Mutations in TSC1, TSC2, and MTOR are associated with response to rapalogs in patients with metastatic Renal Cell Carcinoma

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 six months or longer. Non-responders were defined as those with disease progression during the first three months of therapy. Fisher's 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 non-responders, 4 (11%) of 36 (p=0.06). Mutations in TSC1 or TSC2 alone were also more common in responders, 9 (21%), than non-responders, 2(6%), (p=0.05). Furthermore, 5 (42%) of 12 subjects with PR had mutations in MTOR, TSC1 or TSC2 compared to 4 (11%) of 36 non-responders (p=0.03). Eight additional genes were found to be mutated in at least 4 of 79 tumors (5%); none were associated positively with response. Conclusion: 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 (31 of 43, 72%) had no mTOR pathway mutation identified.

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