San Antonio, Texas USA (UroToday.com) Renal cell carcinoma (RCC) is one of the most genetically understood malignancies starting with the identification of the VHL gene mutation in the early 90’s. This has led to several advances in the treatment of advance RCC with the introduction of VEGF and mTOR inhibitors. The current state of advance RCC treatment is based on the setting on which the drug was approved (1st line vs. 2nd line) and matching side effect profile with existing comorbidities. With new advances in gene profiling there is now the possibility to further the field by providing individualized treatment based on the tumor mutation profiles.
In this session by Dr. Choueiri by the Dana-Faber Cancer Institute discusses advances in targeted therapy with a focus on individualized treatment based on gene profiling. Over the last 10 years there has been great excitement in the identification of several biomarkers (CA-IX, VHL, PBRM1, PD-L1) that would predict response to individual treatment strategies. Sadly, none of these biomarkers have been be able to be translated to the clinical setting. The genomic profiling of RCC by the TCGA has allowed for researchers to find other pathways that may impact tumor progression and potential treatment targets such as chromatic regulation, metabolic shift in aggressive malignancies, and repeated mutations in the mTOR pathway.
Dr. Choueiri discusses the importance of genomic profiling of patients who presents with advance disease as possible target sites can be identified which may improve response. At the Dana Faber Cancer Center all patients are offered gene profiling, free of cost, to help guide treatment. With gene profiling several key mutations can be identified such as the TSC1 and TSC2 mutations in the mTOR pathway which are exquisitely sensitive to mTOR inhibitors, as shown by Dr. Kwiatkowski and colleagues (Clinical Cancer Res, 2016) at the MSKCC which showed this mutations to be predictive of exceptional responders. Similarly in patients treated with VEGF inhibitors patients harboring mutations in PBRM1, TP53 and KDM5C are more likely to be extreme responders.
Similar studies have been done on non-clear cell histologies such as papillary RCC. Genomic profiling of patients with papillary RCC has shown that mutations in the MET pathway are more common in papillary type 1 compared to those with papillary type 2 RCC. That being said this is not always the norm. The speaker gives an example of a patient with advance high grade papillary type II RCC which responded poorly to mTOR inhibitor, but on gene profiling was found to harbor mutation in the MET gene (METL1195F). The patient was the treated with savolitinib (pure MET inhibitor) with a dramatic response.
Gene profiling has also allowed identification of treatment targets for uncommon malignancies such as collecting duct carcinoma. Gene profiling of collecting duct carcinoma has shown mutations in NF2 which could be associated with everolimus sensitivity and SMARCB1 which could be associated with EZH2 inhibitor sensitivity. In addition, gene profiling has allowed treatment cross-over from malignancy type such as the use of mTOR inhibitors in patients with advance urothelial carcinoma with poor response to platinum based chemotherapy, given the identification of tumor mutation in the mTOR pathway.
In conclusion, genomic profiling has the potential to further guide targeted therapy to improve responses and side effects profiles in patients with advance RCC.
Presented By: Toni Choueiri, MD, Dana Faber Cancer Institute
Written By: Andres F. Correa, MD, Society of Urologic Oncology Fellow, Fox Chase Cancer Center
17th Annual Meeting of the Society of Urologic Oncology - November 30 -December 2, 2016 – San Antonio, Texas USA