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Tumor fraction in cell-free DNA as a biomarker in prostate cancer
Atish D. Choudhury, … , William C. Hahn, Viktor A. Adalsteinsson
Atish D. Choudhury, … , William C. Hahn, Viktor A. Adalsteinsson
Published November 2, 2018
Citation Information: JCI Insight. 2018;3(21):e122109. https://doi.org/10.1172/jci.insight.122109.
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Clinical Medicine Oncology

Tumor fraction in cell-free DNA as a biomarker in prostate cancer

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Abstract

BACKGROUND. Tumor content in circulating cell-free DNA (cfDNA) is a promising biomarker, but longitudinal dynamics of tumor-derived and non–tumor-derived cfDNA through multiple courses of therapy have not been well described. METHODS. CfDNA from 663 plasma samples from 140 patients with castration-resistant prostate cancer (CRPC) was subject to sparse whole genome sequencing. Tumor fraction (TFx) estimated using the computational tool ichorCNA was correlated with clinical features and responses to therapy. RESULTS. TFx associated with the number of bone metastases (median TFx = 0.014 with no bone metastases, 0.047 with 1–3 bone metastases, 0.190 for 4+ bone metastases; P < 0.0001) and with visceral metastases (P < 0.0001). In multivariable analysis, TFx remained associated with metastasis location (P = 0.042); TFx was positively correlated with alkaline phosphatase (P = 0.0227) and negatively correlated with hemoglobin (Hgb) (P < 0.001), but it was not correlated with prostate specific antigen (PSA) (P = 0.75). Tumor-derived and non–tumor-derived cfDNA track together and do not increase with generalized tissue damage from chemotherapy or radiation at the time scales examined. All new treatments that led to ≥30% PSA decline at 6 weeks were associated with TFx decline when baseline TFx was >7%; however, TFx in patients being subsequently maintained on secondary hormonal therapy was quite dynamic. CONCLUSION. TFx correlates with clinical features associated with overall survival in CRPC, and TFx decline is a promising biomarker for initial therapeutic response. TRIAL REGISTRATION. Dana-Farber/Harvard Cancer Center (DF/HCC) protocol no. 18-135. FUNDING. Wong Family Award in Translational Oncology, Dana Farber Cancer Institute Medical Oncology grant, Gerstner Family Foundation, Janssen Pharmaceuticals Inc., and Koch Institute Support (core) grant P30-CA14051 from the National Cancer Institute (NCI).

Authors

Atish D. Choudhury, Lillian Werner, Edoardo Francini, Xiao X. Wei, Gavin Ha, Samuel S. Freeman, Justin Rhoades, Sarah C. Reed, Gregory Gydush, Denisse Rotem, Christopher Lo, Mary-Ellen Taplin, Lauren C. Harshman, Zhenwei Zhang, Edward P. O’Connor, Daniel G. Stover, Heather A. Parsons, Gad Getz, Matthew Meyerson, J. Christopher Love, William C. Hahn, Viktor A. Adalsteinsson

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Figure 3

Tumor fraction and cfDNA yield with PSA over time in 3 patients receiving chemotherapy.

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Tumor fraction and cfDNA yield with PSA over time in 3 patients receivin...
Left panels: Depiction of TFx (orange markers, left axis) and PSA (blue markers, right axis) over time (measured in days) for 3 patients in the cohort treated with chemotherapy. Start and stop dates for treatments are depicted with a diamond; lines continuing to the edge of the graph without a diamond denote that the therapy was initiated prior to the time points depicted in the graph or completed after the time points depicted in the graph. IA, investigational agent. Two markers from the same time point on day 120 for patient 85 denote replicates from the same cfDNA isolate but with independent library construction and sequencing steps. Right panels: Depiction of total cfDNA yield (in ng/ml of plasma, lavender), tumor DNA yield (TFx × total cfDNA yield, orange), and noncancerous (“normal”) DNA yield ([1 – TFx] × total cfDNA yield, blue) in the same 3 patients over time. Note that the scales of total cfDNA yield (y axes) are different for the 3 patients.

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