Citations 1
Mutations in TSC1, TSC2, and MTOR Are Associated with Response to Rapalogs in Patients with Metastatic Renal Cell Carcinoma
Choueiri, Toni K. , Fay, André P. , Velasco, Guillermo de , Tyburczy, Magdalena E. , Hamieh, Lana , Albigès, Laurence , Ho, Thai H. , Song, Jiaxi , Pignon, Jean‐Christophe , Barrios, Pablo M. , Michaelson, M. Dror , Krajewski, Katherine M. , Porta, Camillo , Pal, Sumanta K. , Heng, Daniel Y.C., Gray, Kathryn P. , Kwiatkowski, David J. , Rini, Brian I. , Thorner, Aaron R. , Agarwal, Neeraj , Van Allen, Eliezer M , Bellmunt, Joaquim , McDermott, David F. , Signoretti, Sabina , Ho, Thai , Choueiri, Toni K
Clinical Cancer Research | February 1, 2016 | Volume: 22 | Issue: 10 | Pages: 2445-2452
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 AACR. See related commentary by Voss and Hsieh, p. 2320