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

David J Kwiatkowski1,2,3, Toni K Choueiri1,2,3, André P Fay1,4

  • 1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, US.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|February 3, 2016
PubMed
Abstract

Insights

Mutations in mTOR pathway genes like MTOR, TSC1, or TSC2 were more frequent in metastatic renal cell carcinoma patients who responded to rapalogs. However, many responders lacked these specific mutations.

Area of Science:

  • Oncology
  • Genetics
  • Pharmacology

Background:

  • Metastatic renal cell carcinoma (mRCC) is a complex cancer.
  • Rapalogs are a class of drugs targeting the mTOR pathway.
  • Predicting response to rapalogs in mRCC remains a challenge.

Purpose of the Study:

  • To investigate the association between mutations in mTOR pathway genes and patient response to rapalog therapy in mRCC.
  • To identify potential genetic biomarkers for predicting rapalog efficacy.

Main Methods:

  • Targeted next-generation sequencing of 560 cancer genes was performed on tumor DNA from 79 mRCC patients.
  • Patients were categorized as responders or nonresponders based on RECIST criteria and treatment duration.
  • Fisher exact test was used to analyze the association between gene mutations and treatment response.

Main Results:

  • Mutations in MTOR, TSC1, or TSC2 were more common in responders (28%) compared to nonresponders (11%) (P=0.06).
  • Mutations in TSC1 or TSC2 alone showed a significant association with response (21% in responders vs. 6% in nonresponders, P=0.05).
  • Partial responders (PR) were more likely to have mTOR pathway mutations (42%) than nonresponders (11%) (P=0.03).

Conclusions:

  • Mutations in MTOR, TSC1, or TSC2 are more prevalent in mRCC patients who benefit from rapalogs.
  • These mutations may serve as predictive biomarkers for rapalog treatment in mRCC.
  • A significant proportion of responders did not have detectable mTOR pathway mutations, suggesting other mechanisms of response.

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