Comparative Analysis of Genomic Alterations across Castration Sensitive and Castration Resistant Prostate Cancer via Circulating Tumor DNA Sequencing.

Abstract

To explore the genomic profiles of Chinese patients with castration sensitive prostate cancer and those with metastatic castration resistant prostate cancer via germline and circulating tumor DNA sequencing. A hybridization capture based next-generation sequencing assay was used to identify germline and somatic alterations in 50 genes including androgen receptor pathway genes, DNA damage repair pathway genes, TP53 and RB1. We successfully sequenced DNA from 396 blood samples and 32 matched tumor tissue samples from 396 patients. We observed a similar frequency of deleterious germline alterations between patients with castration sensitive prostate cancer and metastatic castration resistant prostate cancer (8.9% vs 9.8%, p >0.05). There was a high consistency (90.9%) between metastatic tumor tissue and matched circulating tumor DNA. Among patients who were circulating tumor DNA positive we observed significantly higher alteration frequencies of CDK12 (27.2% vs 6.4%, p <0.001) and FOXA1 (36.8% vs 15.3%, p <0.001) in our metastatic castration resistant prostate cancer cohort compared with the SU2C-PCF (Stand Up to Cancer-Prostate Cancer Foundation) cohort. Alteration frequencies of DNA damage repair pathway genes (66.7% vs 41.5%, p=0.015) and androgen receptor pathway genes (71.9% vs 48.8%, p=0.018) in patients with metastatic castration resistant prostate cancer were higher than in patients with de novo metastatic castration sensitive prostate cancer. Androgen receptor alteration was selectively enriched in metastatic castration resistant prostate cancer. Through genomic profiling of prostate cancer across clinical states we identified a similar frequency of deleterious germline alterations between patients with castration sensitive prostate cancer and metastatic castration resistant prostate cancer. We explored the genomic diversity of androgen receptor and DNA damage repair pathway genes between patients with metastatic castration sensitive prostate cancer and metastatic castration resistant prostate cancer. Higher alteration frequencies of CDK12 and FOXA1 were observed in our metastatic castration resistant prostate cancer cohort than in the SU2C-PCF cohort. Our findings support the view that circulating tumor DNA sequencing could guide clinical treatment for metastatic prostate cancer.