH classification (low/intermediate vs high), Ki-67 quantitation, and recurrence-free survival (RFS). We compared two IA processes for whole slide imaging (WSI) and manually captured image (MCI) methods. A Ki-67 quantitation cutoff was determined by receiver operator characteristics curve analysis. In the survival analysis, the high-risk group of a modified NIH classification, a mitotic count >5 per 20 high-powered fields, and Ki-67 cutoffs of ≥6% and ≥8% obtained by IA of the WSI and MCI methods, respectively, had an adverse impact on RFS. On multivariate analysis, each Ki-67 quantitation method strongly predicted prognosis, more strongly than the modified NIH classification. In addition, Ki-67 quantitation using IA of the MCI method could stratify low or intermediate risk and high risk GIST patients. Thus, IA is an excellent tool for quantifying Ki-67 to predict the prognosis of GIST patients, and this semiautomated approach may be preferable for patient care.

Evaluation of high-risk clinicopathological indicators in gastrointestinal stromal tumors for prognosis and imatinib treatment outcome.

BackgroundAlthough the clinical benefit of imatinib adjuvant therapy for high-risk patients with gastrointestinal stromal tumor (GIST) has been proven, the recurrence rate still remains high. This study aimed to sub-divide high-risk GIST patients with some “very high-risk” factors for more precise prognostic indicator, and possible association with efficiency of imatinib adjuvant therapy.MethodsClinicopathological data were confirmed by pathological diagnosis and clinical records. Recurrence-free survivals (RFS) were evaluated in 370 GIST patients (212 cases as test cohort and 158 cases as validation cohort) and 48 high-risk GISTs with imatinib adjuvant therapy after R0 resection.ResultsMitosis count > 10/50 high-power fields (HPF) and serosal invasion are independent prognostic factors for RFS of GIST patients. Mitosis count > 10/50HPF and serosal invasion can sub-divide high-risk GIST patients effectively and significantly improve the area under the curve (AUC) of receiver operating characteristics (ROC) curve for prognostic indicator both in test and validation cohort. Patients with serosal invasion after R0 resection showed a poorer prognosis with imatinib adjuvant therapy.ConclusionsSub-division of high-risk GIST patients helps to more precisely predicting the prognosis. Serosal invasion may be an adverse predictive factor in high-risk patients and imatinib treatment outcome.

Risk of disease recurrence and mortality in gastrointestinal stromal tumor (GIST) patients receiving short-term versus long-term imatinib adjuvant therapy: A chart review analysis.

e20511 Background: The benefits of long-term (36 months) use of adjuvant imatinib (IM) in high risk GIST patients (pts) have been demonstrated in a recent multicenter, prospective clinical trial that compared efficacy and safety of 3 years vs 1 year IM treatment. However, in clinical practice, there is no consensus on the optimal IM treatment duration after surgery. The objective of this retrospective observational study was to compare the risk of recurrence and survival among primary resectable Kit positive GIST pts treated with adjuvant IM for a short vs an extended period of time in a real-world setting. Methods: Information on adult pts with primary resectable Kit positive GIST initiating imatinib ≤84 days after surgery was collected from 248 U.S. oncologists using an online data collection form. Detailed pt information following first GIST diagnosis, including demographic, GIST-related characteristics (e.g., risk profile), comorbidity profile, IM treatment characteristics, disease recurrence and mortality was collected for pts with short-term (6-12 months) and long-term IM use (≥24 months). Disease recurrence and mortality rates were estimated from the 1st surgery date to the 1st evidence of recurrence, mortality, or end of observation period. Multivariate Cox proportional hazard models were used to compare recurrence and mortality rates between short vs long term IM use pts. Results: Among the 246 short-term and 395 long-term IM pts, the median follow up was 884 and 963 days, respectively. The average age was similar [59.0 (10.4) vs 58.1 (9.5); p=.23] but short-term pts had less males [57.7% vs 69.6% (p&lt;.01)] and a lower Miettinen risk score [0.3 vs 0.4, p&lt; .01)] than long-term pts. Disease recurrence [7.3 vs 1.8%, (p&lt; .01)] and mortality rates [6.9% vs 2.3%, (p &lt; .01)] were also higher in short- vs long-term pts. The adjusted risk of recurrence was 4.77 times [95% CI: 1.98 – 11.48, (p&lt;.01)] higher and mortality risk was 3.44 times [CI: 1.53 – 7.75, (p&lt;.01)] higher in short- vs long-term pts. Conclusions: Use of IM over an extended period of time is associated with a reduction in long-term risk of disease recurrence and mortality.

