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. 2019 May 15;12(1):275.
doi: 10.1186/s13104-019-4312-2.

Monitoring dynamic cytotoxic chemotherapy response in castration-resistant prostate cancer using plasma cell-free DNA (cfDNA)

Katherin Patsch  1 , Naim Matasci  1 , Anjana Soundararajan  1 , Patricia Diaz  1 , David B Agus  1 , Daniel Ruderman  2 , Mitchell E Gross  3
Affiliations

Monitoring dynamic cytotoxic chemotherapy response in castration-resistant prostate cancer using plasma cell-free DNA (cfDNA)

Katherin Patsch et al. BMC Res Notes. .

Abstract

Objective: Cell-free DNA (cfDNA) is an attractive cancer biomarker, as it is thought to reflect a component of the underlying genetic makeup of the tumor and is readily accessible in serial fashion. Because chemotherapy regimens are expected to act rapidly on cancer and cfDNA is cleared from the blood within minutes, we hypothesized that cfDNA would reflect immediate effects of treatment. Here, we developed a method for monitoring long cfDNA fragments, and report dynamic changes in response to cytotoxic chemotherapy.

Results: Peripheral blood was obtained from 15 patients with metastatic castration-resistant prostate cancer (CRPC) immediately before and after cytotoxic chemotherapy infusion. cfDNA was extracted and quantified for long interspersed nuclear elements (LINE1; 297 bp) using qPCR. Targeted deep sequencing was performed to quantify the frequency of mutations in exon 8 of the androgen receptor (AR), a mutational hotspot region in CRPC. Single nucleotide mutations in AR exon 8 were found in 6 subjects (6/15 = 40%). Analytical variability was minimized by pooling independent PCR reactions for each library. In 5 patients, tumor-derived long cfDNA levels were found to change immediately after infusion. Detailed analysis of one subject suggests that cytotoxic chemotherapy can produce rapidly observable effects on cfDNA.

Keywords: Androgen receptor; Cell-free DNA; Chemotherapy; Prostate cancer; Sequencing.

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Conflict of interest statement

Ethics approval and consent to participate

Ethical approval and oversight for prospective sample collection was performed with the consent of all research subjects under auspices of the University of Southern California Institutional Review Board (IRB Protocol number: HS-11-00450). Prospective, voluntary written informed consent was obtained from all subjects prior to data and specimen collection.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Rapid changes in SNV frequency of cfDNA in response to docetaxel infusion. Mutation frequencies measured in patients’ pre- and post-samples
Fig. 2
Fig. 2
Dynamic response of cfDNA in patient P17 in two consecutive cycles of chemotherapy. cfDNA was isolated from plasma samples collected pre, post and 24 h after infusion of docetaxel at cycles 1 and 2, 21 days apart. a PSA plotted over time. Doc markings indicate treatment start dates. b LINE1 qPCR to quantify cfDNA dynamics. c Mutation frequencies of T878A and H875Y AR
See this image and copyright information in PMC

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