Getting the GIST of it: Why Molecules Matter to Surgeons

Transcription

1 Getting the GIST of it: Why Molecules Matter to Surgeons Surgery Grand Rounds November 21, 2011 Martin McCarter, M.D. Associate Professor of Surgery GI Tumor & Endocrine Surgery University of Colorado Denver

2 Conflict of Interest Employee of University of Colorado School of Medicine

3 Getting the GIST of it: Why Molecules Matter to Surgeons Outline: GIST as a paradigm What is GastroIntestinal Stromal Tumor Natural history of GIST Molecular classification Signaling kinases The imatinib story Metastatic and adjuvant treatment GIST post imatinib What s next for GIST

4 GIST Formerly Known As: Leiomyoma Leiomyosarcoma Leiomyoblastoma

5 GIST: Identification of KIT Gain-of-Function Mutations KIT staining was positive in 46 of 49 GIST (94%) 5 of 6 GIST had mutations in KIT gene Mutant forms of KIT are constitutively active Proposed that GIST may originate from Interstitial cells of Cajal KIT is receptor for Stem Cell Factor Hirota et al. Science. 1998;279:577.

6 GIST: Interstitial Cells of Cajal Originally described by Ramon Cajal KIT-positive fibroblast-like cells Pacemaker cells of the gut Intercalated between intramural neurons and smooth muscle cells Generate electrical slow waves Loss of ICC function has been implicated in diabetic gastroenteropathy and gastroenteric arrhythmia Takayama et al. Arch Histol Cytol. 2002;65:1.

7 Scope of the Problem ~ 10,000 new soft tissue sarcomas per year ~ 3000 GIST per year in the United States Estimated annual incidence ~ 10 cases per million

8 Staging of GIST T1 = <2 cm T2 = 2-5 cm T3 = 5-10 cm T4 = >10 cm Mitotic Rate Low <5/50HPF High >5/50HPF AJCC Staging Manual 7 th ed.

9 Pathologic Features of GIST Median age at presentation is 63 Size about 5-7 cm Location Stomach 55% Small Intestine 35% Rectum 5% Other 5% Joensuu H and DeMatteo RP. Annu Rev Med Jan 26. [Epub ahead of print]

10 Natural History of GIST DeMatteo RP et al. Ann Surg 2000 Jan;231(1):51-8.

11 GIST: Recurrence-Free Survival Following Surgical Treatment of Primary GIST Proportion surviving free of recurrence P=0.03 <5 cm <5-10 cm >10 cm Length of study (mo) Proportion surviving free of recurrence P= mitoses/30 hpf >3 to 15 mitoses/30 hpf >15 mitoses/30 hpf Length of study (mo) Singer et al. J Clin Oncol. 2002;20:3898.

12 KIT and PDGFRα Mutations in GIST Joensuu H, DeMatteo RP. Annu Rev Med Jan 26. [Epub ahead of print]

13 Signaling Protein Kinases Transient signal from surface membrane receptor through to intracellular and nuclear machinery Regulate cell functions Dependant on a phosphorylation step Potential target IF cancer cell is largely dependant on it for growth

14 Development of Imatinib CML was the target Known (Philadelphia 9/22) chromosomal translocation Resulted in BCR-ABL fusion protein Screened designer drugs to fit BCR-ABL phosphate pocket and inhibit tyrosine kinase

15 Imatinib and GIST An International Story 1 1 BCR-ABL protein described 1973

16 Imatinib and GIST An International Story BCR-ABL protein described Imatinib developed for BCR-ABL 1990 s

17 Imatinib and GIST An International Story BCR-ABL protein described Imatinib developed for BCR-ABL 1990 s 3 KIT mutation described 1998

18 Imatinib and GIST An International Story BCR-ABL protein described Imatinib developed for BCR-ABL 1990 s 3 KIT mutation described First GIST patient treated with Imatinib 2000

19 Imatinib Mesylate (Gleevec): Proposed Mechanism of Action Inhibits KIT, Bcr-Abl, PDGFR Occupies the ATP binding pocket of the KIT kinase domain This prevents substrate phosphorylation and signaling A lack of signaling inhibits proliferation and survival Adapted from Savage and Antman. N Engl J Med. 2002;346:683. Scheijen and Griffin. Oncogene. 2002;21:3314. Kinase domains Imatinib mesylate P ATP P P P SIGNALING

20 First Patient With GIST to Receive Imatinib Mesylate: Proof-of-Concept Exploratory study with oral imatinib mesylate at 400 mg/d Dramatic clinical response Disappearance of excess metabolic activity at 4 weeks by 18 FDG-PET 75% reduction in tumor size at 8-month follow-up Tumor biopsies showed histologic evidence of myxoid degeneration and lack of mitotic activity Symptomatic relief Joensuu et al. N Engl J Med. 2001;344:1052.

