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JCI Insight. 2018 Nov 2;3(21). pii: 122109. doi: 10.1172/jci.insight.122109.

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

Author information

1
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
2
Harvard Medical School, Boston, Massachusetts, USA.
3
Eli and Edythe L. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
4
Sapienza University of Rome, Rome, Italy.
5
The Ohio State University, Columbus, Ohio, USA.
6
Massachusetts General Hospital, Boston, Massachusetts, USA.
7
Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.

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).

KEYWORDS:

Oncology; Prostate cancer

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