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

Andrea P Myers; Virginia L Filiaci; Yuping Zhang; Michael Pearl; Kian Behbakht; Vicky Makker; Parviz Hanjani; Susan Zweizig; James J Burke II; Gordon Downey; Kimberly K Leslie; Paul Van Hummelen; Michael J Birrer; Gini F Fleming

doi:10.1016/j.ygyno.2016.02.025

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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

Journal article

Peer reviewed

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

Andrea P Myers, Virginia L Filiaci, Yuping Zhang, Michael Pearl, Kian Behbakht, Vicky Makker, Parviz Hanjani, Susan Zweizig, James J Burke II, Gordon Downey, …

Gynecologic oncology, Vol.141(1), pp.43-48

04/2016

DOI: 10.1016/j.ygyno.2016.02.025

PMCID: PMC5119517

PMID: 27016228

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http://doi.org/10.1016/j.ygyno.2016.02.025View

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Abstract

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.

Mutation

PTEN Phosphohydrolase - genetics

Sirolimus - analogs & derivatives

Sirolimus - therapeutic use

Prospective Studies

Endometrial Neoplasms - mortality

Humans

Tamoxifen - administration & dosage

Proto-Oncogene Proteins c-akt - genetics

Phosphatidylinositol 3-Kinases - genetics

Megestrol Acetate - administration & dosage

Sirolimus - administration & dosage

Class I Phosphatidylinositol 3-Kinases

Endometrial Neoplasms - genetics

Tumor Suppressor Proteins - genetics

Endometrial Neoplasms - drug therapy

Female

Tuberous Sclerosis Complex 1 Protein

Details

Title: Subtitle: 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
Creators: Andrea P Myers - Dana Farber Cancer Institute, Boston, MA, United States. Electronic address: andrea.myers@novartis.com
Virginia L Filiaci - NRG Oncology Statistics and Data Management Center, Buffalo, NY, United States
Yuping Zhang - University of Iowa Hospitals and Clinics, Iowa City, IA, United States
Michael Pearl - Stony Brook Medicine, Stony Brook, NY, United States
Kian Behbakht - Rush University Medical Center, Chicago, IL, United States
Vicky Makker - Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, United States
Parviz Hanjani - Abington Memorial Hospital, Gladwyne, PA, United States
Susan Zweizig - University of Massachusetts Memorial Health Care, Worcester, MA, United States
James J Burke II
Gordon Downey - Gynecologic Oncology of West Michigan, Grand Rapids, MI, United States
Kimberly K Leslie - University of Iowa Hospitals and Clinics, Iowa City, IA, United States
Paul Van Hummelen - Dana Farber Cancer Institute, Boston, MA, United States
Michael J Birrer - Massachusetts General Hospital/Dana Farber Cancer Center, Boston, MA, United States
Gini F Fleming - The University of Chicago Medical Center, Chicago, IL, United States
Resource Type: Journal article
Publication Details: Gynecologic oncology, Vol.141(1), pp.43-48
DOI: 10.1016/j.ygyno.2016.02.025
PMID: 27016228
PMCID: PMC5119517
NLM abbreviation: Gynecol Oncol
ISSN: 1095-6859
eISSN: 1095-6859
Publisher: United States
Grant note: U10 CA180868 / NCI NIH HHS U10 CA180822 / NCI NIH HHS U24 CA196067 / NCI NIH HHS U10 CA027469 / NCI NIH HHS U10CA180822 / NCI NIH HHS CA 27469 / NCI NIH HHS P30 CA008748 / NCI NIH HHS U10 CA037517 / NCI NIH HHS CA 37517 / NCI NIH HHS P30 CA086862 / NCI NIH HHS U10 CA180834 / NCI NIH HHS
Language: English
Date published: 04/2016
Academic Unit: Obstetrics and Gynecology
Record Identifier: 9983930389902771

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