Background: Tumor mutational burden (TMB) is an emerging genomic biomarker in cancer that has been associated with improved response to immune checkpoint inhibitors (ICIs) in adult cancers. It was described that variability in TMB assessment is introduced by different laboratory techniques and various settings of bioinformatic pipelines. In pediatric oncology, no study has been published describing this variability so far. Methods: In our study, we performed whole exome sequencing (WES, both germline and somatic) and calculated TMB in 106 patients with high-risk/recurrent pediatric solid tumors of 28 distinct cancer types. Subsequently, we used WES data for TMB calculation using an in silico approach simulating two The Food and Drug Administration (FDA)-approved/authorized comprehensive genomic panels for cancer. Results: We describe a strong correlation between WES-based and panel-based TMBs; however, we show that this high correlation is significantly affected by inclusion of only a few hypermutated cases. In the series of nine cases, we determined TMB in two sequentially collected tumor tissue specimens and observed an increase in TMB along with tumor progression. Furthermore, we evaluated the extent to which potential ICI indication could be affected by variability in techniques and bioinformatic pipelines used for TMB assessment. We confirmed that this technological variability could significantly affect ICI indication in pediatric cancer patients; however, this significance decreases with the increasing cut-off values. Conclusions: For the first time in pediatric oncology, we assessed the reliability of TMB estimation across multiple pediatric cancer types using real-life WES and in silico analysis of two major targeted gene panels and confirmed a significant technological variability to be introduced by different laboratory techniques and various settings of bioinformatic pipelines.
Background: Despite major improvements in the survival of pediatric cancer patients that were achieved through the intensification of chemotherapy and the perfection of supportive care in the past decades, treatment outcomes for high-risk, relapsed, and refractory solid cancers remain unsatisfactory. Accelerating the progress of pediatric oncology requires both therapeutic advances and attention to reducing the long-term cytotoxic treatment-related side effects. This could be achieved by targeting specific molecular changes that drive pediatric malignancies. Material and Methods: From September 2016 to August 2020, a total of 192 patients with pediatric high-risk solid tumors successfully underwent comprehensive genomic profiling. Since more than thirty patients had two or more biopsies from recurrent relapses, the total number of samples examined was 295. In the cohort, there were 78 cases of central nervous system tumors, 68 sarcomas, 14 neuroblastomas, 10 lymphomas, and 22 tumors of other histology. Whole-exome sequencing was performed in all patients, fusion gene analysis in 96% of patients, whole-transcriptome profiling in 84% of patients, and CNV analysis in 63% of patients. Results: The diagnostic yield of therapeutically actionable findings was 40%, with single-nucleotide variants and small insertions/deletions being the most common actionable alteration types. In 23% of patients, a clinically relevant gene fusion was identified. The majority of the identified fusions were of diagnostic significance, and 18% of those were therapeutically targetable gene fusions involving BRAF, RAF1, ALK, FGFR1, or NTRK2. Four patients were eligible for immunotherapy based on high tumor mutational burden (>10 mut/Mb). Lymphomas and CNS tumors showed the highest rate of patients with therapeutically actionable findings (60% and 56%, respectively), followed by neuroblastomas (36%), sarcomas (25%), and other solid tumors (23%). All results and individual treatment plans were discussed at multidisciplinary molecular tumor boards. Conclusion: Precision medicine in pediatric oncology has rapidly developed over the last decade and resulted in new therapeutic options based on molecular biomarkers and increased our understanding of the complexity of pediatric malignancies. Supported by the Ministry of Health of the Czech Republic, grant nr. NU20-03-00240 and the project National Institute for Cancer Research (Programme EXCELES, ID Project No. LX22NPO5102) - Funded by the European Union - Next Generation EU. Citation Format: Petra Pokorna, Hana Palova, Sona Adamcova, Vojtech Bystry, Michal Kyr, Dagmar Al Tukmachi, Sona Mejstrikova, Peter Mudry, Jaroslav Sterba, Ondrej Slaby. Impact of the comprehensive genomic profiling on the individual therapeutic planning in high-risk/refractory tumors: real-world precision medicine in pediatric oncology. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4511.
Despite the great achievements in treating pediatric cancer patients in the last several decades, approximately one fifth of patients remains uncurable using standard therapeutic modalities and require search for innovative therapeutic approaches. Advances in sequencing techniques and bioinformatic data processing enabled identification of wide spectrum of molecular alterations including single nucleotide variants, copy number aberrations, fusion genes or changes in expression and methylation patterns, which could serve as therapeutic targets. Translation of comprehensive molecular profiling into clinical practice is still limited, however, multiple precision oncology initiatives have already explored feasibility of this approach. From September 2016 to December 2020, a total of 160 patients with high-risk solid tumors that were treated or consulted at Department of Pediatric Oncology of University Hospital Brno were subjected to molecular analysis of tumor tissue using whole-exome sequencing, targeted RNA sequencing, whole-transcriptome profiling and array-CGH. In 18 patients, 2 or more biopsies were analyzed due to relapse or progression of the disease. In the cohort, CNS tumors were the most prevalent (41%), followed by sarcomas (33%) and neuroblastoma (9%). All patients were presented at multidisciplinary molecular tumor board, where treatment recommendations were discussed. In 37% of patients (n = 59), therapeutic targets were identified. Most commonly identified targets included BRAF (n = 9), FGFR1 (n = 7), NF1 (n = 6), NRAS (n = 5) and PIK3CA (n = 4), making RAS/MAPK signaling most frequently altered pathway in the subgroup. Single nucleotide variants or small indels accounted for 65% of actionable findings, followed by fusion genes (12%), copy number aberrations (9%), CD274 expression (7%, confirmed by IHC staining for PD-L1 protein), and high tumor mutational burden (7%). Clinically relevant fusions were found in 25% of patients and 20% of identified fusions were targetable. 8 patients were eligible for immunotherapy based on either PD-L1 expression, or high tumor mutational burden (>10 mut/Mb). Using molecular-based approach in treating high-risk patients represents a promising strategy and helps to understand the complexity of pediatric malignancies though examining tumor biology at multiple levels. Implementing the concept of precision oncology into clinical practice could not only be beneficial in the context of chances for improved survival of high-risk patients, but might also be convenient for other patients, whose successful treatment comes at cost of various secondary complications due to intensive chemotherapy/radiotherapy approaches. Supported by Ministry of Health of the Czech Republic, grant nr. NV19-03-00562, NV19-03-00501, NV19-03-00559 and NU20-03-00240. All rights reserved. Citation Format: Petra Pokorna, Hana Palova, Tina Catela Ivkovic, Sona Adamcova, Michal Kyr, Vojtech Bystry, Robin Jugas, Karolina Trachtova, Dagmar Al Tukmachi, Tomas Merta, Jaroslav Juracek, Jiri Sana, Sona Mejstrikova, Marta Jezova, Peter Mudry, Zdenek Pavelka, Jaroslav Sterba, Ondrej Slaby. Comprehensive genomic profiling as an approach to guide therapeutic planning in pediatric patients with high-risk solid tumors [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 76.
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