The management of choroid plexus carcinoma is challenging and multifaceted. Here, we discuss a three-year-old girl with choroid plexus carcinoma and Li-Fraumeni syndrome who achieved full remission after surgery and chemotherapy, with radiation therapy spared. At recurrence, we used a novel, standard-dose cytotoxic chemotherapy regimen, focal proton radiation therapy, and targeted agents based on morphoproteomic analysis to achieve long-term survival. We highlight the rationale for our therapy at recurrence, as well as the risk-benefit analyses necessary in decision making for these patients. Our strategy may be effective in managing other patients with recurrent choroid plexus carcinoma and Li-Fraumeni syndrome.

Background While rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and adolescents, past epidemiology studies of this malignancy used data that covered <30% of the US population. Therefore, we evaluated RMS incidence using data from U.S. Cancer Statistics (USCS) and survival trends using the National Program of Cancer Registries (NPCR), which covers 100% and 94% of the U.S. population, respectively. Methods Incidence and survival were assessed for pediatric patients diagnosed with RMS during 2003–2017 and 2001–2016, respectively. Both demographic and clinical variables were evaluated. Age‐adjusted incidence rates, average annual percent change (AAPC), and 5‐year relative survival (RS) were calculated, all with corresponding 95% confidence intervals (CIs). Cox regression models were used to evaluate the impact of demographic and clinical variables on survival. Results We identified 5656 primary RMS cases in USCS during 2003–2017. The age‐adjusted incidence rate was 4.58 per 1 million (95% CI: 4.46–4.70) with an AAPC of 0.3% (95% CI: −0.7 to 1.2%). In NPCR, 5‐year RS for all cases was 68.0% (95% CI: 66.6–69.3%). In multivariable analyses, non‐Hispanic (NH) Black cases had worse survival compared with NH White cases (hazard ratio [HR] = 1.16, 95% CI: 1.01–1.33). Conclusion The incidence and survival rates were stable in the largest and most comprehensive population‐based analysis for pediatric RMS cases in the U.S. Additionally, we observed a survival disparity among NH Black cases. Findings from this study could inform interventions to address disparities, risk stratification strategies, and clinical trial design.

Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and has one of the poorest survival rates among pediatric cancers, underscoring the need to identify factors which may be leveraged to improve therapeutic options for these individuals. Methods: We carried out a genome-wide association study of overall survival (OS) and event-free survival (EFS) in 920 RMS patients from COG protocols and randomly divided them into discovery (n=642) and replication (n=278) cohorts. Genotyping was conducted using the Illumina OmniExpress or Global Screening Array and imputed using the Haplotype Reference Consortium. We used Cox proportional hazards regression to calculate an adjusted hazard ratio (aHR) and P value for each common variant (minor allele frequency [MAF]&gt;5%) for OS and EFS while adjusting for age at diagnosis, tumor stage, histological subtype, and the top five principal components. Analyses were also conducted by histological subtype: embryonal RMS (ERMS, n=544) and alveolar RMS (ARMS, n=268). Finally, we performed a meta-analysis of the results from the discovery and replication cohorts to generate a summary aHR and P value for each single nucleotide polymorphism (SNP). Results: We identified an intergenic SNP at chr8q21.13 associated with worse RMS EFS across subtypes (aHR=2.08, P=2.80x10-9), which had consistent effects across the discovery (aHR=1.91, P=5.05x10-6) and replication (aHR=2.62, P=7.16x10-5) cohorts. This SNP lies in a region which spans the genomic binding site for GATA2 and GATA3, transcription factors that are recognized to contribute to cancer development. We also identified a significant association between a SNP at chr12q21.1 and worse EFS (aHR=2.04, P=3.35x10-8) with consistent effects across the discovery and replication cohorts. Based on data from the Genotype-Tissue Expression project (GTEx), this SNP is associated with expression of SLCO1B1, a gene which encodes a liver anion transporter linked to RMS treatment-related toxicities. In subtype-specific analyses, we identified a SNP at chr17q21.32 that was significantly associated with worse ARMS OS (129 events; aHR=3.18, P=3.12x10-8; discovery: aHR=3.19, P=6.23x10-4; replication: aHR=3.16, P=1.43x10-3). In GTEx, this SNP is associated with expression and splicing of genes including PITPNM3, KIAA0753, and MED31 across various tissues. No SNPs were significantly associated with ERMS OS or EFS. Conclusion: In the first GWAS of RMS survival outcomes, we identified two SNPs that were significantly associated with worse EFS across RMS subtypes. Further, we identified a SNP that was associated with OS in ARMS patients, a subtype that is associated with worse outcomes. Additional investigation of the impact of these SNPs may further support their consideration for novel risk stratification protocols. Citation Format: Bailey A. Martin-Giacalone, Michael E. Scheurer, Javed Khan, Stephen J. Chanock, Shengchao Alfred Li, Meredith Yeager, Deborah A. Marquez-Do, Donald A. Barkauskas, David Hall, Matthew T. McEvoy, Melissa A. Richard, Pagna Sok, Austin L. Brown, Aniko Sabo, Stephen X. Skapek, Douglas S. Hawkins, Rajkumar Venkatramani, Lisa Mirabello, Philip J. Lupo. Identification of common germline variants associated with pediatric rhabdomyosarcoma survival: A report from the Children's Oncology Group (COG) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 683.

Background Relative to other pediatric cancers, survival for rhabdomyosarcoma has not improved in recent decades, suggesting the need to enhance risk stratification. Therefore, we conducted a genome-wide association study for event-free survival (EFS) and overall survival (OS) to identify genetic variants associated with outcomes in individuals with rhabdomyosarcoma. Methods The study included 920 individuals with newly diagnosed rhabdomyosarcoma who were enrolled on Children’s Oncology Group protocols. To assess the association of each single nucleotide polymorphism (SNP) with EFS and OS, we estimated hazard ratios (HR) and 95% confidence intervals (CI) using multivariable Cox proportional hazards models, adjusted for clinical covariates. All statistical tests were two sided. We also performed stratified analyses by histological subtype (alveolar and embryonal rhabdomyosarcoma) and carried out sensitivity analyses of statistically significant SNPs by PAX3/7-FOXO1 fusion status and genetic ancestry group. Results We identified that rs17321084 was associated with worse EFS (HR = 2.01, 95% CI = 1.59-2.53, P = 5.39x10-9) and rs10094840 was associated with worse OS (HR = 1.84, 95% CI = 1.48-2.27, P = 2.13x10-8). Using publicly available data, we found that rs17321084 lies in a binding region for transcription factors GATA2 and GATA3, and rs10094840 is associated with SPAG1 and RNF19A expression. We also identified that CTNNA3 rs2135732 (HR = 3.75, 95% CI = 2.34-5.99, P = 3.54x10-8) and MED31 rs74504320 (HR = 3.21, 95% CI = 2.12-4.86, P = 3.60x10-8) were associated with worse OS among individuals with alveolar rhabdomyosarcoma. Conclusions We demonstrated that common germline variants are associated with EFS and OS among individuals with rhabdomyosarcoma. Additional replication and investigation of these SNP effects may further support their consideration in risk stratification protocols.