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The Gist of GIST
- 1. Gastrointestinal Stromal Cell Tumors Joshua D. I. Ellenhorn, M.D. Clinical Professor of Surgery “GIST”
- 2. •46 year-old female presented with a 20 pound weight loss melena and dyspnea. •Abdominal exam revealed an ill defined left upper quadrant mass. •Hgb 4.9 Case Presentation
- 3. •The patient was transfused up to a Hgb of 11 •Abdominal CT scan was performed
- 4. mass 1 mass 3 mass 2
- 5. H&E c-Kit CT guided core biopsy of the mid-abdominal mass revealed a spindle cell neoplasm which was positive for c-Kit by immunohistochemistry
- 7. How would you treat this patient?
- 8. How would you treat this patient?
- 9. How would you treat this patient?
- 10. GIST Near GEJ How would you treat this patient?
- 11. How would you treat this patient?
- 12. GIST Is a Rare Gastrointestinal Sarcoma • 4000 - 6000 new cases/year in US • 1500 - 2000 cases/year in Japan • Most common GI mesenchymal neoplasm – 5%-6% of all sarcomas • Wide age range – 75% of patients >50 years – Median age: ~58 years • No gender predilection
- 13. GISTs Present With Variable Symptoms • Often asymptomatic, especially when small • Symptoms nonspecific – GI bleeding (53%) – Abdominal pain (32%) – Palpable mass (13%) • Other symptoms may include – Early satiety – Fatigue from anemia – Rare obstruction
- 14. GISTs Occur Mainly in the Stomach • Occur anywhere along the GI tract or elsewhere in the abdomen or retroperitoneum Corless CL J Clin Oncol. 22:3813-3825 2004 Miettinen M J Arch Pathol Lab Med. 130:1466-1478 2006
- 15. Arise From Interstitial Cells of Cajal • Interstitial cells of Cajal (ICC)1 – “Pacemaker” cells associated with Auerbach’s plexus •GISTs share several characteristics with ICC1 – CD117 (c-KIT) expression, structural similarities • Other markers often positive in GIST2 – CD34 (60%-70%), muscle actin (SMA), S- 100 – ~4%-5% of GISTs are KIT-negative 1. Kindblom L-G et al. Am J Pathol. 1998;152:1259-1269 2. Fletcher CDM et al. Hum Pathol. 2002;33:459-65 c-KIT Staining Cells of Cajal GIST
- 16. Structure of KIT Receptor • Type III receptor tyrosine kinase • Extracellular domain binds ligand: stem cell factor (SCF) • Downstream effects of SCF binding to KIT are proliferative and antiapoptotic • Intracellular domain has – 2 tyrosine kinase domains – Multiple autophosphorylation sites − SCF binding site − 5 IgG domains Cell membrane Tyrosine kinase domains Taylor and Metcalfe. Hematol Oncol Clin North Am. 2000;14:517.
- 17. Normal KIT Signaling PP P ADP P P PP P ATP SIGNALING Kinase domains Substrate Effector • The KIT kinase domain activates a substrate protein • This activated substrate initiates a signaling cascade culminating in cell proliferation and survival Savage and Antman. N Engl J Med. 2002;346:683. Scheijen and Griffin. Oncogene. 2002;21:3314.
- 19. Patient Workup Guides Surgical Procedure • Initial patient workup should include – Complete lab studies – CT of abdomen and pelvis with oral IV contrast • Selective use of tissue biopsy – EUS or CT-FNA – Cytology/pathology for spindle cell morphology, CD117(c-KIT) • Comorbidity assessment
- 20. Surgical Treatment of GISTs • Surgery optimal for resectable GIST • Goals of surgery – Complete gross resection – Negative microscopic margins (R0 resection) • If recurrence develops after surgery, disease is usually not curable
- 21. Important Surgical Considerations for the Treatment of GIST • Metastasis commonly develop in liver and peritoneum1,2 – Liver (65%-72%) – Peritoneum (21%-64%) – Bone (4%-6%) – Lung (2%-4%) – Lymph node metastases are rare • Tumors typically grow extraluminal3 • Careful tumor handling is critical – Soft fragile tumors that may rupture during surgery – Rupturing of pseudocapsule may cause tumor bleeding and/or dissemination 1. DeMatteo RP et al. Ann Surg. 2000;231:51-58. 2. Burkill GJC et al. Radiology. 2003;226:527-532. 3. Corless CL et al. J Clin Oncol. 2004;22(18):3813-3825.
