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Ashley Polski, Liya Xu, Rishvanth K. Prabakar, Jonathan W. Kim, Rachana Shah, Rima Jubran, Peter Kuhn, David Cobrinik, James Hicks, Jesse L. Berry; Cell-Free DNA Tumor Fraction in the Aqueous Humor Is Associated With Therapeutic Response in Retinoblastoma Patients. Trans. Vis. Sci. Tech. 2020;9(10):30. doi: https://doi.org/10.1167/tvst.9.10.30.
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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.
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.
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).
Longitudinal changes in AH-derived cfDNA TFx and SCNA amplitude are concordant with clinical responses of intraocular RB during active therapy.
Longitudinal evaluation of AH cfDNA may provide an objective, quantitative way to monitor therapeutic response and disease burden in RB patients.
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