AIMS:Wild-type gastrointestinal stromal tumours (wtGIST) are frequently caused by inherited pathogenic variants, or somatic alterations in the succinate dehydrogenase subunit genes (SDHx). Succinate dehydrogenase is a key enzyme in the citric acid cycle. SDH deficiency caused by SDHx inactivation leads to an accumulation of succinate, which inhibits DNA and histone demethylase enzymes, resulting in global hypermethylation. Epigenetic silencing of the DNA repair gene MGMT has proven utility as a positive predictor of the therapeutic efficacy of the alklyating drug temozolomide (TMZ) in tumours such as glioblastoma multiforme. The aim of this study was to examine MGMT promoter methylation status in a large cohort of GIST. METHODS:MGMT methylation analysis was performed on 65 tumour samples including 47 wtGIST (33 SDH-deficient wtGIST and 11 SDH preserved wtGIST) and 21 tyrosine kinase (TK) mutant GIST. RESULTS:MGMT promoter methylation was detected in 8 cases of SDH-deficient (dSDH) GIST but in none of the 14 SDH preserved wild-type GIST or 21 TK mutant GIST samples analysed. Mean MGMT methylation was significantly higher (p 0.0449) and MGMT expression significantly lower (p<0.0001) in dSDH wtGIST compared with TK mutant or SDH preserved GIST. No correlation was identified between SDHx subunit gene mutations or SDHC epimutation status and mean MGMT methylation levels. CONCLUSION:MGMT promoter hypermethylation occurs exclusively in a subset of dSDH wtGIST. Data from this study support testing of tumour MGMT promoter methylation in patients with dSDH wtGIST to identify those patients who may benefit from most from TMZ therapy.

11534 Background: GISTs are the most common mesenchymal tumours of the gastrointestinal tract with an annual incidence of 10-15 per million. 10% of GISTS have activating mutations in the PDGFRA gene. We report our 13 year experience of all the PDGFRA-mutated GISTs in our regional centre in Cambridge. Methods: PDGFRA-mutant GISTs were identified from the Cambridge GIST database. Demographics, clinical and histopathological features, survival and response to tyrosine kinase inhibitors of all the patients from 2008-2021 were reviewed. Results: n = 50 (male:female 1.5:1) Median age 68 years (range 19-87). 8% of patients were under the age of 40 years. Tumour size ranged from 1-26 cm with a median of 5 cm. Mitotic index ranged from 1-51 with a median of 1 mitosis/5mm2. 52% of GISTs were located in the gastric body. Histological subtypes: 44% epithelioid, 36% mixed and 20% spindle cell. 38% of cases had high KIT expression (immunohistochemistry), whilst 48% had patchy expression and 14% were negative. Most were DOG1-positive (94%). 76% had radical surgery, 60% had laparoscopic resection. 24% were assessed as being high risk GISTs using the modified AFIP model contrasted to 13% being high risk with prognostic contour mapping. 13% developed metastatic disease with liver being the most common metastatic site. The table shows PDGFRA mutational analysis results: 58% had a D842V mutation. None had a KIT mutation. With a median follow up of 55.1 months, 82% were alive. 6 patients died from metastatic GIST and 3 from other causes. Median time to metastatic disease in resected GISTs was 30.1 months and median time from metastatic diagnosis to death was 18.5 months. Patients who presented with metastatic disease had poor survival compared with patients with localised disease ( p=0.001). 8 patients were treated with tyrosine kinase inhibitors including imatinib, sunitinib and regorafenib prior to 2020 with no objective responses. 3 patients were treated with Avapritinib since 2020 within the compassionate use programme. All 3 patients had partial responses and 2 patients are continuing Avapritinib with no grade 3 adverse events. Conclusions: We report the largest single centre PDGFRA-mutant GIST cohort from Europe. Male preponderance and exclusive gastric location were observed. KIT expression was patchy to negative in the majority of patients. 58% had PDGFRA D842V mutations for which Avapritinib has been recently approved. No objective responses were seen with imatinib, sunitinib or regorafenib. Our early experience with Avapritinib is promising.[Table: see text]

