Abstract】With the development of molecular tumor diagnosis and the promotion and application of targeted drugs in recent years, cancer treatment has gradually entered a new era of precision medicine. The diagnosis and treatment of gastrointestinal stromal tumor (GIST) fully embodies the concept of precision medicine, but there are still a lot of urgent challenges to be explored in many aspects of clinical diagnosis and treatment of GIST (such as the correlation between gene mutation and prognosis, treatment strategy of wild-type GIST and the response to drug resistance phenomenon). [Keywords] Gastrointestinal mesenchymal tumor; precision medicine; diagnosis; treatment In early 2015, President Barack Obama threw $215 million at a powerful program called “precision medicine”, the core of which is to analyze a pool of more than 1 million volunteers of various ages and physical conditions of men and women to study The core of the program is to study the impact of genetic variation on human health and disease formation by analyzing a database of more than one million volunteers of all ages and physical conditions, so as to better understand the mechanism of disease formation and pave the way for the development of corresponding drugs and the realization of “precision medicine”. With this impetus, the concept of precision medicine is spreading rapidly around the world. So, what exactly is “precision medicine”? If we want to summarize it in the most concise words, we can refer to the definition given by the National Cancer Institute: Precision Medicine is the medicine that uses genetic information of individual diseases to guide its diagnosis or treatment. The key words are “genetic information” and “diagnosis or treatment”. Academician Zhan Qimin, vice president of the Chinese Academy of Medical Sciences and head of the National Expert Group on Precision Medicine Strategy, interpreted “precision medicine” as: applying modern genetic technology, molecular imaging technology and bio-information technology, combining with patients’ living environment and clinical data, to achieve accurate disease classification and diagnosis, and to formulate personalized prevention and treatment. In fact, from the above definition, precision medicine is the most effective way of diagnosis and treatment. In fact, from the above definition, precision medicine is not a new thing to us, especially in the field of oncology. With the development of molecular diagnosis of tumors and the wide application of targeted drugs in recent years, cancer treatment has gradually entered the new era of precision medicine, and the medical community has moved from the traditional pathological typing to the molecular typing under the guidance of genes. Among the many diseases that are ripe for targeted therapy for specific genetic alterations, gastrointestinal stromal tumor (GIST) is undoubtedly one of the brightest “stars”. It has been just over 30 years since Mazur et al. introduced the concept of “gastric stromal tumor” in 1983, but in this short period of time, the extent and speed of change in the diagnosis and treatment of GIST has been unparalleled by any other solid tumor. The decisive role in this process was played by the discovery by Hirota et al. in 1998 of a characteristic genetic alteration in GIST, the gain-of-function mutation in the c-kit gene. This genetic alteration directly drove the practice of imatinib mesylate (IM) in the treatment of GIST, and IM for GIST has now become the most classic model for the application of targeted drug therapy in solid tumors. Reviewing the development of IM in GIST, it can be seen that each step of progress in the treatment of GIST with this targeted drug has been based on the accumulation of evidence-based medicine. First, the population that could benefit from IM treatment was limited to advanced unresectable or recurrent metastatic GIST, and a classic clinical study B2222 was conducted around this application, whose results confirmed the efficacy and safety of IM at a dose of 400 mg/day for advanced GIST on the one hand, and found an important phenomenon, namely, the remission rate of 9 On the other hand, an important finding was made, namely, the remission rate of exon 9 GIST was higher in the 600 mg/day IM treatment than in the 400 mg/day dose treatment group, and this finding directly promoted the study and application of subsequent higher doses (800 mg/day) of IM in the treatment of exon 9. The subsequent S0033 and EORTC62005 studies validated the feasibility of dosing to 800 mg/day after disease progression under 400 mg/day dose IM treatment and provided evidence for the application of high-dose (800 mg/day) IM treatment for c-kit gene exon 9 mutation GIST. The BFR14 study provided clues to the duration of IM treatment for advanced GIST and found that IM treatment combined with surgery significantly improved progression-free survival (PFS) in patients with advanced GIST. The tremendous success of these treatments for advanced GIST quickly led to the use of IM in the adjuvant treatment of high-risk GIST. It was on the basis of this finding that the FDA approved IM as an adjuvant treatment indication. The SSG-XVIII/AIO study concluded that 3 years of adjuvant therapy is significantly better than 1 year of therapy. Clinical studies on the need for further extension of adjuvant therapy as well as clinical studies on IM in preoperative treatment are also ongoing. Following the findings of Demetri et al. in the Lancet in 2006, the status of another tyrosine kinase receptor inhibitor, sunitinib malate (SU), as