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Clin Cancer Res. 2016 May 15;22(10):2445-2452. doi: 10.1158/1078-0432.CCR-15-2631. Epub 2016 Feb 1.

Mutations in TSC1, TSC2, and MTOR Are Associated with Response to Rapalogs in Patients with Metastatic Renal Cell Carcinoma.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, US.
2
Department of Medicine, Brigham and Women's Hospital, Boston, MA, US.
3
Harvard Medical School, Boston, MA, US.
4
PUCRS School of Medicine, Porto Alegre, Brazil.
5
Department of Medical Oncology, Cleveland Clinic, Cleveland, US.
6
Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA, US.
7
Institut Gustave Roussy, Villejuif, France.
8
Department of Medical Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
9
Department of Medical Oncology, Mayo Clinic, Arizona, Scottsdale, AZ, US.
10
Department of Pathology, Brigham and Women's Hospital, Boston, MA, US.
11
Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA.
12
Department of Radiology, Dana Farber Cancer Institute, Boston, MA.
13
San Matteo University Hospital Foundation, Pavia, Italy.
14
Department of Medical Oncology & Therapeutics Research, City of Hope, US.
15
Deparment of Medical Oncology, Beth-Israel Deaconess Medical Center, Boston, MA, US.
16
Tom Baker Cancer Center and University of Calgary, Calgary, Canada.
17
Biostatistics & Computational Biology, Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA, US.
#
Contributed equally

Abstract

PURPOSE:

We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC).

EXPERIMENTAL DESIGN:

We studied a cohort of mRCC patients who were treated with mTOR inhibitors with distinct clinical outcomes. Tumor DNA from 79 subjects was successfully analyzed for mutations using targeted next-generation sequencing of 560 cancer genes. Responders were defined as those with partial response (PR) by RECIST v1.0 or stable disease with any tumor shrinkage for 6 months or longer. Nonresponders were defined as those with disease progression during the first 3 months of therapy. Fisher exact test assessed the association between mutation status in mTOR pathway genes and treatment response.

RESULTS:

Mutations in MTOR, TSC1, or TSC2 were more common in responders, 12 (28%) of 43, than nonresponders, 4 (11%) of 36 (P = 0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than nonresponders, 2(6%), (P = 0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1, or TSC2 compared with 4 (11%) of 36 nonresponders (P = 0.03). Eight additional non-mTOR pathway genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response.

CONCLUSIONS:

In this cohort of mRCC patients, mutations in MTOR, TSC1, or TSC2 were more common in patients who experienced clinical benefit from rapalogs than in those who progressed. However, a substantial fraction of responders (24 of 43, 56%) had no mTOR pathway mutation identified. Clin Cancer Res; 22(10); 2445-52. ©2016 AACRSee related commentary by Voss and Hsieh, p. 2320.

PMID:
26831717
PMCID:
PMC4976069
DOI:
10.1158/1078-0432.CCR-15-2631
[Indexed for MEDLINE]
Free PMC Article

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