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

Abstract

<div>Abstract<p><b>Purpose:</b> We examined the hypothesis that mutations in mTOR pathway genes are associated with response to rapalogs in metastatic renal cell carcinoma (mRCC).</p><p><b>Experimental Design:</b> 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.</p><p><b>Results:</b> Mutations in <i>MTOR, TSC1</i>, or <i>TSC2</i> were more common in responders, 12 (28%) of 43, than nonresponders, 4 (11%) of 36 (<i>P</i> = 0.06). Mutations in <i>TSC1</i> or <i>TSC2</i> alone were also more common in responders, 9 (21%), than nonresponders, 2(6%), (<i>P</i> = 0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in <i>MTOR, TSC1</i>, or <i>TSC2</i> compared with 4 (11%) of 36 nonresponders (<i>P</i> = 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.</p><p><b>Conclusions:</b> In this cohort of mRCC patients, mutations in <i>MTOR, TSC1</i>, or <i>TSC2</i> 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. <i>Clin Cancer Res; 22(10); 2445–52. ©2016 AACR</i>.</p><p><i>See related commentary by Voss and Hsieh, p. 2320</i></p></div>