21 Imatinib Induced Pathologic Changes CD 117 H&E Demetri GD, et al. N Engl J Med. 2002;347:472-80

22 Key Studies in GIST Metastatic Disease B2222 Trial Demetri GD, et al. N Engl J Med. 2002;347:472-80

23 Key Studies in GIST Long Term F/U of B2222 Trial Significant correlation between tumor bulk and OS (P=0.0043) Nine-year OS rate all patients was 35% (38% for patients with CR/PR; 49% for patients with SD) Nine-year OS by tumor bulk at baseline was: 58% in group 1, 40% in group 2, 20% in group 3, and 23% in group 4 von Mehren et al. ASCO June 2011

24 Key Studies in GIST Adjuvant Treatment Following Resection ACOSOG Z-9001 Completely resected GIST >3 cm Randomized to placebo vs. imatinib for 12 months Primary endpoint is recurrence free survival Recurrence Free Survival Overall Survival DeMatteo RP et al. Lancet Mar 28;373(9669): Epub 2009 Mar 18.

25 Key Studies in GIST Adjuvant Treatment Following Resection DeMatteo RP et al. Lancet Mar 28;373(9669): Epub 2009 Mar 18.

26 Key Studies in GIST Adjuvant Treatment Following Resection SSGXVIII/AIO Completely resected High Risk GIST (>5 mitosis/50hpf) Randomized to 12 vs. 36 months of imatinib Primary endpoint is recurrence free survival Recurrence Free Survival Overall Survival Joensuu et al. Presented at ASCO June 2011

27 Results of SSGXVIII/AIO: Subgroup Analysis Subgroup No. of patients Hazard ratio (95% CI), RFS P-value 36 mo better 12 mo better Age ( ) > ( ) 0.01 Sex Male ( ) Female ( ) Tumor site Stomach ( ) Other ( ) <0.001 Tumor size 10 cm ( ) <0.001 >10 cm ( ) Mitoses/50 HPF (local) 10 mitoses ( ) 0.33 >10 mitoses ( ) <0.001 Mitoses/50 HPF (central) 10 mitoses ( ) 0.04 >10 mitoses ( ) <0.001 Tumor rupture No ( ) <0.001 Yes ( ) 0.02 Tumor mutation site KIT exon ( ) 0.34 KIT exon ( ) <0.001 Wild type ( ) 0.16 Other ( ) Joensuu et al. Presented at ASCO June 2011

28 Lessons Post Imatinib Approval Mutation Analysis GIST: KIT and PDGFRA Mutations Predict Event-Free Survival Event-free survival (%) KIT exon 9 (n=23) No kinase mutation (n=9) KIT exon 11 vs exon 9 (P<0.0001) KIT exon 11 vs no mutation (P<0.0001) KIT exon 9 vs no mutation (P=0.1428) Days KIT exon 11 (n=85) Heinrich et al. J Clin Oncol. 2003;21:4342.

29 Lessons Post Imatinib Approval Risk Stratification Miettinen M, Lasota J Semin Diag Pathol 2006;23(2):70-83, NCCN Guidelines 2010 J Natl Compr Canc Netw Apr;8 Suppl 2:S1-41

30 Gold et al. Lancet Oncol Nov;10(11): Prediction Tools

31 The More We Learn About GIST The More Questions We Generate Questions What are the surgical goals for GIST? Can we stop or interrupt treatment? How long to treat metastatic, adjuvant? What about imatinib resistance? What to do with incidental or micro GIST s? Should we use imatinib in the neoadjuvant setting? If so, how long? Is surgery ever needed? Is there a role for debulking GIST? What to do with a margin positive (R1) resection? Is pediatric or familial GIST any different?