a second-line agent for GIST has been progressively confirmed through a series of clinical study data. A newer multicenter, randomized, controlled, double-blind phase III clinical study, the GRID study, found that regorafenib significantly improved the prognosis of GIST patients who failed IM and SU therapy compared to placebo, and therefore the FDA has approved the drug as a third-line treatment for GIST. From the above history of targeted drug application, we can easily see that with the development of molecular pathology, genetics and bioinformatics technology, and thanks to a large number of evidence-based medical achievements, the field of tumor treatment represented by GIST has already had a target to hit and a drug to use, and new targets and new drugs are emerging all the time. In a sense, GIST has become a model of clinical practice of “precision medicine”, and through precise and efficient treatment of tumor targets, it has achieved efficacy far superior to traditional chemotherapy for gastric and intestinal cancers, saving the lives of countless GIST patients and greatly improving their quality of life. However, we must not judge that the current GIST treatment has been fully in line with the concept of precision medicine. Looking back at the history of GIST treatment, especially in the past decade or so when targeted drugs were used in its treatment, there are still many clinical challenges that need to be explored. Correlation between gene mutation and patient prognosis Currently, the 2008 updated NIH risk classification criteria are mostly used to predict the prognosis of GIST patients in China. In this risk classification system, tumor diameter, nuclear division phase, site of origin and tumor rupture are the key factors affecting the prognosis of GIST. However, the biological behavior of GIST is diverse, and the prognosis of some patients is difficult to be explained by the above criteria. In recent years, domestic and foreign researchers have successively tried to find the relationship between c-kit/PDGFRA gene mutation characteristics and GIST prognosis. However, different studies have come up with very different conclusions. Early studies found that GIST with c-kit gene exon 11 mutations had a worse prognosis than GIST with wild-type c-kit gene exon 11; GIST with c-kit gene exon 9 mutations occurred mainly in the small intestine and had a poorer prognosis. Recently, Rossi et al. analyzed the mutation status of KIT, PDGFRA and BRAF genes in 451 GIST specimens, and their study found that the risk of recurrence of GIST can be stratified at the molecular level according to the mutation status of the three genes mentioned above: GIST with PDGFRA12 exon mutations, BRAF mutations and KIT13 exon mutations Singer et al. suggested that the type of mutation may also have an impact on the prognosis of GIST, and they found that the presence of mutations in exons 9 and 11 and exon D842V in PDGFFRA18 had the worst prognosis. Martin-Broto et al. showed that GISTs with deletion/insertion mutations in codon 557/558 of the c-kit gene had a higher rate of postoperative recurrence/metastasis in a study of 162 GISTs. However, other studies have suggested that the mutational status of the c-kit or PDGFRA genes is not an independent factor influencing postoperative survival in GIST patients. By reviewing the mutation characteristics of 275 GIST cases in our unit, my research team found that the prognosis of GIST with mutations involving large segments (>=3 codons) in c-kit gene exon 11 was significantly worse than that of those involving small segments, and the results were published in 2014. Similarly, in early 2015, Joensuu et al. published in the Journal of Clinical Oncology the results of a study in which they examined more than 1500 GIST specimens for mutations and found that GIST patients with deletion mutations involving a single codon had a significantly better prognosis than those with multiple codons. The results of our single-center study and multicenter studies from abroad corroborate each other that deletion mutations in large segments of exon 11 may predict a poor prognosis for GIST patients and vice versa. Thus, it seems that specific mutation characteristics may be associated with the prognosis of GIST patients, however, there is still a long way to go before the mutation characteristics can be maturely applied to determine the prognosis of GIST patients, and further evidence-based medical evidence is needed to support this. Therapeutic strategies for wild-type GIST The primary mutation sites of the c-kit and PDGFRα genes in GIST are not random, but there are hotspots. c-kit primary mutations occur in exons 9, 11, 13, and 17, which encode the extra-membrane ligand binding domain, transmembrane structural domain, and first and second kinase structural domains of the KIT receptor protein, respectively. Accordingly, primary mutations in the PDGFRα gene occur in exons 12, 14 and 18. Approximately 10-15% of GISTs do not have mutations in the c-kit gene and known mutation hotspots in the PDGFRα gene as described above, i.e., wild-type GIST (wild-type GIST, wt-GIST). Although this subgroup does not account for a large proportion of GISTs, its pathogenesis and biological characteristics are significantly different from those of mutant GISTs, and its clinical diagnosis and treatment strategies are somewhat specific. Recently, an epidemiological analysis of 180 patients with wild-type GIST at Peking University Cancer Hospital in China showed that wild-type GIST is more common in younger patients and in the stomach