Abstract B030: Advancing precision management in retinoblastoma via aqueous humor liquid biopsy: A case of TP53 and MDM4 alterations
Authors: Xu Liya , Huang Elaine , Lee Berry Jesse 
Published: November 2024

Abstract
Background: Precision medicine has revolutionized cancer treatment, but its application in retinoblastoma (RB) has been limited due to the risks associated with traditional tumor biopsies, which can lead to the spread of cancer outside the eye. Blood plasma has not been effective in intraocular RB management because the blood-brain barrier (BBB) prevents tumor-derived material from entering the bloodstream, and in cases of bilateral RB—occurring in over 40% of patients—each eye may harbor distinct genomic alterations, complicating the use of blood-based biomarkers. Given these challenges, the discovery of tumor-derived genomic material in the aqueous humor (AH) offers a promising and safer alternative—a liquid biopsy that provides localized and specific insights into the tumor's genetic makeup. Although AH liquid biopsies have been valuable in identifying genomic changes in RB, they have yet to guide treatment decisions. This is primarily due to the rarity of the disease, the heterogeneity of treatment modalities, and the unclear definition of in vivo RB subtype classifications. Consequently, translating these genomic insights into actionable, personalized treatment strategies has been challenging. Now, we present the first application of AH-monitored treatment in a 35-month-old male with unilateral RB, characterized by TP53 alteration and ecDNA-MDM4 amplification, highlighting a significant advancement in the precision management of RB. Methods: AH samples were obtained via clear corneal paracentesis and analyzed for copy number alterations and somatic variants using shallow whole-genome sequencing and targeted sequencing. The patient initially received systematic CEV, followed with intravitreal melphalan (IVM) monotherapy. Due to resistance, treatment was escalated to a combination of intravitreal melphalan and topotecan (IVM+IVT), monitored by the AH liquid biopsy genomic findings. Results:The patient initially showed resistance to monotherapy with intravitreal melphalan (IVM), but dual therapy with melphalan and topotecan (IVM+IVT) significantly reduced tumor fraction (TFx) from 81.61% to 26.63% and decreased tumor size. Continued dual therapy and subsequent topotecan monotherapy resulted in complete regression of vitreous seeds and stabilization of the disease, as indicated by a final AH TFx of 0%. At our institution, Children's Hospital Los Angeles (CHLA), the majority of RB cases are treated using IAC or IVM, with dual chemotherapy regimens rarely employed. Conclusions: This case underscores the importance of tailoring treatment protocols to genetic profiles identified through AH liquid biopsy in managing aggressive RB. The successful combination of genomic profiling and personalized therapy has potential to significantly improve clinical outcomes, marking a critical step toward real precision management of RB. Further clinical collaboration is essential to validate and refine protocols for TP53-altered and ecDNA-MDM4-driven RB.
Citation Format: Liya Xu, Elaine Huang, Jesse Lee Berry. Advancing precision management in retinoblastoma via aqueous humor liquid biopsy: A case of TP53 and MDM4 alterations [abstract]. In: Proceedings of the AACR Special Conference: Liquid Biopsy: From Discovery to Clinical Implementation; 2024 Nov 13-16; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(21_Suppl):Abstract nr B030.