Circulating tumor DNA (ctDNA) landscape in metastatic castrate-resistant prostate cancer patients with germline alterations.

Abstract

200 Background: Circulating tumor-DNA (ctDNA) in mCRPC patients (pts) provides a viable approach for examining the genetic landscape of prostate cancer. In this follow-up, we report ctDNA variants in germline tested mCRPC pts. Methods: ctDNA alterations in 73 genes were detected using Guardant360 (G360) assays. Alteration types assessed were missense, frameshift, insertions, splice variants, truncations, amplifications (amp), deletions, and other. Pts included in the analysis received germline genetic testing (Invitae Corporation, San Francisco, CA) and ctDNA assays at various treatment timepoints. Statistical analyses were performed using chi-square and fisher exact test with p-value <0.05 for significance. Results: Germline and ctDNA testing was completed in 270 mCRPC pts. 13% (35/270) of pts had pathogenic germline alterations. Germline alterations detected were BRCA2 (43%, n=15), ATM (8.5%, n=3), CHEK2 (8.5%, n=3), and BRCA1 (6%, n=2). Of the 673 alterations detected in G360 assays, TP53 (25%, n=167) and AR (17%, n=117) were most commonly observed. ctDNA alteration breakdown for germline negative/positive pts is summarized in Tables A/B. Germline negative pts had more AR alterations compared to germline positive (p = 0.023). Also, germline negative pts presented with more amps (p < 0.001) and germline positive pts with more frameshift alterations (p = 0.005). The association of ctDNA alteration to clinical outcomes in germline positive/negative pts was also assessed and is ongoing. Conclusions: Pts with germline positive alterations had few somatic AR alterations and higher frequency of deleterious mutation in comparison to their germline negative counterparts.[Table: see text][Table: see text]