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[PMID]: | 27016228 |
[Au] Autor: | 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 |
[Ad] Endereço: | Dana Farber Cancer Institute, Boston, MA, United States. Electronic address: andrea.myers@novartis.com. |
[Ti] Título: | 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. |
[So] Source: | Gynecol Oncol;141(1):43-8, 2016 Apr. | [Is] ISSN: | 1095-6859 |
[Cp] País de publicação: | United States |
[La] Idioma: | eng |
[Ab] Resumo: | OBJECTIVE: Rapamycin analogs have reproducible but modest efficacy in endometrial cancer (EC). Identification of molecular biomarkers that predict benefit could guide clinical development. METHODS: 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. RESULTS: 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. CONCLUSIONS: Mutations in AKT1, TSC1 and TSC2 are rare, but may predict clinical benefit from temsirolimus. CTNNB1 mutations were associated with longer PFS on temsirolimus. |
[Mh] Termos MeSH primário: |
Neoplasias do Endométrio/genética Acetato de Megestrol/administração & dosagem Mutação Sirolimo/análogos & derivados Tamoxifeno/administração & dosagem
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[Mh] Termos MeSH secundário: |
Classe I de Fosfatidilinositol 3-Quinases Neoplasias do Endométrio/tratamento farmacológico Neoplasias do Endométrio/mortalidade Feminino Seres Humanos PTEN Fosfo-Hidrolase/genética Fosfatidilinositol 3-Quinases/genética Estudos Prospectivos Proteínas Proto-Oncogênicas c-akt/genética Sirolimo/administração & dosagem Sirolimo/uso terapêutico Proteínas Supressoras de Tumor/genética
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[Pt] Tipo de publicação: | CLINICAL TRIAL, PHASE II; JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (Tumor Suppressor Proteins); 0 (tuberous sclerosis complex 1 protein); 094ZI81Y45 (Tamoxifen); 624KN6GM2T (temsirolimus); EC 2.7.1.- (Phosphatidylinositol 3-Kinases); EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases); EC 2.7.1.137 (PIK3CA protein, human); EC 2.7.11.1 (AKT1 protein, human); EC 2.7.11.1 (Proto-Oncogene Proteins c-akt); EC 3.1.3.67 (PTEN Phosphohydrolase); EC 3.1.3.67 (PTEN protein, human); TJ2M0FR8ES (Megestrol Acetate); W36ZG6FT64 (Sirolimus) |
[Em] Mês de entrada: | 1608 |
[Cu] Atualização por classe: | 171116 |
[Lr] Data última revisão:
| 171116 |
[Sb] Subgrupo de revista: | IM |
[Da] Data de entrada para processamento: | 160327 |
[St] Status: | MEDLINE |
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