- 22. Important to Differentiate Between Adenocarcinoma and GIST Small Proximal Gastric GIST Infiltrating adenocarcinoma
- 23. GIST vs Adenocarcinoma Resections Entail Different Considerations GIST Adenocarcinoma Margins • Wide margins not required • For clear margins, need a 4-cm distance from tumor • Need 10-cm margins for diffuse-type tumors Gastrectomy •Wedge or segmental resection often sufficient • Formal gastrectomy for large proximal gastric GISTs •Total gastrectomy for tumors in proximal third of stomach Lymphadenectomy •Lymphadenectomy unnecessary • Lymphadenectomy for staging and therapeutic purposes
- 24. •No difference in OR time •No difference in margin clearance or recurrence •Less blood loss (25 vs. 100 ml) •Shorter hospital stay (4 vs. 7 days) Laparoscopic Resection of Gastric GIST Size Matched comparison to Open (<8cm) 40 open patients 40 laparoscopic patients Karakoussis, Ann Surg 18:1599 2011
- 34. Imatinib Mesylate: Mechanism of Action P PP P ATP SIGNALING Imatinib mesylate Kinase domains • Imatinib mesylate occupies the ATP binding pocket of the KIT kinase domain • This prevents substrate phosphorylation and signaling • A lack of signaling inhibits proliferation and survival Savage and Antman. N Engl J Med. 2002;346:683. Scheijen and Griffin. Oncogene. 2002;21:3314.
- 35. Imatinib Mesylate • Metastatic or Unresectable • Adjuvant • Neoadjuvant
- 36. Advanced GIST (N = 147) Imatinib, 400-600 mg once daily (QD) Multicenter trial of Imatinib in Advanced GIST Demetri GD, et al. N Eng J Med. 2002;347:472-480 54% response rate 28% stable disease
- 37. Metastatic GIST Survival Before and After Imatinib Survival Pre-Imatinib Imatinib Artinyan and Ellenhorn, Cancer Epidemiol Biomarkers Prev 17:2194
- 38. Artinyan and Ellenhorn, Cancer Epidemiol Biomarkers Prev 17:2194 Metastatic GIST Before and After Imatinib 552 patients
- 39. Imatinib in Advanced GIST • 5-yr OS differed according to c-KIT mutation status Blanke CD, et al. Proc Am Soc Clin Oncol. 2007. Abstract 21. 0 10 20 30 40 50 60 70 80 90 100 Exon 11 Exon 9 No Mutation 87% 48% 0% Survivalat5years
- 40. Impact of Initial Dose of Imatinib on Time To Progression Debiec-Rychter, et al. European Journal of Cancer. 2006;42:1093-1103. Am J Clin Pathol 2004;122:11-13 100 90 80 70 60 50 40 30 20 10 0 0 4 8 12 16 20 24 28 32 36 Progression free survival Patients harboring KIT exon 9 mutations (months) O N Number of patients at risk: 26 27 14 10 9 6 4 3 1 0 21 31 26 21 20 18 14 9 8 6 800 mg P=0.0013 400 mg 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 Progression free survival Patients harboring KIT exon 11 mutations (years) O N Number of patients at risk: 67 118 94 53 11 68 130 113 67 22 Treatment 800 mg 400 mg P = 0.25 800 mg 400 mg
- 41. Imatinib Duration in Advanced Disease Non-progression after 3 years of Imatinib Le Cesne The Lancet Oncology 11:942 – 949 2010
- 42. Management of Imatinib-Resistant GIST: Sunitinib • Approved for treatment of GIST resistant to or intolerant of imatinib • Inhibits multiple receptor tyrosine kinases • Antitumor and anti-angiogenic activities in preclinical studies
- 43. Phase III, Trial of Sunitinib Imatinib Failures Demetri GD, et al. Lancet. 2006;368:1329-1338. 100 90 80 70 60 50 40 30 20 10 0 0 6 12 18 24 30 36 42 48 54 Time (weeks) Time-to-tumour-progressionprobability(%) P<0.0001 Sunitinib (n=207) Placebo (n=105)
- 44. Relapsefreesurvival(%) Placebo Regorafenib Demetri, Lancet 381:295 2013 Regorafenib after Failure of Imatinib and Sunitinib
- 45. Imatinib Mesylate • Metastatic or Unresectable • Adjuvant • Neoadjuvant
- 46. Resectable GIST >3cm R A N D O M I Z E Palcebo ACOSOG Z9001: Adjuvant Imatinib in Resected Localized Primary GISTACOSOG Z9001: Adjuvant Imatinib in Resected Localized Primary GIST Imatinib 400mg/d DeMatteo R, et al.DeMatteo R, et al. Lancet. 2009; 373:1097-1104. Crossover at Recurrence
- 47. ACOSOG Z9001: Adjuvant Imatinib in Resected LocalizedACOSOG Z9001: Adjuvant Imatinib in Resected Localized Primary GISTPrimary GIST DeMatteo R, et al.DeMatteo R, et al. Lancet. 2009; 373:1097-1104.
