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Relation of tumor pathologic and molecular features to outcome after surgical resection of localized primary gastrointestinal stromal tumor (GIST): Results.

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Presentation on theme: "Relation of tumor pathologic and molecular features to outcome after surgical resection of localized primary gastrointestinal stromal tumor (GIST): Results."— Presentation transcript:

1 Relation of tumor pathologic and molecular features to outcome after surgical resection of localized primary gastrointestinal stromal tumor (GIST): Results of the intergroup phase III trial ACOSOG Z9001 C. L. Corless, K. V. Ballman, C. Antonescu, C. Blanke, M. E. Blackstein, G. D. Demetri, M. von Mehren, R. G. Maki, P. W. T. Pisters, R. P. DeMatteo American College of Surgeons Oncology Group (ACOSOG) Intergroup Adjuvant GIST Study Team Oregon Health & Science Univ, Portland, OR; University of Toronto, Toronto, ON; Mayo Clinic, Rochester, MN; University of British Columbia/British Columbia Cancer Agency, Vancouver, BC; Dana Farber Cancer Inst, Boston, MA; Fox Chase Cancer Ctr, Philadelphia, PA; UT MD Anderson Cancer Ctr, Houston, TX; Memorial Sloan- Kettering Cancer Center, New York, NY

2 Primary GIST > 3 cm Complete Gross Resection Tumor KIT + Recurrence/Survival Imatinib x 1 yr Placebo x 1 yr Double-blind Cross-over if recur 713 evaluable patients Trial halted early ACOSOG Phase III Z9001 Adjuvant Trial

3 Recurrence-Free Survival Lancet 2009; 373:1097

4 ACOSOG Z9001 Cases Genotyped For KIT & PDGFRA Placebo (n=261) Imatinib (n=252) All Patients (n=513) Tumor Size <5 cm107102209 (40.7%) 5-10 cm8983172 (33.5%) >10 cm6567132 (25.7%) Mitotic Rate <5/50149150299 (61.3%) ≥5/5010188189 (38.7%)

5 Mitotic Index: Inter-Observer Comparison (45 Cases) r=0.94 Pathologist #1: 65% of cases Pathologist #2: 35% of cases No statistical difference between observers p=.4851 by Wilcoxon signed rank test

6 Multivariate Analyses For Recurrence Risk Placebo Group p valueHazard Ratio(95% CI) Mitotic rate <5/50 hpf <0.000117.07(6.620, 44.043) ≥5/50 hpf Genotype WT---- Exon 90.451.74(0.413, 7.359) Exon 110.0422.97(1.307, 8.537) PDGFRA0.2552.30(0.547, 9.722) Tumor location Stomach---- Small intestine0.02672.08(1.089, 4.001) Rectum0.78951.31(0.178, 9.681) Tumor size <5 cm 0.00261.70(1.203, 2.402) >5-10 cm >10 cm

7 Mitotic Index Vs Tumor Size & Location <5/50 hpf ≥5/50 hpf

8 PDGFRA (n=28) Wild-type (n=32) Exon 9 (n=22) RFS For Placebo Cases By Genotype 0 10 20 30 40 50 60 70 80 90 100 06121824303642485460 Time in Months % Recurrence-Free and Alive Exon 11 Deletion (n=93) Exon 11 PM (n=55) Exon 11 Insertion (n=25) p=0.0240 vs WT HR 3.45 (95% CI 1.177 -10.137)

9 RFS For PDGFRA-Mutant Cases by Arm 0 10 20 30 40 50 60 70 80 90 100 061218243036424854 Time in Months % Recurrence-Free and Alive Imatinib (n=29) Placebo (n=28) p<0.01 Treatment

10 RFS For PDGFRA D842V-Mutant Cases by Arm 0 10 20 30 40 50 60 70 80 90 100 061218243036424854 Time in Months % Recurrence-Free and Alive Imatinib (n=15) Placebo (n=13) Treatment

