616 Rare KIT gene mutation in a recurrent GIST: Case Report

Introduction The diagnosis and treatment of Gastro-intestinal stromal tumours (GISTs) has been revolutionized by molecular pathology and targeted therapy. Description This patient was diagnosed with locally advanced gastric GIST in 2009. He was initially treated neoadjuvantly with imatinib from 2009- 2010. He underwent laparoscopic resection in 2010. Pathology showed almost complete response with only 1.5mm focus of viable tumour. He did not receive adjuvant imatinib as this was not established practice in 2010. Recurrent disease was resected in 2011. Mitotic count was 200/50hpf. Adjuvant imatinib was given for 5 years then discontinued in 2016. Imaging showed no recurrence over this time period. Molecular testing showed Kit Exon 11 mutation- this is common in GISTs and associated with response to imatinib. Recurrent disease was diagnosed 2018 with a 10x9cm mass between residual stomach and liver– he recommenced imatinib with partial response (maximal response was reached in 2020, but a new 3cm lesion was noted) He underwent further resection of the residual stomach and liver segmentectomy in 2020. Histology showed acellular areas of myxoid degeneration, indicating treatment response however viable tumour remained. Sequencing was performed. This showed the expected mutation in exon 11 but also a mutation in exon 13 of KIT- this has been shown recently to confer resistance to imatinib. Discussion Over 90% of GISTs harbour mutations in c-KIT. Recent work has demonstrated that some tumours acquire secondary mutations conferring resistance, following prolonged TKI therapy. Radiological and histopathological features correlate with such events and assist in deciding surgical management.

Clinical, pathological, radiological characteristics, risk stratification and immunohistochemistry profile of gastrointestinal stromal tumors treated in a tertiary cancer centre located in Sub-Himalayan region: institutional experience of 20 patients and review of literature

GIST (gastrointestinal stromal tumors) are the rare mesenchymal tumors. Treatment includes curative surgery along with targeted agents like TKI in neoadjuvant/adjuvant settings. A total of 20 patients of histology proven GIST who were registered between 2014 to 2020 were reviewed for clinico-pathological data, endoscopic and radiological investigations, sites, primary treatment received, histology, immunohistochemistry, stage, risk stratification and imatinib therapy. GIST was more common in males than females. Age group varied between 25 years to 76 years. Majority of patients consumed non vegetarian diet, half of them being smokers and consumed alcohol. Pain abdomen, abdominal lump, dysphagia, haematemesis, melena and blood in stools were presenting complaints. CECT revealed heterogeneously enhancing mass with necrosis as most common finding. Upper GI endoscopy/colonoscopy revealed extrinsic bulge, polypoidal growth or ulcers as main findings. Stomach was the most common site followed by jejunum. Few patients presented with metastatic disease to liver and lungs. HPE revealed spindle cell GIST as main histology (with one patient with mixed spindle and epithelioid cells) with all patients having immunoreactivity to CD117. Majority of patients belonged to stage III and high-risk category by NIH stratification criteria. In majority of patients treatment received was surgery followed by adjuvant imatinib. Few patients had unresectable disease at presentation and received imatinib as upfront therapy. Imatinib was well tolerated in majority of patients. Few experienced manageable side effects like headache, irritability, leukopenia, pain abdomen, vomiting. Duration of treatment was one to three years. GIST is a rare tumor with varied presentations. Surgery is the mainstay of treatment offering chances of cure and revolutionary adjuvant imatinib is well tolerated with mild and manageable side effects in our centre. Being a resource limited centre, affordability for special investigations like IHC (immunohistochemistry) for CD117 (which helps in further confirmation of the diagnosis), remains a challenge for the patient and so does the 2nd line agent like sunitinib in case of recurrence.

Chromosomal complexity as a biomarker to de-escalate adjuvant imatinib treatment in high-risk gastrointestinal stromal tumor.

11535 Background: Gastrointestinal stromal tumors (GISTs) are characterized molecularly by oncogenic KIT or platelet-derived growth factor alpha ( PDGFRA) mutations. Malignant progression of primary GISTs occurs through stepwise accumulation of additional chromosomal aberrations, such as losses of chromosome arms 14q, 22q, 1p, 15q and Xp. After surgical resection of primary GIST, three years of adjuvant imatinib treatment is recommended for patients with an estimated high risk of recurrence. Still, nearly half of high-risk patients are cured by surgery alone, indicating that selection of patients could be improved. We hypothesized that high-risk GISTs with few chromosomal aberrations had a favorable outcome, and might not benefit from adjuvant therapy. The aim of the study was to investigate if chromosomal complexity could be used as a biomarker in de-escalation of adjuvant imatinib treatment. Methods: GIST patients undergoing surgical resection of their primary tumor between 1998 and 2020 were identified in the sarcoma database at Oslo University Hospital. All samples with available karyotype analysis made on fresh tumor tissue were included. Karyotypes were categorized as simple if they had ≤5 chromosomal changes, and complex if there were > 5 chromosomal aberrations. Results: Chromosomal aberrations were detected in 226 tumors, of which 181 (80.1 %) were gastric. The most frequent resulting imbalances were loss of 14q (75.9 %), 22q (43.5 %), 1p (36.6 %), and 15q (29.6 %). One-hundred and thirty-six tumors (60.2 %) had simple karyotypes whereas 90 (39.8 %) were complex. Cytogenetically complex tumors were larger ( P< 0.001), had a higher mitotic count ( P= 0.009), and were more often non-gastric ( P< 0.001). There was a strong association between chromosomal complexity and risk classification according to the modified NIH criteria ( P< 0.001). Thirty-eight of 58 (65.5 %) high-risk tumors were karyotypically complex compared to 37 of 144 (25.7 %) tumors that were not high-risk. In the high-risk group, 17 patients experienced disease recurrence, of whom one had a simple and 16 had a complex tumor karyotype. Estimated 5-year recurrence-free survival (RFS) for patients with simple tumor karyotypes was 94 % compared to 51 % for patients with cytogenetically complex tumors ( P= 0.004). Adjuvant and/or neoadjuvant imatinib treatment was administered to 40 high-risk patients with a median treatment duration of 33 months (range 2-60 months). A complex karyotype was associated with poor RFS both in patients with ( P= 0.016) and without ( P= 0.046) adjuvant imatinib. Conclusions: Chromosomal complexity was strongly associated with poor RFS in localized, high-risk GIST. Recurrences were infrequent for tumors with simple karyotypes, indicating that de-escalation of adjuvant imatinib treatment should be further explored in patients with cytogenetically simple GISTs.

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 < 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.