Predictive Genomic Markers of Response to VEGF-Targeted Therapy in RCC Patients

TP53 and VHL may be candidate genes to serve as predictive biomarkers in patients with metastatic renal cell carcinoma (mRCC). A composite model of TP53, VHL, and FLT1 genes was found to be predictive of response to vascular endothelial growth factor (VEGF)-targeted therapy in a dose-dependent manner in patients with mRCC, according to data presented at the 16th International Kidney Cancer Symposium held November 3-4, 2017 in Miami, Florida.

Currently, treatment options for mRCC are changing, according to investigators. However, they note that treatment selection and sequencing are significant challenges for oncologists because there are no predictive biomarkers to help personalize treatment for individual patients.

“We found that mutation in TP53 and absence of mutation in VHL are predictive of inferior response to first-line VEGF-targeted therapy. Furthermore, a composite model of mutated TP53, wild-type VHL, and germline FLT1 C/C was predictive of response to first-line VEGF-targeted therapy in a dose-dependent manner,” said study investigator Andrew Hahn, MD, who is with the University of Utah/Huntsman Cancer Institute in Salt Lake City, Utah.

Dr. Hahn presented data on 80 patients who were treated with first-line VEGF-targeted therapy and had primary tumor tissue available for analysis. In this cohort, 78% of the patients had received first-line sunitinib. The primary objective of the study was to identify tumor-based genomic markers of response to VEGF-targeted therapy to optimize treatment selection in mRCC patients.

The cohort was mainly clear cell predominant mRCC patients who were treated between 2000 and 2015. Dr. Hahn and colleagues conducted a retrospective chart review to determine first-line treatment, duration of response, International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, and sites of metastasis.

“We were surprised and excited by our findings. Neither TP53 or VHL has previously been reported as a predictive biomarker for VEGF-targeted therapy,” Dr. Hahn told OncoTherapy Network. “Our findings are an advance because no predictive biomarkers are routinely used in the clinic, and if independently validated, mutated TP53 and non-mutated VHL could be used to predict response to first-line VEGF-targeted therapy. Both genes are tested in commercially available next-generation sequencing platforms.”

The researchers used genomic DNA to assess genomic alterations in 76 RCC-relevant genes and 7 prognostic single nucleotide polymorphisms. They also examined copy number alterations by array comparative genomic hybridization. The study demonstrated that the median progression-free survival on first-line VEGF-targeted therapy did not differ for the PBRM1, SETD2, BAP1, KDM5C, mTOR, and ROS1 genes. 

Dr. Hahn said immunotherapy and VEGF-targeted therapies are currently approved for treatment of mRCC and in the near future it is anticipated combination regimens will be approved. “While more treatment options are better, little guidance exists for personalizing treatment to optimize outcomes. Predictive biomarkers, such as TP53 or VHL, could help improve outcomes by personalizing treatment selection,” said Dr. Hahn.