CfDNA analysis of mCRPC patients expressing mutations in Wnt signaling.

Abstract

256 Background: Alterations in Wnt signaling have been shown to play a role in the development of castrate resistant prostate cancer. Cell free DNA (cfDNA) isolated from patient plasma can provide a non-invasive way to further assess this role. The goal of this study was to identify patients with cfDNA alterations in major canonical Wnt signaling components (APC and/or beta-catenin), and relate the emergence of these mutations during treatment to alterations in other common mutations. Methods: 134 clinically progressive metastatic CRPC patients from Tulane Cancer Center underwent cfDNA analysis through Guardant360 test (Guardant Health, Redwood City, CA). This analysis consisted of exonic coverage of 70 genes as well as amplifications in 18 genes, with mutations categorized as either pathologic, non-pathologic or as variants of unknown significance (VUS). Clinical annotation of prior treatment history was recorded. Results: 21.6% (29/134) of the mCRPC patients evaluated had a canonical Wnt signaling (APC and/or CTNNB) alteration. Of these patients, 62.1% (18/29) had mutations identified as pathologic. 77.8% (14/18) of patients identified with a pathologic Wnt mutation were treated with abiraterone and/or enzalutamide prior to Guardant360 testing. To determine potential associations between Wnt signaling alterations and other detected changes in cfDNA, the relationship between Wnt mutations (APC and/or CTNNB1) with pathologic TP53 mutations, AR mutations, BRAF amplifications, and MYC amplifications was assessed using a patient’s latest Guardant360 test. A significant positive association was found between Wnt mutations (n = 18) and MYC amplifications (n = 22), (p = 0.0373). 33.3% (6/18) of patients with a pathologic Wnt mutation were found to have amplification in MYC. Other notable associations included Wnt mutations and AR mutations (n = 74), which approached statistical significance (p = 0.112). Conclusions: While the understanding of the role of Wnt signaling in the treatment of mCRPC is still evolving, co-segregation of Wnt-signaling alterations with other oncogenic alterations, particularly MYC, which has been identified as a target of canonical Wnt signaling, may provide insights with regards to future management of mCRPC.