Researchers Identify Mutations Common In Patients Who Benefit From mTOR Inhibitors

Mutations in mTOR, TSC1, and TSC2 were found to be common in patients with metastatic renal cell carcinoma (mRCC) who experienced a clinical benefit from mTOR inhibitors like everolimus and temsirolimus, a study published in the journal Clinical Cancer Research has shown.¹

Because signal pathway genes are often associated with clinical benefit from therapy in various cancer types, researchers sought to evaluate whether mTOR pathway genes are associated with response to mTOR inhibitors in mRCC.

For the study, researchers analyzed tumor DNA using next-generation sequencing of 560 cancer genes from 79 subjects who were treated with mTOR inhibitors with distinct clinical outcomes. Patients who achieved a partial response per RECIST v1.0 or stable disease with any tumor shrinkage for 6 months or longer were considered responders, while nonresponders experienced disease progression during the first 3 months of therapy.

Results showed that mutations in mTOR, TSC1, and TSC2 were detected in 28% of the 43 responders compared with 11% of the 36 nonresponders (P = .06); however, a substantial proportion (56%) of responders had no identified mTOR pathway mutations. Researchers also found mutations in TSC1 and TSC2 in 21% of responders vs 6% of nonresponders (P = .05).

The study further demonstrated that 42% of the 12 patients who achieved a partial response had mutations in 1 of those 3 genes compared with 11% of the 36 nonresponders (P = .03).

Of note, researchers identified 8 other genes not part of the mTOR pathway that were mutated in at least 5% of all subjects, but none were associated positively with response.

Reference

1. Kwiatkowski DJ, Choueiri TK, Fay AP, et al. Mutations in TSC1, TSC2, and MTOR are associated with response to rapalogs in patients with metastatic renal cell carcinoma [published online ahead of print February 1, 2016]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-15-2631.