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Cell-free DNA profiling in retinoblastoma patients with advanced intraocular disease: An MSKCC experience.

ABSTRACT: PURPOSE:The enucleation rate for retinoblastoma has dropped from over 95% to under 10% in the past 10 years as a result of improvements in therapy. This reduces access to tumor tissue for molecular profiling, especially in unilateral retinoblastoma, and hinders the confirmation of somatic RB1 mutations necessary for genetic counseling. Plasma cell-free DNA (cfDNA) has provided a platform for noninvasive molecular profiling in cancer, but its applicability in low tumor burden retinoblastoma has not been shown. We analyzed cfDNA collected from 10 patients with available tumor tissue to determine whether sufficient tumorderived cfDNA is shed in plasma from retinoblastoma tumors to enable noninvasive RB1 mutation detection. METHODS:Tumor tissue was collected from eye enucleations in 10 patients diagnosed with advanced intra-ocular unilateral retinoblastoma, three of which went on to develop metastatic disease. Tumor RB1 mutation status was determined using an FDA-cleared tumor sequencing assay, MSK-IMPACT. Plasma samples were collected before eye enucleation and analyzed with a customized panel targeting all exons of RB1. RESULTS:Tumor-guided genotyping detected 10 of the 13 expected somatic RB1 mutations in plasma cfDNA in 8 of 10 patients (average variant allele frequency 3.78%). Without referring to RB1 status in the tumor, de novo mutation calling identified 7 of the 13 expected RB1 mutations (in 6 of 10 patients) with high confidence. CONCLUSION:Plasma cfDNA can detect somatic RB1 mutations in patients with unilateral retinoblastoma. Since intraocular biopsies are avoided in these patients because of concern about spreading tumor, cfDNA can potentially offer a noninvasive platform to guide clinical decisions about treatment, follow-up schemes, and risk of metastasis.

SUBMITTER: Kothari P

PROVIDER: S-EPMC7476838 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Cell-free DNA profiling in retinoblastoma patients with advanced intraocular disease: An MSKCC experience.

Kothari Prachi P Kothari Prachi P Marass Francesco F Yang Julie L JL Stewart Caitlin M CM Stephens Dennis D Patel Juber J Hasan Maysun M Jing Xiaohong X Meng Fanli F Enriquez Jeanette J Huberman Kety K Viale Agnes A Francis Jasmine H JH Berger Michael F MF Shukla Neerav N Abramson David H DH Dunkel Ira J IJ Tsui Dana W Y DWY

Cancer medicine 20200707 17

<h4>Purpose</h4>The enucleation rate for retinoblastoma has dropped from over 95% to under 10% in the past 10 years as a result of improvements in therapy. This reduces access to tumor tissue for molecular profiling, especially in unilateral retinoblastoma, and hinders the confirmation of somatic RB1 mutations necessary for genetic counseling. Plasma cell-free DNA (cfDNA) has provided a platform for noninvasive molecular profiling in cancer, but its applicability in low tumor burden retinoblasto ...[more]

PMID: 32633890

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Project description:Purpose To evaluate topotecan-based therapy for advanced intraocular retinoblastoma. Patients and Methods Twenty-seven patients with bilateral retinoblastoma (male patients, n = 14; median age, 8.4 months) received chemotherapy: two courses of topotecan plus vincristine followed by three alternating administrations of carboplatin and vincristine for two courses and topotecan plus vincristine for one course, with optional periocular carboplatin. Focal therapy was applied after cycle 2. Event-free survival was defined as avoidance of external-beam radiotherapy (EBRT) and enucleation. Results Of 54 eyes, 42 were Reese-Ellsworth group IV to V, and 37 were International Classification of Retinoblastoma group C to E. Eleven eyes were enucleated: one at diagnosis, nine with progressive disease including three eyes treated with EBRT, and one that developed neovascular glaucoma after completion of therapy. One patient was removed from protocol with prolonged infection in course 1; 26 patients (51 eyes) were analyzed. At 10 years, cumulative incidence of EBRT was 5.9% (SE ± 3), and event-free survival was 69.2% (SE ± 27.2). Ocular survival for Reese-Ellsworth group IV to V eyes was 77.5% (SE ± 21.2); it was 74.3% (SE ≥ 18.8) for International Classification group C to E eyes. Vision testing (median age, 7 years; range, 5 to 10 years) documented 20/70 vision or better in one eye of 23 patients; 19 (76%) of 25 patients demonstrated 20/40 vision or better in one eye. All patients experienced thrombocytopenia (41 episodes in 275 courses; 15%). There were 29 episodes of febrile neutropenia (10%). Grade 3 diarrhea was present in nine of 27 patients, and one patient had an allergic reaction to carboplatin. All patients are alive at median follow-up 7.4 years (range, 2.7 to 10 years). Conclusion Topotecan combined with vincristine, carboplatin, and aggressive focal therapies is an effective regimen for the treatment of advanced retinoblastoma and results in globe salvage with vision. Toxicities were anticipated and managed with appropriate supportive care.

