First-line treatment for metastatic renal cell carcinoma (mRCC) is rapidly changing. It currently includes VEGF targeted therapies (TT), multi-target tyrosine kinase inhibitors (TKIs), mTOR inhibitors, and immunotherapy. To optimize outcomes for individual patients, genomic markers of response to therapy are needed. Here, we aim to identify tumor-based genomic markers of response to VEGF TT to optimize treatment selection.
From an institutional database, primary tumor tissue was obtained from 79 patients with clear cell mRCC, and targeted sequencing was performed. Clinical outcomes were obtained retrospectively. Progression-free survival (PFS) on first-line VEGF TT was correlated to genomic alterations (GAs) using Kaplan-Meier methodology and Cox proportional hazard models. A composite model of significant GAs predicting PFS in the first-line setting was developed.
Absence of VHL mutation was associated with inferior PFS on first-line VEGF TT. A trend for inferior PFS was observed with GAs in TP53 and FLT1 C/C variant. A composite model of these 3 GAs was associated with inferior PFS in a dose-dependent manner.
In mRCC, a composite model of TP53 mutation, wild type VHL, and FLT1 C/C variant strongly predicted PFS on first-line VEGF TT in a dose-dependent manner. These findings require external validation.
PloS one. 2019 Jan 25*** epublish ***
David D Stenehjem, Andrew W Hahn, David M Gill, Daniel Albertson, Banumathy Gowrishankar, Joseph Merriman, Archana M Agarwal, Venkata Thodima, Erik B Harrington, Trang H Au, Benjamin L Maughan, Jane Houldsworth, Sumanta K Pal, Neeraj Agarwal
College of Pharmacy, University of Minnesota, Duluth, MN, United States of America., Department of Internal Medicine, Division of Medical Oncology, University of Utah Huntsman Cancer Institute, Salt Lake City, UT, United States of America., Department of Pathology, University of Utah and ARUP Laboratories, Salt Lake City, UT, United States of America., Cancer Genetics Inc., Rutherford, NJ, United States of America., Pharmacotherapy Outcomes Research Center (PORC), College of Pharmacy, University of Utah, Salt Lake City, UT, United States of America., Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, United States of America.