Phase II Trial of Neoadjuvant/adjuvant Imatinib Mesylate for Advanced Primary and Metastatic/recurrent Operable Gastrointestinal Stromal Tumors: Long-term Follow-up Results of Radiation Therapy Oncology Group 0132

Imatinib inhibits the KIT and PDGFR tyrosine kinases, resulting in its notable antitumor activity in gastrointestinal stromal tumor (GIST). We previously reported the early results of a multi-institutional prospective trial (RTOG 0132) using neoadjuvant/adjuvant imatinib either in primary resectable GIST or as a planned preoperative cytoreduction agent for metastatic/recurrent GIST. METHODS.: Patients with primary GIST (≥5 cm, group A) or resectable metastatic/recurrent GIST (≥2 cm, group B) received neoadjuvant imatinib (600 mg/day) for approximately 2 months and maintenance postoperative imatinib for 2 years. We have now updated the clinical outcomes including progression-free survival, disease-specific survival, and overall survival at a median follow-up of 5.1 years, and we correlate these end points with duration of imatinib therapy. Sixty-three patients were originally entered (53 analyzable: 31 in group A and 22 in group B). Estimated 5-year progression-free survival and overall survival were 57% in group A, 30% in group B; and 77% in group A, 68% in group B, respectively. Median time to progression has not been reached for group A and was 4.4 years for group B. In group A, in 7 of 11 patients, disease progressed >2 years from registration; 6 of 7 patients with progression had stopped imatinib before progression. In group B, disease progressed in 10 of 13 patients>2 years from registration; 6 of 10 patients with progressing disease had stopped imatinib before progression. There was no significant increase in toxicity compared with our previous short-term analysis. This long-term analysis suggests a high percentage of patients experienced disease progression after discontinuation of 2-year maintenance imatinib therapy after surgery. Consideration should be given to studying longer treatment durations in intermediate- to high-risk GIST patients.

Adjuvant imatinib therapy for gastrointestinal stromal tumors

Surgery is the standard of care for primary resectable gastrointestinal stromal tumors (GISTs), but half of surgically treated patients relapse. Imatinib (IM) has been shown to prolong recurrence-free survival after complete surgery and is now approved as adjuvant therapy (400 mg/day) for high-risk GIST patients. IM is well tolerated, with mild to moderate side effects observed. Whether adjuvant IM prolongs overall survival is under evaluation in two ongoing clinical trials.

Phase II trial of neoadjuvant/adjuvant imatinib mesylate (IM) for advanced primary and metastatic/recurrent operable gastrointestinal stromal tumor (GIST): Long-term follow-up results of RTOG 0132.

10057 Background: Imatinib mesylate (IM), which inhibits the KIT and PDGFR tyrosine kinases, has known activity against GIST. We previously reported early results of the first reported multi-institutional prospective trial (RTOG 0132) using neoadjuvant imatinib mesylate (IM) either in primary resectable GIST or as a planned preoperative cytoreduction agent for metastatic GIST (Eisenberg et al., JSO 2009). Methods: Patients with primary GIST (≥5cm, Group A) or operable metastatic/recurrent GIST (≥2 cm, Group B) received neoadjuvant IM (600 mg/day) for approximately two months and maintenance IM after surgery for 2 years. We have now updated the clinical outcomes including progression-free survival (PFS), disease-specific survival (DSS), and overall survival (OS) at a median follow-up of 5.1 years and correlate these endpoints with duration of IM therapy. Results: Sixty-three patients were originally entered (53 analyzable), 31 patients in Group A and 22 in Group B. Estimated 5-year PFS and DSS were 57% A, 30% B; and 77% A, 77% B, respectively. Estimated 5-year OS was 77% for A, and 68% for B. Median time to progression has not been yet reached for Group A and is 4.4 years for Group B. In Cohort A, 7/11 patients progressed > 2 years from registration; 6/7 progressing patients had stopped IM prior to progression. In Cohort B, 10/13 patients progressed> 2 years from registration; 6/10 progressing patients had stopped IM prior to progression. The rate of treatment-related grade 4/5 toxicities was 23% (12/53). There was no increase in long term surgical complications using neoadjuvant and extended IM therapy. Conclusions: This long-term analysis of RTOG 0132 suggests a high percentage of patients progressed after discontinuation of 2-year maintenance IM therapy following surgical resection. Consideration should be given to studying longer treatment durations in high-risk GIST patients.