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Gynecol Oncol. 2016 Apr;141(1):43-8. doi: 10.1016/j.ygyno.2016.02.025.

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.

Author information

1
Dana Farber Cancer Institute, Boston, MA, United States. Electronic address: andrea.myers@novartis.com.
2
NRG Oncology Statistics and Data Management Center, Buffalo, NY, United States.
3
University of Iowa Hospitals and Clinics, Iowa City, IA, United States.
4
Stony Brook Medicine, Stony Brook, NY, United States.
5
Rush University Medical Center, Chicago, IL, United States.
6
Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, United States.
7
Abington Memorial Hospital, Gladwyne, PA, United States.
8
University of Massachusetts Memorial Health Care, Worcester, MA, United States.
9
Mercer University School of Medicine, Savannah, GA, United States.
10
Gynecologic Oncology of West Michigan, Grand Rapids, MI, United States.
11
Dana Farber Cancer Institute, Boston, MA, United States.
12
Massachusetts General Hospital/Dana Farber Cancer Center, Boston, MA, United States.
13
The University of Chicago Medical Center, Chicago, IL, United States.

Abstract

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.

PMID:
27016228
PMCID:
PMC5119517
DOI:
10.1016/j.ygyno.2016.02.025
[Indexed for MEDLINE]
Free PMC Article

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