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The Use of Reverse Phase Protein Arrays RPPA to Explore Protein Expression Variation within Individual Renal Cell Cancers
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Mutations and Response to Rapalogs in Patients with Metastatic Renal Cell Carcinoma

Amin H Nassar1,2, Lana Hamieh1,2, Kathryn P Gray3

  • 1Cancer Genetics Lab, Division of Pulmonary Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.

Molecular Cancer Therapeutics
|October 27, 2019
PubMed

Insights

This study found no correlation between mTOR pathway gene mutations and clinical benefit in metastatic renal cell carcinoma (mRCC) patients treated with rapalogs. Genetic alterations did not predict response to this targeted therapy in a broad patient group.

Area of Science:

  • Oncology
  • Genetics
  • Pharmacology

Background:

  • Previous research suggested mTOR pathway gene alterations correlate with response to rapalog therapy in metastatic renal cell carcinoma (mRCC), but this was based on extreme response groups.
  • Understanding genetic predictors of treatment response is crucial for optimizing therapy in mRCC.

Purpose of the Study:

  • To investigate the correlation between mutations in mTOR pathway genes and other commonly mutated genes in renal cell carcinoma (RCC) with response to rapalog therapy in a larger, unselected patient cohort.
  • To determine if specific gene mutations predict clinical benefit (CB) from rapalog treatment in mRCC.

Main Methods:

  • Somatic mutations in 27 genes, including 5 mTOR pathway genes (TSC1, TSC2, MTOR, PTEN, PIK3CA) and 6 common RCC genes (BAP1, KDM5C, PBRM1, SETD2, TP53, VHL), were analyzed in tumors from 109 mRCC patients treated with rapalogs.
  • Clinical benefit (CB) was defined as complete remission, partial response, or stable disease for at least 22 weeks.
  • Mutational status was compared with CB rates between mutated and wild-type groups.

Main Results:

  • Of 109 patients, 31 (28%) achieved CB. No significant association was found between mutations in mTOR pathway genes (individual or combined) and CB.
  • Patients with mTOR pathway mutations had a CB rate of 30% (9/30), compared to 28% (22/79) in the wild-type group.
  • Mutations in commonly mutated RCC genes also did not correlate with CB, including TSC1 mutations (3/7 patients showed CB).

Conclusions:

  • In a large and diverse population of mRCC patients, there is no evidence to support a correlation between rapalog therapy response and the mutation status of mTOR pathway genes or other commonly mutated RCC genes.
  • The findings suggest that mutations in these specific genes are not reliable biomarkers for predicting response to rapalog treatment in mRCC.

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