Clinicopathological features and prognosis of gastrointestinal stromal tumors with KIT/PDGFRA gene "homozygous mutation": a multicenter retrospective cohort study.
10.3760/cma.j.cn.441530-20210720-00293
- Author:
Yan Ying SHEN
1
;
Xiao Qi LI
1
;
Lin Xi YANG
2
;
Yong FANG
3
;
Ming Ming NIE
4
;
Zi Rui HE
5
;
Ying Yong HOU
6
;
Hui CAO
2
;
Ming WANG
2
;
Kun Tang SHEN
3
Author Information
1. Department of Pathology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China Shanghai GIST Diagnosis and Treatment Cooperative Group.
2. Department of Gastrointestinal Surgery, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China Shanghai GIST Diagnosis and Treatment Cooperative Group.
3. Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China Shanghai GIST Diagnosis and Treatment Cooperative Group.
4. Department of General Surgery, Changhai Hospital, Navy Medical University, Shanghai 200433, China Shanghai GIST Diagnosis and Treatment Cooperative Group.
5. Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China Shanghai GIST Diagnosis and Treatment Cooperative Group.
6. Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China Shanghai GIST Diagnosis and Treatment Cooperative Group.
- Publication Type:Multicenter Study
- Keywords:
Clinicopathological features;
Gastrointestinal stromal tumor;
KIT/PDGFRA gene, homozygous mutation;
Prognosis
- MeSH:
Aged;
Aged, 80 and over;
Antineoplastic Agents/therapeutic use*;
China;
Female;
Gastrointestinal Stromal Tumors/genetics*;
Humans;
Male;
Middle Aged;
Mutation;
Neoplasm Recurrence, Local;
Prognosis;
Proto-Oncogene Proteins c-kit/genetics*;
Pyrazoles;
Pyrroles;
Receptor, Platelet-Derived Growth Factor alpha/genetics*;
Retrospective Studies;
Triazines
- From:
Chinese Journal of Gastrointestinal Surgery
2021;24(9):804-813
- CountryChina
- Language:Chinese
-
Abstract:
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.
