Longitudinal ctDNA alterations in germline positive CRPC patients.

Abstract

275 Background: Circulating tumor-derived DNA (ctDNA) is an accessible method for characterizing somatic alterations. We report longitudinal ctDNA screenings of mCRPC patients (pts) who have had germline testing. Methods: Patients with both germline testing and ctDNA assessment were included. Germline testing was performed with a multi-gene cancer panel from Invitae (50-83 genes) and somatic alterations in ctDNA were identified by testing with Guardant 360 (70-83 genes). ctDNA alterations were characterized as deletions, frameshift, missense, nonsense, and other mutations. A total of 177 patients in various stages of therapy had both ctDNA and germline DNA tested. Results: From 2015-2021, 177 mCRPC patients were included and had an average of 3 ctDNA tests. 11.3% (20/177) had pathogenic or likely-pathogenic germline mutations. The common pathogenic germline mutations were in BRCA2 (25%; 5/20), ATM (10%; 2/20), and MSH2 (10%; 2/20). In ctDNA, missense mutations were the most prevalent type of gene alteration in germline negative (n = 539/790, 68%) and germline positive (n = 124/218, 57%) followed by frameshift mutations at 22% (n = 48/218) in germline positive and 10% (n = 80/790) in germline negative patients. Germline positive patients were more likely to have somatic frameshift mutations (OR = 2.09, 95% C.I. (1.3792, 3.1618), p = 0.001) and less likely to have missense mutations (OR = 0.61, 95% C.I. (0.4519, 0.8351), p = 0.002). Other alterations including deletions, nonsense, and other mutations were not significantly different. Of the germline positive pts, BRCA2 mutation was associated with the highest number of somatic alterations. Conclusions: Germline positive CRPC patients were more likely to have frameshift mutations and less likely to missense mutations compared to germline negative CRPC patients. Patients with germline mutations in BRCA2 and TP53 had the highest number of somatic alterations detected in ctDNA over the course of ctDNA evaluation.