with smaller tumors than mutant GIST, but unfortunately, the prognosis and outcome of this group of patients have not been analyzed in this study. Although IM for GIST has become a paradigm in the era of targeted tumor therapy, there is still far from a consensus on the treatment of wild-type GIST. Wild-type GIST is significantly less sensitive to IM than GIST with exon 11 mutations, and in the ACOSOG Z9001 clinical trial investigating IM adjuvant therapy, there was no significant difference in disease-free survival time (RFS) between wild-type GIST treated with IM 400 mg and the placebo group, respectively. The SSGXVIII/AIO clinical trial, which investigated IM three-year adjuvant therapy, also yielded similar results. A domestic study of IM for progressive GIST at Peking University Cancer Hospital showed that wild-type GIST had a significantly lower response rate to IM treatment than mutant GIST, with response rates of 68.5%, 47.8% and 36.4% for c-kit gene exon 11 mutant GIST, exon 9 mutant GIST and wild-type GIST, respectively, to imatinib treatment. Studies have shown that progressive neurofibromatosis type 1 (NF1)-associated wild-type GIST does not benefit from IM therapy. However, further studies are currently pending to confirm whether wild-type GIST associated with succinate dehydrogenase (SDH) or BRAF mutations can benefit from adjuvant imatinib therapy. The dilemma in the treatment of wild-type GIST is due to the uncertainty regarding the genetic alterations in this GIST subgroup. A subset of wild-type GISTs may not be truly “wild-type”, i.e., they may have site-specific mutations in the c-kit/PDGFFRA gene, but this locus is not a commonly detected locus and is therefore not detected. This “wild-type GIST” may still be sensitive to conventional first-line targeted therapy, and if this portion of GIST can be identified by adding detection sites, it will benefit from targeted therapy. For the remaining portion of GISTs that do not have c-kit/PDGFFRA mutations, subsequent research should focus on finding those genes other than c-kit/PDGFFRA mutations that can lead to tumorigenesis and their downstream alterations in signaling pathways, i.e., alternative mechanisms of GIST pathogenesis, and only by revealing the pathogenesis of this category of GISTs at the molecular level Only by revealing the pathogenesis of this type of GIST at the molecular level is it possible to make the treatment fundamentally consistent with the concept of precision medicine. Countermeasures against drug resistance due to secondary mutations during targeted drug therapy Over the past decade since the mature application of IM in the late treatment and adjuvant therapy of GIST, drug resistance has increasingly become a problem that plagues the clinical treatment of GIST. It has been proven that adjuvant IM therapy for GIST patients with high risk of recurrence/metastasis often only delays tumor recurrence/metastasis, and some patients develop recurrence/metastasis while taking the drug, and the tumor recurrence rate increases significantly once the drug is discontinued. Approximately 5-10% of patients are primary resistant to IM, while many more patients present as effective on initial IM therapy but inevitably eventually develop secondary resistance, which occurs between 6 months and 2 years after the start of initial therapy. Wardelmann E et al. found that 83% of GIST specimens resistant to IM or SU treatment had more than one c-kit secondary mutation. drug binding efficiency, ultimately leading to disease progression. Unlike the common sites of primary mutations, the common sites of secondary mutations are mostly located in exon 13 (e.g. V654A), exon 14 (e.g. T670I or S709F), and exon 17 of the c-kit gene. Exons 13 and 14 encode the ATP-binding domain of KIT protein, while exon 17 encodes the activating loop of KIT protein. Some studies have reported that the V654A mutation is IM-resistant but SU-sensitive, and some have found that the T670I mutation is also IM-resistant but SU-sensitive; however, most studies have found that the secondary mutation in exon 17 is resistant to both IM and SU. A recent study found that panatinib inhibits multiple KIT secondary mutation types, including activating loop mutations, which may be a boon for patients with drug-resistant GIST. These findings have led us to think about the different therapeutic strategies that can and should be developed for different types of secondary mutant clones. However, it is important to point out that the above studies are all based on small sample findings and are mostly in vitro level studies due to the rather limited source of specimens for secondary mutations. It is still a challenging task to accurately identify and subdivide the secondary mutations to guide the subsequent targeted drug therapy. The current exploration and progress in the field of GIST diagnosis and treatment is a microcosm of the practice of precision medicine. With the concept of precision medicine gradually gaining attention, a series of histology, molecular imaging, and analysis of big data around a variety of diseases have been carried out worldwide and have achieved certain results. We have reasons to believe that in the near future we will be able to use the concept and means of precision medicine to treat more diseases, further improve the effectiveness of treatment, reduce the side effects of drugs, and save medical costs. With the in-depth exploration and research of some outstanding issues in GIST treatment, the precision treatment of GIST will also become more precise and accurate!