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 transcript:

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

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

Recurrence-Free Survival Lancet 2009; 373:1097

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

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

Multivariate Analyses For Recurrence Risk Placebo Group p valueHazard Ratio(95% CI) Mitotic rate <5/50 hpf < (6.620, ) ≥5/50 hpf Genotype WT---- Exon (0.413, 7.359) Exon (1.307, 8.537) PDGFRA (0.547, 9.722) Tumor location Stomach---- Small intestine (1.089, 4.001) Rectum (0.178, 9.681) Tumor size <5 cm (1.203, 2.402) >5-10 cm >10 cm

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

PDGFRA (n=28) Wild-type (n=32) Exon 9 (n=22) RFS For Placebo Cases By Genotype Time in Months % Recurrence-Free and Alive Exon 11 Deletion (n=93) Exon 11 PM (n=55) Exon 11 Insertion (n=25) p= vs WT HR 3.45 (95% CI )

RFS For PDGFRA-Mutant Cases by Arm Time in Months % Recurrence-Free and Alive Imatinib (n=29) Placebo (n=28) p<0.01 Treatment

RFS For PDGFRA D842V-Mutant Cases by Arm Time in Months % Recurrence-Free and Alive Imatinib (n=15) Placebo (n=13) Treatment

RFS For PDGFRA-Mutant Cases by Arm Time in Months % Recurrence-Free and Alive All PDGFRA (n=29) - imatinib All PDGFRA (n=28) - placebo Treatment D842V (n=13) - placebo

RFS For Exon 11-Mutant Cases by Arm Time in Months % Recurrence-Free and Alive Imatinib (n=173) Placebo (n=173) Treatment p< HR 3.42 (95% CI )

RFS for Exon 11 Deletion by Arm Time in Months % Recurrence-Free and Alive Imatinib (n=52) Placebo (n=57) p= HR 4.07 (95% CI ) Treatment

RFS for Exon 11 Other Deletion by Arm Time in Months % Recurrence-Free and Alive Imatinib (n=42) Placebo (n=36) p= HR 4.85 (95% CI ) Treatment

RFS For Wild-type Cases by Arm Time in Months % Recurrence-Free and Alive Imatinib (n=32) Placebo (n=32) Treatment p=0.6126

RFS For Exon 9-Mutant Cases by Arm Time in Months % Recurrence-Free and Alive Imatinib (n=13) Placebo (n=22) Treatment p=0.8443

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 May;23(2):70-83 Miettinen et al. Older model microscope Area of 50 high power fields 5.3 mm mm 2 Newer microscope in this study Is 5/50 hpf still valid?

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/ cm Gastric>5/50>5 cm HighNon-gastric>5/50Any >10 cm Miettinen M, Lasota J. Semin Diagn Pathol May;23(2): Low risk (n=270) Moderate risk (n=148) High risk (n= 201)

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