Cell-Free DNA Tumor Fraction in the Aqueous Humor Is Associated With Therapeutic Response in Retinoblastoma Patients

Ashley Polski; Liya Xu; Rishvanth K Prabakar; Jonathan W Kim; Rachana Shah; Rima Jubran; Peter Kuhn; David Cobrinik; James Hicks; Jesse L Berry

doi:10.1167/tvst.9.10.30

Cell-Free DNA Tumor Fraction in the Aqueous Humor Is Associated With Therapeutic Response in Retinoblastoma Patients

Transl Vis Sci Technol. 2020 Sep 30;9(10):30. doi: 10.1167/tvst.9.10.30. eCollection 2020 Sep.

Authors

Ashley Polski^{1

2}, Liya Xu^{1

3}, Rishvanth K Prabakar⁴, Jonathan W Kim^{1

2}, Rachana Shah⁵, Rima Jubran⁵, Peter Kuhn^{3

6}, David Cobrinik^{1

2

6

7

8}, James Hicks^{3

6}, Jesse L Berry^{1

2

6

8}

Affiliations

¹ The Vision Center at Children's Hospital Los Angeles, Los Angeles, CA, USA.
² USC Roski Eye Institute, Keck School of Medicine of the University of Southern California, Los Angeles, CA, USA.
³ Department of Biological Sciences, Dornsife College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, CA, USA.
⁴ Department of Molecular and Computational Biology, University of Southern California, Los Angeles, CA, USA.
⁵ Cancer and Blood Disease Institute at Children's Hospital Los Angeles, Los Angeles, CA, USA.
⁶ Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁷ Department of Biochemistry and Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁸ The Saban Research Institute, Children's Hospital Los Angeles, Los Angeles, CA, USA.

Abstract

Purpose: The aqueous humor (AH) liquid biopsy enables in vivo evaluation of tumor-derived cell-free DNA (cfDNA) from retinoblastoma (RB) eyes. Herein, we test our hypothesis that longitudinal dynamics of AH cfDNA-including tumor fraction (TFx) and somatic copy number alteration (SCNA) amplitude-correspond to therapeutic response.

Methods: Eyes with ≥3 AH extractions during intravitreal chemotherapy (IVM) or at secondary enucleation between 2015 to 2019 were included. AH cfDNA was sequenced to assess RB SCNA amplitude; ichorCNA software was used to estimate TFx. Eyes without SCNAs or with TFx < 0.10 across all samples were excluded. Therapeutic responses for each eye were determined from clinical records. Statistical analyses included Mann-Whitney U and Pearson correlation tests.

Results: Twenty eyes of 20 patients underwent ≥3 AH extractions; 6 eyes lacked SCNAs or had TFx < 0.10 throughout sampling and were excluded. Clinical progression was associated with significantly higher SCNA amplitudes and TFx values than regression (P ≤ 0.04). Relative increases in TFx (ΔTFx 1.86 ± 2.22) were associated with disease progression, whereas relative decreases in TFx (ΔTFx 0.53 ± 0.36) were associated with disease regression (P < 0.00001). A ≥15% increase in TFx relative to baseline during treatment was associated with an over 90-fold increased likelihood of clinical progression (odds ratio = 90.67, 95% confidence interval = 8.30-990.16, P = 0.0002). TFx and SCNA amplitude were significantly positively correlated throughout sampling (P ≤ 0.002).

Conclusions: Longitudinal changes in AH-derived cfDNA TFx and SCNA amplitude are concordant with clinical responses of intraocular RB during active therapy.

Translational relevance: Longitudinal evaluation of AH cfDNA may provide an objective, quantitative way to monitor therapeutic response and disease burden in RB patients.

Keywords: aqueous humor; liquid biopsy; retinoblastoma; somatic copy number alteration; tumor fraction.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Aqueous Humor
Cell-Free Nucleic Acids*
DNA Copy Number Variations / genetics
Humans
Retinal Neoplasms* / drug therapy
Retinoblastoma* / drug therapy

Substances

Cell-Free Nucleic Acids

Abstract

Publication types

MeSH terms

Substances

Grants and funding