- 48. ACOSOG Z9001: Adjuvant Imatinib in Resected LocalizedACOSOG Z9001: Adjuvant Imatinib in Resected Localized Primary GISTPrimary GIST DeMatteo R, et al.DeMatteo R, et al. Lancet. 2009; 373:1097-1104.
- 49. Adjuvant Imatinib 12 vs. 36 Months : Final Results of a Randomized Trial (SSGXVIII/AIO) • 400 patients randomized 1-yr vs. 3-yr (400 mg/day) • 5-yr RFS: 65.6% v. 47.9% (HR 0.46; p<0.001) Joensuu et al. JAMA 307:1265 2012Joensuu et al. JAMA 307:1265 2012 Relapse
- 50. Adjuvant Imatinib 12 vs. 36 Months : Final Results of a Randomized Trial (SSGXVIII/AIO) • 400 patients randomized 1-yr vs. 3-yr (400 mg/day) • 5-yr OS: 92.0% v. 81.7% (HR 0.45; p=0.19) Joensuu et al. JAMA 307:1265 2012Joensuu et al. JAMA 307:1265 2012 Survival
- 52. • Adjuvant therapy for >3 years should be considered in patients with intermediate to high risk GIST • The optimal duration has not yet been determined • Adjuvant Imatinib should be continued if any persistent gross disease is seen after resection Adjuvant Imatinib
- 53. Imatinib Mesylate • Metastatic or Unresectable • Adjuvant • Neoadjuvant
- 54. Neoadjuvant Imatinib for GIST (RTOG 0132/ACRIN 6665) • Phase II trial of pre-operative imatinib for advanced GIST – Primary Kit+ GIST > 5cm; median 9 cm. – Metastatic/recurrent Kit+ GIST > 2cm • Treatment: – 600 mg imatinib/day for 8-12 weeks prior to surgery – Resume imatinib post-op for 2 years adjuvantly Eisenberg BL et al. J Surg Oncol 2009; 99:42-47.Eisenberg BL et al. J Surg Oncol 2009; 99:42-47.
- 55. Neoadjuvant Imatinib for GIST (RTOG 0132/ACRIN 6665) • Results: 63 patients enrolled; 52 analyzable – Locally advanced (PR 7%; SD 83%; unknown 10%) • Surgery: R0 (77%); R1 (15%); R2 (8%) – Recurrent/Metastatic (PR 4.5%; SD 91%; PD 4.5%) • Surgery: R0 (58%); R1 (5%); R2 (32%); unspecified (5%) – 2 yr PFS: Loc Advanced (82.7%), Rec/Met (77.3%) – 2 yr OS: Loc Advanced (93.3%), Rec/Met (90.9%) Eisenberg BL et al. J Surg Oncol 2009; 99:42-47.Eisenberg BL et al. J Surg Oncol 2009; 99:42-47.
- 56. •Unresectable or metastatic GIST •Marginally resectable GIST • Surgical morbidity could be improved by preoperative reduction of tumor size • Recommended starting dose is 400 mg/day •dose of 800 mg/day for patients with KIT exon 9 mutations • Dosing can be stopped right before surgery and restarted as soon as the patient is able to tolerate oral medications Neoadjuvant Imatinib
- 57. • Anemia and Neutropenia • Nausea and vomiting • Edema (swelling of the face, feet, hands) • Muscle cramps and bone pain • Diarrhea • Hemorrhage • Skin rash • Fever Imatinib – Side Effects
- 58. •46 year-old female presented with a 20 pound weight loss melena and dyspnea. •Abdominal exam revealed an ill defined left upper quadrant mass. •Hgb 4.9 Case Presentation
- 59. •The patient was transfused up to a Hgb of 11 •Abdominal CT scan was performed
- 60. mass 1 mass 3 mass 2
- 61. H&E c-Kit CT guided core biopsy of the mid-abdominal mass revealed a spindle cell neoplasm which was positive for c-Kit by immunohistochemistry
- 62. Day 0 Day 60 Imatinib Day 5 Imatinib
- 63. 10 weeks
- 64. •At the time of operation the patient was found to have a bilobed mass involving the third portion of the duodenum and an additional lesion involving segments 2/3 of the liver. •She underwent resection of the third portion of the duodenum along with the proximal jejunum. A left lateral segmentectomy of the liver was performed.
