Evaluation of ctDNA in Patients With CRPC, Pathogenic Germline Mutations in BRCA2

A new study presented at the 2023 American Society of Clinical Oncology Genitourinary Cancers Symposium examined the relationship between pathogenic germline BRCA2 mutation and somatic changes in circulating tumor DNA (ctDNA).

Prior research has shown that up to 5% of patients with advanced prostate cancer harbor pathogenic BRCA2 mutations. Characterizing the mutational landscape in BRCA2 germline-mutated patients may help define disease biology.

A group of researchers from Tulane sought to better understand the relationship between pathogenic germline BRCA2 mutation and somatic changes in ctDNA of castration-resistant prostate cancer (CRPC). Germline screenings were performed and included 50 to 84 genes. ctDNA alterations were detected by Guardant360 assays, which report somatic changes in 70 to 83 genes.

Researchers noted that all ctDNA samples were collected in patients after treatment for CRPC with abiraterone or enzalutamide. Any pathogenic or likely pathogenic somatic alterations in ctDNA with more than 0.1% of allelic fraction were included in the analysis.

Results of the germline screenings showed 11 patients had germline BRCA2 pathogenic mutations and ctDNA assays, whereas 267 patients had no germline DNA pathogenic alterations or ctDNA assays. Notably, when compared with the germline-normal patients, those with germline BRCA2 mutations were less likely to have AR alterations on ctDNA (odds ratio, 0.2133; 95% CI, 0.087-0.525; P=.0003).

Furthermore, patients with germline BRCA2 mutations were more likely to have a mutated BRCA1, BRCA2, and TP53 ctDNA. These patients were less likely to have copy number alterations and more likely to have frameshift mutations, researchers added.

“Those with BRCA-mutated germline may be less likely to have AR-driven tumors,” they concluded. “More study is needed to better understand patients with underlying DNA repair defects.”