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. 2020 Apr:54:102728.
doi: 10.1016/j.ebiom.2020.102728.

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

Manish Kohli  1 , Winston Tan  2 , Tiantian Zheng  3 , Amy Wang  3 , Carlos Montesinos  3 , Calven Wong  3 , Pan Du  3 , Shidong Jia  3 , Siddhartha Yadav  4 , Lisa G Horvath  5 , Kate L Mahon  5 , Edmond M Kwan  6 , Heidi Fettke  7 , Jianjun Yu  3 , Arun A Azad  8
Affiliations

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

Manish Kohli et al. EBioMedicine. 2020 Apr.

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, 1.13-4.65]; 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.

Keywords: Circulating tumor DNA; Genomic alterations; Metastatic prostate cancer.

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Conflict of interest statement

Declaration of Competing Interest Manish Kohli received travel/accommodation from Celgene; Tiantian Zheng, Amy Wang, Carlos Montesinos, Calven Wong, Pan Du, Shidong Jia, and Jianjun Yu are stockholders in Predicine, Inc.; Lisa Horvath received research funding from Astellas Pharma, travel/accommodation from Astellas Pharma and Pfizer, and is on the Scientific Advisory Board for Imagion; Kate Mahon received travel/accommodation from Astellas Pharma; Edmond M Kwan received honoraria from Janssen, research funding from Astellas Pharma and AstraZeneca, and travel /accommodations from Astellas Pharma, Pfizer, and Ipsen; Arun A Azad is a consultant for Astellas Pharma, Janssen, and Novartis, is on the speakers bureau for Astellas Pharma, Janssen, Novartis and Amgen received honoraria from Astellas Pharma, Janssen, Novartis, Tolmar, Amgen, Pfizer, and Telix, is on the Scientific Advisory Board for Astellas Pharma, Novartis, Sanofi, AstraZeneca, Tolmar, Pfizer, and Telix, and received research funding from Astellas Pharma, and Merck Serono.

Figures

Fig 1
Fig. 1
A. Distribution of ctDNA fractions across metastatic groups with significant differences in yield observed across the 4 independent groups of patients (P  < . 001, Kruskal–Wallis test). B. Distribution of plasma-based tumor mutation burden across groups. C. Distribution of cfDNA yields based on metastatic volume in the untreated hormone-sensitive group and serum alkaline phosphatase (ALP) in mCRPC states. Samples are dichotomized into low and high groups based on the median value of cfDNA yields (median: 9.6 ng/mL) and ALP levels (Median: 83 IU/L), respectively. Percentage of samples with different ctDNA fractions are shown in different colors for each description. D. Combined analysis of ctDNA fraction and metastatic volume for the prediction of ADT failure in mHSPC patients. High and low ctDNA fractions are defined based on the third quartile of ctDNA fraction across the samples. E. Overall survival in the mHSPC group based on the combined analysis of volume of metastatic disease with ctDNA fraction in mHSPC patients. F. Combined analysis of ctDNA fraction and serum ALP levels of overall survival in mCRPC patients.
Fig 2
Fig. 2
A: Individual patient ctDNA fractions and variant counts across metastatic groups. B. Overall heatmap of individual somatic alterations observed in metastatic prostate cancer groups. C. Overall heatmap of deleterious/likely deleterious alterations detected in genes involved in DNA damage repair pathways. Copy number loss is shown as a blue box, and germline deleterious/likely deleterious mutations are marked with a green diamond shape.
Fig 3
Fig. 3
A. Alteration frequencies in key genes between mCRPC and mHSPC groups. B. Lollipop plot of AR somatic mutations detected in mHSPC and mCRPC patients. Known hotspot AR mutations are labeled with detailed amino acid changes. C. Distribution of AR hotspot mutations across exon regions in mCRPC patients. Each dot represents a patient, and the distinct colors indicate different levels of variant allelic frequency (VAF). D. Distribution of AR mutations and AR copy number gain along with matching ctDNA fractions in mCRPC patients detected with these alterations. Each colored bar represents an individual patient.
Fig 4
Fig. 4
A. PSA changes after 3-months of ADT in untreated mHSPC paired patient samples. B. ctDNA fraction changes after 3-months of ADT in untreated mHSPC paired patient samples. C. ctDNA-based somatic alterations of top frequently mutated genes detected in 29 paired untreated mHSPC patients before and after 3 months of androgen deprivation therapy.
Fig 5
Fig. 5
A. RB1 wild type vs copy number deletion and overall survival in mCRPC patients. B. AR copy number gain compared to wild type and overall survival in mCRPC patients. C. TP53 mutations vs wild type and overall survival in mCRPC patients.
See this image and copyright information in PMC

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