- 65. Pathology revealed an 8 cm GIST in the liver and two separate GIST tumors adjacent to the duodenum 7.5 and 10 cm in size. All lesions were resected with negative margins She is currently 4 years postop and has no evidence of disease. She remains on 400 mg of imatinib daily.
- 66. Day 1 Day 4 Day 45
- 67. Patient Case Example: How Would You Treat This Patient?
- 70. GIST Near GEJ
- 71. GIST Near GEJ
- 73. Conclusions • Surgery is first-line treatment for patients with resectable GISTs – Up to 50% patients have recurrence after complete resection • Tyrosine kinase inhibitor imatinib now standard treatment for unresectable or metastatic or advanced GIST • Adjuvant Imatinib now standard treatment for high risk GIST • Neoadjuvant Imatinib for locally advanced GIST
Notes de l'éditeur
- KIT functions as a transmembrane tyrosine kinase receptor. The KIT receptor has 5 immunoglobulin-like extracellular domains and an intracellular split tyrosine kinase domain. The cytokine SCF (also referred to as mast cell growth factor or Steel factor) is KIT’s physiologic ligand. KIT is the product of the KIT proto-oncogene. It has structural homology with 2 other protein tyrosine kinases: The platelet-derived growth factor receptor (PDGFR) Bcr-Abl tyrosine kinase KIT is localized to chromosome 4q11-q12.
- KIT signaling begins when adenosine triphosphate (ATP) binds to KIT’s membrane-proximal kinase domain. This allows the binding of the substrate to be phosphorylated. Following phosphate transfer, the phosphosubstrate is able to bind to and activate downstream effector molecules.
- Schematic of c-Kit and platelet derived growth factor receptor alpha (PDGFR-receptors andmutations characteristic of GIST Mutually exclusive gain-of-function Kit or PDGFR-alpha mutations occur in a majority of GISTs In-frame deletions, point mutations, duplications, insertions Mutations in Kit juxtamembrane domain (exon 11) most common in GISTs of all sites Rare Kit extracellular domain (exon 9) Ala502-Tyr503 duplication specific for intestinal GISTs. Mutations in PDGFR-alpha have been identified in juxtamembrane (exon 12) and tyrosine kinase domains (exons 14 and 18) Nearly exclusively in gastric GISTs, mostly in epithelioid variants Some Kit and PDGFRA mutations have a prognostic value.
- At the molecular level, imatinib mesylate targets a specific part of the tyrosine kinase region in KIT, Bcr-Abl, and PDGFRA/B. Based on its activity on Bcr-Abl, the proposed mechanism of action of imatinib mesylate in GIST is as follows: Imatinib mesylate is an ATP-mimetic agent that binds KIT with greater affinity than ATP and at its ATP-binding site. The tyrosine kinase activity of KIT is dependent on its ATPase activity. KIT-bound imatinib mesylate prevents ATP binding and hydrolysis and hence the tyrosine kinase action of KIT. This blocks the downstream substrate of KIT, which is dependent on phosphorylation for activation. This in turn blocks downstream signal transduction pathways activated by KIT.
- Four year follow-up data reveal that long-term use of imatinib in GIST patients is feasible and responses are sustained. Imatinib most effective in patients with c-Kit mutations in exon 11, followed by exon 9, and least effective in patients with no c-Kit activating mutations.
- Four year follow-up data reveal that long-term use of imatinib in GIST patients is feasible and responses are sustained. Imatinib most effective in patients with c-Kit mutations in exon 11, followed by exon 9, and least effective in patients with no c-Kit activating mutations.
- Tumor genotype is of major prognostic significance for progression-free survival and overall survival in patients treated with imatinib for advanced GISTS. Findings suggest the need for differential treatment of patients with GISTs, with KIT exon 9 mutant patients benefiting the most from the 800 mg daily dose.
- PDGFR, platelet-derived growth factor receptor
- TTP, time to progression