11 RFS For PDGFRA-Mutant Cases by Arm 0 10 20 30 40 50 60 70 80 90 100 061218243036424854 Time in Months % Recurrence-Free and Alive All PDGFRA (n=29) - imatinib All PDGFRA (n=28) - placebo Treatment D842V (n=13) - placebo

12 RFS For Exon 11-Mutant Cases by Arm 0 10 20 30 40 50 60 70 80 90 100 06121824303642485460 Time in Months % Recurrence-Free and Alive Imatinib (n=173) Placebo (n=173) Treatment p<0.0001 HR 3.42 (95% CI 1.93 - 6.06)

13 RFS for Exon 11 Deletion 557-558 by Arm 0 10 20 30 40 50 60 70 80 90 100 061218243036424854 Time in Months % Recurrence-Free and Alive Imatinib (n=52) Placebo (n=57) p=0.0013 HR 4.07 (95% CI 1.73 - 9.57) Treatment

14 RFS for Exon 11 Other Deletion by Arm 0 10 20 30 40 50 60 70 80 90 100 06121824303642485460 Time in Months % Recurrence-Free and Alive Imatinib (n=42) Placebo (n=36) p=0.0087 HR 4.85 (95% CI 1.49 -15.76) Treatment

15 RFS For Wild-type Cases by Arm 0 10 20 30 40 50 60 70 80 90 100 06121824303642485460 Time in Months % Recurrence-Free and Alive Imatinib (n=32) Placebo (n=32) Treatment p=0.6126

16 RFS For Exon 9-Mutant Cases by Arm 0 10 20 30 40 50 60 70 80 90 100 06121824303642485460 Time in Months % Recurrence-Free and Alive Imatinib (n=13) Placebo (n=22) Treatment p=0.8443

17 Size Gastric (n=1055) Jejunum/Ileum (n=629) Duodenum (n=144) Rectum (n=111) Mitotic ≤ 2 cm0% Index > 2 ≤ 5 cm1.9%4.3%8.3%8.5% ≤5 per 50 hpf > 5 ≤ 10 cm3.6%24%Insuff. data > 10 cm10%52%34%57% Mitotic ≤ 2 cm(None)(High)Insuff. data54% Index > 2 ≤ 5 cm16%73%50%52% >5 per 50 hpf > 5 ≤ 10 cm55%85%Insuff. data > 10 cm86%90%86%71% Miettinen M, Lasota J. Semin Diagn Pathol. 2006 May;23(2):70-83 Miettinen et al. Older model microscope Area of 50 high power fields 5.3 mm 2 11.87 mm 2 Newer microscope in this study Is 5/50 hpf still valid?

18 Risk of Recurrence In Placebo Group By Miettinen Risk Assessment Criteria Mitoses Size Gastric≤5/50≤10 cm Low Non-gastric≤5/50≤5 cm Gastric≤5/50>10 cm Moderate >5/50≤5 cm Non-gastric≤5/505 - 10 cm Gastric>5/50>5 cm HighNon-gastric>5/50Any >10 cm Miettinen M, Lasota J. Semin Diagn Pathol. 2006 May;23(2):70-83. Low risk (n=270) Moderate risk (n=148) High risk (n= 201)

19 Summary & Conclusions The Z9001 trial represents the largest cohort of adjuvant GIST patients followed to date Risk of recurrence in untreated patients is related to: –Mitotic index (HR 17.1) –KIT exon 11 mutation (vs WT; HR 3.0) –Small bowel primary (vs gastric; HR 2.1) –Tumor size (HR 1.7) 12 months of adjuvant imatinib significantly delays recurrence of: –KIT exon 11-mutant tumors –PDGFRA-mutant tumors (primarily non-D842V) –but not wild-type tumors More data are needed to define the impact of adjuvant imatinib on recurrence of exon 9-mutant tumors Miettinen criteria for risk stratification remain valid using a newer microscope with a larger field of view

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