Background [ 68 Ga]Ga-DOTATATE PET/CT is now recognised as the most sensitive functional imaging modality for the diagnosis of well-differentiated neuroendocrine tumours (NET) and can inform treatment with peptide receptor radionuclide therapy with [ 177 Lu]Lu-DOTATATE. However, somatostatin receptor (SSTR) expression is not unique to NET, and therefore, [ 68 Ga]Ga-DOTATATE PET/CT may have oncological application in other tumours. Molecular profiling of gastrointestinal stromal tumours that lack activating somatic mutations in KIT or PDGFRA or so-called ‘wild-type’ GIST (wtGIST) has demonstrated that wtGIST and NET have overlapping molecular features and has encouraged exploration of shared therapeutic targets, due to a lack of effective therapies currently available for metastatic wtGIST. Aims To investigate (i) the diagnostic role of [ 68 Ga]Ga-DOTATATE PET/CT; and, (ii) to investigate the potential of this imaging modality to guide treatment with [ 177 Lu]Lu-DOTATATE in patients with wtGIST. Methods [ 68 Ga]Ga-DOTATATE PET/CT was performed on 11 patients with confirmed or metastatic wtGIST and one patient with a history of wtGIST and a mediastinal mass suspicious for metastatic wtGIST, who was subsequently diagnosed with a metachronous mediastinal paraganglioma. Tumour expression of somatostatin receptor subtype 2 (SSTR2) using immunohistochemistry was performed on 54 tumour samples including samples from 8/12 (66.6%) patients who took part in the imaging study and 46 tumour samples from individuals not included in the imaging study. Results [ 68 Ga]Ga-DOTATATE PET/CT imaging was negative, demonstrating that liver metastases had lower uptake than background liver for nine cases (9/12 cases, 75%) and heterogeneous uptake of somatostatin tracer was noted for two cases (16.6%) of wtGIST. However, [ 68 Ga]Ga-DOTATATE PET/CT demonstrated intense tracer uptake in a synchronous paraganglioma in one case and a metachronous paraganglioma in another case with wtGIST. Conclusions Our data suggest that SSTR2 is not a diagnostic or therapeutic target in wtGIST. [ 68 Ga]Ga-DOTATATE PET/CT may have specific diagnostic utility in differentiating wtGIST from other primary tumours such as paraganglioma in patients with sporadic and hereditary forms of wtGIST.

Inflammatory myofibroblastic tumour (IMT) is a rare malignancy with limited responses to corticosteroids and chemotherapy. About half of cases have activating rearrangements in the ALK gene which could be targeted with ALK inhibitors. A 40-year-old man presented with a large right lung mass and nodal, trapezius and cerebral metastases. Biopsy confirmed IMT with TPM4-ALK fusion. He was treated with prednisolone without clinical benefit. He received the Trk/ROS1/ALK inhibitor entrectinib in a clinical trial but his disease progressed in less than 3 months. Ifosfamide and etoposide in addition to radiotherapy to the brain and chest were administered. Transient improvement in the radiotherapy-treated areas was observed but his disease progressed shortly afterwards on all sites including the development of new adrenal metastasis. Compassionate use of the third-generation ALK inhibitor lorlatinib resulted in excellent partial response on all disease sites after 2 months, followed by a further 6 months of disease stabilisation. Repeat imaging showed slight increase in size of the cerebral metastasis but stable disease elsewhere, for which he was given stereotactic radiotherapy. His disease progressed 3 months later and lorlatinib was substituted with another ALK inhibitor brigatinib but he deteriorated and died shortly afterwards. Our patient tolerated lorlatinib well for 11 months with minimal toxicities, although he developed unilateral right-sided lung consolidation that was probably related to a combination of infection, radiotherapy and lorlatinib, which needed treatment with antibiotics and corticosteroids. This case demonstrates a role of lorlatinib in the treatment of TPM4-ALK-rearranged IMT despite failure of entrectinib.

11035 Background: NF1 is an inherited autosomal dominant condition characterised by multifocal neurofibromas, café au lait spots, Lisch nodules, freckling. GISTs are the most common mesenchymal tumour of the gastrointestinal tract occurring in NF1 patients. We present our 5 year experience of NF1 associated GISTs from a regional centre in United Kingdom. Methods: 15 patients with GISTs associated with NF1 syndrome were identified from the database. Clinical, pathological, molecular and treatment outcomes were analysed. Results: N = 15. Male-3 and female-12. Median age 46 years. 33% were multifocal and 67% unifocal. Primary site Stomach-6.6%, duodenum-33%, small bowel-67%, colon 6.6%. Presenting symptoms: Abdominal pain-47%, anemia/bleed-40% and incidental finding-13%. Tumour size 0.5-23 cm, median 9 cm. Mitotic index 0-15, median 4 mitoses/5mm2. Risk stratification-Low/intermediate risk 60% and high risk 40%. Histology was spindle cell in 87% and mixed in 13%. All GISTs were CD117 and DOG-1 +ve. SDHB expression was preserved in all GISTs. No activation mutations were detected in KIT (exons 9, 11, 13, 17), PDGFRA (exons 12, 14, 18) and BRAF. Treatment: 67% had the primary GIST resected. None had adjuvant imatinib. 6 patients had been treated with tyrosine kinase inhibitors. 1 partial response lasting < 3 months was observed with Imatinib. No durable responses were seen with Imatinib or Sunitinib or Regorafenib. All 5 patients with metastatic disease died within one year of diagnosis. Conclusions: GISTs associated with NF1 syndrome are rare. Median age of diagnosis is a decade earlier than KIT/PDGFRA mutated GISTs. We observed that NF1 associated GISTs occur predominantly in small bowel, are mostly spindle cell histology and have female preponderance. No durable responses were noted with Imatinib or Sunitinib or Regorafenib. There is an urgent need for systematic international collaboration to identify druggable pathways/targets in NF1 GISTs. Any trials should be multicentre/ multinational to expedite recruitment.