Project description:Fundoscopy is the standard method for diagnosis and follow-up of intraocular retinoblastoma, but it is sometimes insufficient to discern whether tumors are inactivated following treatments. In this work, we hypothesized that the amount of conserved nuclear DNA sequences in the cell-free DNA (cfDNA) fraction of the aqueous humor (AH) might complement fundoscopy for retinoblastoma follow-up. To address our hypothesis, we developed highly sensitive droplet digital polymerase chain reaction (ddPCR) methods to quantify highly conserved DNA sequences of nucleus-encoded genes (GAPDH and B4GALNT1) and of a mitochondrial gene, MT-ATP6. We obtained AH samples during intravitreal treatments. We analyzed 42 AH samples from 25 patients with intraocular retinoblastoma and 11 AH from controls (non-cancer patients). According to clinical criteria, we grouped patients as having progression-free or progressive retinoblastoma. cfDNA concentration in the AH was similar in both retinoblastoma groups. Copy counts for nucleus-derived sequences of GAPDH and B4GALNT1 were significantly higher in the AH from patients with progressive disease, compared to the AH from progression-free patients and control non-cancer patients. The presence of mitochondrial DNA in the AH explained that both retinoblastoma groups had similar cfDNA concentration in AH. The optimal cut-off point for discriminating between progressive and progression-free retinoblastomas was 108 GAPDH copies per reaction. Among patients having serial AH samples analyzed during their intravitreal chemotherapy, GAPDH copies were high and decreased below the cut-off point in those patients responding to chemotherapy. In contrast, one non-responder patient remained with values above the cut-off during follow-up, until enucleation. We conclude that the measurement of conserved nuclear gene sequences in AH allows follow-up of intraocular retinoblastoma during intravitreal treatment. The method is applicable to all patients and could be relevant for those in which fundoscopy evaluation is inconclusive.

Project description:BackgroundPrior ecologic studies suggest that UV exposure through sunlight to the retina might contribute to increased retinoblastoma incidence.AimsOur study objectives were (1) to examine the relationship between exposure to sunlight during postnatal retinal development (prior to diagnosis of sporadic disease) and the risk of retinoblastoma, and (2) to examine the relationship between sun exposure during postnatal retinal development, and the extent of disease among children with unilateral and bilateral retinoblastoma.Methods and resultsWe interviewed 511 mothers in the EpiRbMx case-control study about their child's exposure to sunlight during postnatal retinal cell division by examining three time periods prior to Rtb diagnosis coinciding with developmental stages in which outdoor activities vary. Weekly sun exposure was compared by age period, between unilateral (n = 259), bilateral (n = 120), and control (n = 132) children, accounting for two factors affecting UV exposure: residential elevation and reported use of coverings to shield eyes. For cases, association between sunlight exposure and clinical stage was examined by laterality at each age period. After adjusting for maternal education and elevation, sun exposure was lower in cases than controls in all three age periods especially during the first 6 months, and in children 12-23 months whose mothers did not cover their eyes when outdoors. In children diagnosed after 12 months of age, sun exposure during the second year of life (age 12-23 months) appeared inversely correlated (r = -0.25) with more advanced intraocular disease in bilateral Rtb children after adjusting for maternal education, residential elevation, and age of diagnosis (p < .09) consistent with effects of Vitamin D exposure on intraocular spread in earlier transgenic murine models of retinoblastoma, and suggesting potential chemopreventive strategies.ConclusionSun exposure in early childhood is protective for retinoblastoma and may decrease degree of intraocular spread in children with bilateral Rtb.

Dataset Information

Cell-free DNA profiling in retinoblastoma patients with advanced intraocular disease: An MSKCC experience.

Publications

Cell-free DNA profiling in retinoblastoma patients with advanced intraocular disease: An MSKCC experience.

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