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|Ref Type||Journal Article|
|Authors||Myers AP, Filiaci VL, Zhang Y, Pearl M, Behbakht K, Makker V, Hanjani P, Zweizig S, Burke JJ, Downey G, Leslie KK, Van Hummelen P, Birrer MJ, Fleming GF|
|Title||Tumor mutational analysis of GOG248, a phase II study of temsirolimus or temsirolimus and alternating megestrol acetate and tamoxifen for advanced endometrial cancer (EC): An NRG Oncology/Gynecologic Oncology Group study.|
|Abstract Text||Rapamycin analogs have reproducible but modest efficacy in endometrial cancer (EC). Identification of molecular biomarkers that predict benefit could guide clinical development.Fixed primary tissue and whole blood were collected prospectively from patients enrolled on GOG 248. DNA was isolated from macro-dissected tumors and blood; next-generation sequence analysis was performed on a panel of cancer related genes. Associations between clinical outcomes [response rate (RR) 20%; progression-free survival (PFS) median 4.9months] and mutations (PTEN, PIK3CA, PIK3R1, KRAS, CTNNB1, AKT1, TSC1, TSC2, NF1, FBXW7) were explored.Sequencing data was obtained from tumors of 55 of the 73 enrolled pts. Mutation rates were consistent with published reports: mutations in PTEN (45%), PIK3CA (29%), PIK3R1 (24%), K-RAS (16%), CTNNB1 (18%) were common and mutations in AKT1 (4%), TSC1 (2%), TSC2 (2%), NF1 (9%) and FBXW7 (4%) were less common. Increased PFS (HR 0.16; 95% CI 0.01-0.78) and RR (response difference 0.83; 95% CI 0.03-0.99) were noted for AKT1 mutation. An increase in PFS (HR 0.46; 95% CI 0.20-0.97) but not RR (response difference 0.00, 95% CI -0.34-0.34) was identified for CTNNB1 mutation. Both patients with TSC mutations had an objective response. There were no statistically significant associations between mutations in PIK3CA, PTEN, PIK3R1, or KRAS and PFS or RR.Mutations in AKT1, TSC1 and TSC2 are rare, but may predict clinical benefit from temsirolimus. CTNNB1 mutations were associated with longer PFS on temsirolimus.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|PTEN mutant||endometrial cancer||no benefit||Temsirolimus||Phase II||Actionable||In a retrospective study of a Phase II trial, mutation status of PTEN was not associated with progression-free survival or response rate in advanced endometrial cancer patients treated with Torisel (temsirolimus) (PMID: 27016228).||27016228|
|CTNNB1 mutant||endometrial cancer||predicted - sensitive||Temsirolimus||Phase II||Actionable||In a retrospective study of a Phase II trial, Torisel (temsirolimus) treatment resulted in an increased progression-free survival (HR 0.46) but not response rate (response difference 0.00) in advanced endometrial cancer patients harboring CTNNB1 mutations (PMID: 27016228).||27016228|
|PIK3CA mutant||endometrial cancer||no benefit||Temsirolimus||Phase II||Actionable||In a retrospective study of a Phase II trial, mutation status of PIK3CA was not associated with progression-free survival or response rate in advanced endometrial cancer patients treated with Torisel (temsirolimus) (PMID: 27016228).||27016228|