32 Surgical Goals for GIST Negative margins Avoid rupture Preserve function Nodes generally not necessary (except in young patients)

33 How Long to Treat? Can Treatment be Stopped or Interrupted? 56/147 patients initially enrolled in the B2222 study continued imatinib treatment beyond 3 years, with some patients remaining on treatment for 10yrs 26 patients (17.7%) have remained on continuous imatinib Risk of progression drastically decreased after 6 years of imatinib therapy Years after start of imatinib therapy 0 2 >2 4 >4 6 >6 8 >8 9 >9 10 No. of patients at risk a Progression/Censored b 71/11 22/3 19/1 1/1 1/2 NA Rate of progression (Probability of event [%]) NA Probability of progression according to duration of imatinib therapy (life-table method) von Mehren et al. ASCO June 2011

34 Molecular Basis for Primary and Secondary Tyrosine Kinase Inhibitor Resistance in GIST Secondary mutation induce conformational change altering the ATP binding site Type of secondary mutation may be important in overall survival May manifest as isolated clonal or polyclonal disease Gounder MM, Maki RG. Cancer Chemother Pharmacol Jan;67 Suppl 1:S Epub 2010 Nov 30.

35 Micro GIST s The prevalence is much higher than the clinical incidence Micro GIST s smaller than 1 cm Found in up to 50% of autopsy series Many already have KIT mutation EUS surveillance 13% (3/23) progressed Potential for malignancy unknown Resect any >2cm (consensus) Joensuu H, DeMatteo RP. Annu Rev Med Jan 26. [Epub ahead of print], NCCN Guidelines 2010 J Natl Compr Canc Netw Apr;8 Suppl 2:S1-41

36 Neoadjuvant Therapy for GIST Before After Two phase II trials (19 and 30 patients) Suggest similar response rates Safe to give pre-op (no need to stop) Overall recurrence dictated by size

37 Is there a Role for GIST Tumor Debulking? 69 Patients underwent debulking - pre-operatively determined to have: Stable disease (n=23) bulky (>1cm) disease left in 4% Limited disease progression (n=32) bulky disease in 16% Generalized disease progression (n=14) 50% emergent indication bulky disease left in 43% Raut C, et al. J Clin Oncol 2006 May 20;24(15):

38 Considerations for Debulking GIST Average duration of response ~ 2 years Surgical timing around 6-24 months Stable disease all resectable? Limited disease progression selected resection Impending obstruction GI bleeding Paraneoplastic syndrome

39 Microscopic (R1) Positive Margin Sites of First Recorded Recurrence by Margin Status ACOSOG Z-9000 & Z /819 Pts (8.8%) had R1 resection Median f/u 49 months Resection Margin Recurrence R0 R1 Local 8 (4.4%) 4 (16.0%) Regional 86 (47.5%) 13 (52.0%) Distant 87 (48.1%) 8 (32.0%) Chi Square 6.4, p= % (placebo) to 65% (imatinib) of R1 resections did not experience a recurrence 85-95% of recurrences are regional or distant McCarter et al, Western Surgical Association, Nov 2011

40 Microscopic (R1) Positive Margin Recurrence free survival at 3 years is 60% vs. 76% in the R1 vs. R0 group respectively. HR=1.51 (95% CI: 0.76, 2.99) p=0.24 Recurrence free survival at 3 years is 82% vs. 79% in the R1 vs. R0 group respectively. HR=1.095 (95% CI: 0.66, 1.83) p=0.73 McCarter et al, Western Surgical Association, Nov 2011

41 Familial GIST Joensuu H, DeMatteo RP. Annu Rev Med Jan 26. [Epub ahead of print]

42 Familial GIST Germline Mutation in KIT Mastocytosis Achalasia GIST 90% have GIST by age 70 Hundreds of GIST in small intestine Low mitotic rate Indolent except for blockage and bleeding

43 Pediatric GIST Age <21 Strong CD 117 staining Wild type no identifiable mutation Can involve lymph nodes Higher recurrence rate Longer survival (more indolent course)

44 Cost of Imatinib Standard dose is 400mg QD 100mg tablet costs $20-30 One year of imatinib ~ $64,000

45 What s Next for GIST Serum imatinib concentration and response Improving prediction of micro GIST Targeting secondary mutations Patient initiated tumor banking Gounder MM, Maki RG. Cancer Chemother Pharmacol Jan;67 Suppl 1:S Epub 2010 Nov 30.

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