Clinical and genomic insights into circulating tumor DNA-based alterations across the spectrum of metastatic hormone-sensitive and castrate-resistant prostate cancer

Abstract

Background: Metastatic prostate cancer is a clonally heterogeneous disease state characterized by progressive somatic perturbations. The aim of this study was to identify cell free DNA-(cfDNA-) based alterations and their associations with outcomes in progressive metastatic prostate cancer. Methods: In this longitudinal prospective cohort study plasma cfDNA/circulating tumor DNA (ctDNA) was analyzed before, during, and after androgen deprivation therapy (ADT) in 4 independent patient groups ranging from untreated metastatic hormone sensitive prostate cancer (mHSPC) to metastatic castrate resistant prostate cancer (mCRPC). Next generation sequencing was performed on ctDNA and germline DNA to characterize alterations and associations with clinical outcomes were determined for each group. Findings: cfDNA yields were different in progressive mHSPC and mCRPC states (P < .001). In mHSPC, a higher than median ctDNA fraction was predictive of shorter time to ADT failure (HR, 2.29 [95% CI, 1.13À4.65]; Log-Rank P = .02). cfDNA, ctDNA taken with volume of metastatic disease in mHSPC and with alkaline phosphatase levels prognosticated survival better than clinical factors alone in mHSPC and mCRPC states (Log Rank P = 0.03). ctDNA-based AR, APC mutations were increased in mCRPC compared to mHSPC (P < ¢05).TP53 mutations, RB1 loss, and AR gene amplifications correlated with poorer survival in mCRPC. Mutations in multiple DNA repair genes (ATM, BRCA1, BRCA2, CHEK2) were associated with time to ADT treatment failure and survival in mHSPC. Interpretation: ctDNA fraction can further refine clinical prognostic factors in metastatic prostate cancer. Somatic ctDNA alterations have potential prognostic, predictive, and therapeutic implications in metastatic prostate cancer management. Funding: Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.

Multiplex Digital PCR to Detect Amplifications of Specific Androgen Receptor Loci in Cell-Free DNA for Prognosis of Metastatic Castration-Resistant Prostate Cancer

“…AR amplification has been previously reported in several independent studies to prognosticate survival in mCRPC state, and our group recently also reported AR-En amplification was associated with primary resistance to abiraterone acetate treatments [ 4 , 25 , 30 ]. We now report a quantitative, sensitive four CN altered targets-based multiplex dPCR assay to detect CN changes in AR -En, AR- E1, AR -E8, and OPHN1 genes using cfDNA from plasma of mCRPC patients.…”

“…cfDNA was extracted from plasma and pre-amplified by using a ThruPlex DNA-Seq Kit (Rubicon Genomics, Ann Arbor, MI, USA) as previously described [ 30 ]. The target regions were selected based on our previous sequencing data showing amplification at genomic AR loci, including AR -En, AR , and OPHN1 in mCRPC patients [ 25 ].…”

Volume matters and intensification is needed: emerging trends in the management of advanced prostate cancer

“…A prospective study evaluating ctDNA fluctuations before, during and after ADT initiation showed that patients with mHSPC and cfDNA levels above the median (9.6 ng/mL) had shorter time to progression to CRPC compared to those who did not (HR 2.29, 95% CI 1.13–4.65; log-rank p =0.02). 80 When stratified by CHAARTED-defined volume status, a high-volume burden had higher levels of cfDNA yield compared to low-volume disease (median 5.82 ng/mL versus 3.96 ng/mL; p =0.04). Not surprisingly, it was found that a combination of CHAARTED-defined high-volume disease burden and increased ctDNA had the highest rate of ADT failure and worse OS (log-rank p =0.03 for both).…”

Detection of Circulating Tumor DNA in Solid Tumors

“…Quite recently, Kohli et al reported the results of a longitudinal study involving plasma cfDNA/ctDNA evaluation performed prior to, during, and after androgen deprivation therapy, in various groups of prostate cancer patients ranging from untreated metastatic hormone-sensitive patients to the metastatic castration-resistant tumor bearing ones. [156]. The study involved the use of next-generation sequencing on ctDNA, and the results demonstrated that: the cfDNA levels in progressive hormone-sensitive patients were different from those in the hormone-resistant patients; in hormone-sensitive patients, higher ctDNA fraction was predictive of a shorter time for progression to androgen independency; cfDNA and ctDNA values, together with the volume of metastatic disease were highly predictive of survival; and ctDNA mutations were more frequent among the androgen-independent patients compared to the androgen-sensitive ones, with the TP53 mutations, RB1 loss, and AR gene amplifications correlating with poorer survival [156].…”

“…[156]. The study involved the use of next-generation sequencing on ctDNA, and the results demonstrated that: the cfDNA levels in progressive hormone-sensitive patients were different from those in the hormone-resistant patients; in hormone-sensitive patients, higher ctDNA fraction was predictive of a shorter time for progression to androgen independency; cfDNA and ctDNA values, together with the volume of metastatic disease were highly predictive of survival; and ctDNA mutations were more frequent among the androgen-independent patients compared to the androgen-sensitive ones, with the TP53 mutations, RB1 loss, and AR gene amplifications correlating with poorer survival [156]. These findings further support the consistent clinical utility of ctDNA evaluation in refining the prognosis in metastatic prostate cancer patients.…”