e23519 Background: Paediatric, adolescent, wild type and syndromic Gastro Intestinal Stromal Tumours (PAWS-GIST) consortium was formed in UK as a joint effort between GIST specialists, patients and carers. The aim was to raise awareness,undertake research, understand the biology and develop new treatments. The clinic was established in Cambridge, UK in 2014 and is held 3 times a year. We present our 3 years experience. Methods: Patients with wild type GISTS were invited to register for the clinic on website (www.pawsgistclinic.org.uk). Patients were reviewed by a panel of experts- oncologists, surgeon, pathologist, endocrinologist and cancer geneticist. 8 patients were seen in each clinic. Molecular testing including succinate dehydrogenase (SDH)B immunohistochemistry, sequencing of SDH genes, SDHC promoter hypermethylation were performed. Patients and families were offered germline testing of the SDH genes after counseling. All patients and carers were actively encouraged to provide feedback on their experience. Results: N = 60. Male:female 20:40. Median age 38 years (range 14-76 years). Primary tumour location-67% were gastric and 33% small bowel. SDHB deficient GISTs (n-23) were gastric, with male:female ratio of 9:14. Germline testing preliminary results show SDHA subunit mutations being the most common followed by mutations in SDHB, C and D subunits and epimutations in SDHC. 10 GISTs were observed in patients with neurofibromatosis-1 (NF-1), mostly located in small bowel and often multifocal. 20 patients have been treated with tyrosine kinase inhibitors. No objective responses were seen with imatinib. Stabilization of disease was most commonly seen with regorafenib. Conclusions: PAWS-GIST clinic is the second clinic of its kind in the world after the National Institute of Health USA clinic in Bethesda. The emphasis during first three years was raising the awareness, data collection,gaining experience and developing a research platform. UK national GIST tumour bank has been established. The clinic has helped us to focus on the needs of the patients and carers and to collaborate with other teams for developing new therapies for this rare subgroup of GIST patients.

10541 Background: Cambridge GIST study group was formed in 2003. GIST specialist multidisciplinary team (MDT) and GIST clinic were established with central review of histology/pathology and management plans. We present our 10 year experience of a prospective database which formed the template for the United Kingdom national GIST registry. Methods: All patients (pts) who have been referred to the GIST MDT were included in the study. The following data was prospectively collected: patient demographics, presenting symptoms, site, size, histology including mutational data (where available) risk stratification of the GISTS, surgical interventions, systemic therapies, other tumours occurring in GIST pts. Results: 260 patients (pts) were reviewed in the GIST MDT. 29 pts had endoscopic/imaging diagnosis of a GIST and were not included in the final analysis. 41 pts had other tumours diagnosed when GIST was initially suspected. Histologically confirmed GISTS N=190. Male: Female 52%:48%. Median age 64 years (range 14-94), 4% <40years. 84% had surgical intervention (primary or metastatectomy), 9% had resections on imatinib/sunitinib. Tumour characteristics: Site: Stomach-73%, small bowel-16%, EGIST-4%, colorectal-3%, duodenum-3% and oesophagus-1%. Size 0.1-40 cm. Histology subtype: Spindle cell =84%, mixed=12% and epitheloid=4%. Miettinen risk stratification groups: High risk=27%, intermediate risk=16% and very low risk/low risk=57%. Mutational status results in 36 pts: exon 11=64%, PDGFRA= 14%, wild type=11%, exon 9=5.5%, exon 13=5.5%. 14% of GIST pts had other tumour either prior to diagnosis or during treatment/follow up of GISTS. Conclusions: This is the first prospective regional GIST registry data from UK. Our results mirror other large prospective series. GISTS should be managed by an experienced multidisciplinary specialist team to provide a high quality patient centred service.

e21503 Background: Historically, GISTs were often misdiagnosed as other tumours. However, with the increasing awareness of GISTs, one needs to be careful in confirming the diagnosis since other tumours can simulate GISTs on endoscopy/imaging/histology. We report our 8 year experience of GIST mimics from the CGSG database. Methods: 250 cases discussed in the specialist multidisciplinary meeting from 2004 – 2012 were reviewed. Tumours initially suspected to be GISTs but turned out to be other tumours were included in this analysis. Patient demographics, endoscopic, imaging and histological features were analysed in 41 GIST mimics. Central review by specialist histopathologist was undertaken with immunohistochemical and molecular analysis to differentiate these tumours from GISTs. Results: GIST mimics N= 41. Median age 56 years (range 11 – 82 years), male:female ratio 1:1. Median size 8 cm (range 1.9 – 30 cm). Site of origin of tumours: stomach 34%, oesophagus/junction 15%, mesentery 12%, small bowel 10%, colon 5%, retroperitoneum 5%, pancreas 5%, liver 2% and indeterminate site of origin 12%. Suspicion of GIST was raised from imaging (46%), endoscopy (41%) and histology (39%). The histological subtypes of GIST mimics are summarised in the Table. Conclusions: Many benign and malignant tumours do mimic GISTs on imaging/endoscopy or histology. The diagnosis of GISTs should be made by a specialist multidisciplinary team with experience in imaging and histopathology. Distinguishing GISTs from their mimics is of critical importance both for prognosis and management. [Table: see text]