The Landscape of Pediatric Precision Oncology: Program Design, Actionable Alterations, and Clinical Trial Development.
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ABSTRACT:
SUBMITTER: Langenberg KPS
PROVIDER: S-EPMC8431194 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Neuroblastoma (NB) is the most common extracranial solid tumor encountered in childhood. Although there has been significant improvement in the outcomes of patients with high-risk disease, the prognosis for patients with metastatic relapse or refractory disease is poor. Hence, the clinical integration of genome sequencing into standard clinical practice is necessary in order to develop personalized therapy for children with relapsed or refractory disease. The PeRsonalizEdMEdicine (PREME) project focuses on the design of innovative therapeutic strategies for patients suffering from relapsed NB. We performed whole exome sequencing (WES) of patient-matched tumor-normal samples to identify genetic variants amenable to precision medicine. Specifically, two patients were studied (First case: a three-year-old male with early relapsed NB; Second case: a 20-year-old male who relapsed 10 years after the first diagnosis of NB). Results were reviewed by a multi-disciplinary molecular tumor board (MTB) and clinical reports were issued to the ordering physician. WES revealed the mutation c.G320C in the CUL4A gene in case 1 and the mutation c.A484G in the PSMC2 gene in case 2. Both patients were treated according to these actionable alterations, with promising results. The effective treatment of NB is one of the main challenges in pediatric oncology. In the era of precision medicine, the need to design new therapeutic strategies for NB is fundamental. Our results demonstrate the feasibility of incorporating clinical WES into pediatric oncology practice.
| S-EPMC9570321 | biostudies-literature
Project description:BackgroundMolecular characterization has the potential to advance the management of pediatric cancer and high-risk hematologic disease. The clinical integration of genome sequencing into standard clinical practice has been limited and the potential utility of genome sequencing to identify clinically impactful information beyond targetable alterations has been underestimated.MethodsThe Precision in Pediatric Sequencing (PIPseq) Program at Columbia University Medical Center instituted prospective clinical next generation sequencing (NGS) for pediatric cancer and hematologic disorders at risk for treatment failure. We performed cancer whole exome sequencing (WES) of patient-matched tumor-normal samples and RNA sequencing (RNA-seq) of tumor to identify sequence variants, fusion transcripts, relative gene expression, and copy number variation (CNV). A directed cancer gene panel assay was used when sample adequacy was a concern. Constitutional WES of patients and parents was performed when a constitutionally encoded disease was suspected. Results were initially reviewed by a molecular pathologist and subsequently by a multi-disciplinary molecular tumor board. Clinical reports were issued to the ordering physician and posted to the patient's electronic medical record.ResultsNGS was performed on tumor and/or normal tissue from 101 high-risk pediatric patients. Potentially actionable alterations were identified in 38% of patients, of which only 16% subsequently received matched therapy. In an additional 38% of patients, the genomic data provided clinically relevant information of diagnostic, prognostic, or pharmacogenomic significance. RNA-seq was clinically impactful in 37/65 patients (57%) providing diagnostic and/or prognostic information for 17 patients (26%) and identified therapeutic targets in 15 patients (23%). Known or likely pathogenic germline alterations were discovered in 18/90 patients (20%) with 14% having germline alternations in cancer predisposition genes. American College of Medical Genetics (ACMG) secondary findings were identified in six patients.ConclusionsOur results demonstrate the feasibility of incorporating clinical NGS into pediatric hematology-oncology practice. Beyond the identification of actionable alterations, the ability to avoid ineffective/inappropriate therapies, make a definitive diagnosis, and identify pharmacogenomic modifiers is clinically impactful. Taking a more inclusive view of potential clinical utility, 66% of cases tested through our program had clinically impactful findings and samples interrogated with both WES and RNA-seq resulted in data that impacted clinical decisions in 75% of cases.
| S-EPMC5180407 | biostudies-literature
Project description:Outcome in treatment of childhood cancers has improved dramatically since the 1970s. This success was largely achieved by the implementation of cooperative clinical research trial groups that standardized and developed treatment of childhood cancer. Nevertheless, outcome in certain types of malignancies is still unfavorable. Intensification of conventional chemotherapy and radiotherapy improved outcome only marginally at the cost of acute and long-term side effects. Hence, it is necessary to develop targeted therapy strategies.Here, we review the developments and perspectives in precision medicine in pediatric oncology with a special focus on targeted drug therapies like kinase inhibitors and inducers of apoptosis, the impact of cancer genome sequencing and immunotherapy.
| S-EPMC6119176 | biostudies-other
Project description:PURPOSE OF REVIEW:The current review describes recent advances and unique challenges in precision medicine for pediatric cancers and highlights clinical trials assessing the clinical impact of targeted therapy matched to molecular alterations identified by tumor profiling. RECENT FINDINGS:Multiple prospective clinical sequencing studies in pediatric oncology have been reported in the last 2 years. These studies demonstrated feasibility of sequencing in the clinic and revealed a rate of actionable variants that justifies the development of precision trials for childhood cancer. A number of precision medicine trials are recently completed, underway or in development and these will be reviewed herein, with a focus on highlighting aspects of precision medicine trial design relevant to pediatric oncology. SUMMARY:The primary results of the first round of pediatric precision oncology clinical trials will provide us with a greater understanding of the clinical impact of linking tumor profiling to selection of targeted therapies. The aggregation of sequencing and clinical data from these trials and the results of biologic investigations linked to these trials will drive further discoveries and broaden opportunities for precision medicine for children with cancer.
| S-EPMC5770114 | biostudies-literature
Project description:Improvements in outcome have been seen in children and adolescents with cancer. Nevertheless, challenges remain in trying to improve the outcomes for all children diagnosed with cancer, particularly in patients with metastatic disease or with cancers that are resistant or recur after standard treatment. Precision medicine trials using individualized tumor molecular profiling for selection of targeted therapies are ongoing in adult malignancies. Similar approaches are being applied to children and adolescents with cancer. This article describes how precision medicine is being applied to pediatric oncology and the unique challenges being faced with these efforts.
| S-EPMC7819485 | biostudies-literature
Project description:The field of oncology is currently undergoing a paradigm shift. Advances in the understanding of tumor biology and in tumor sequencing technology have contributed to the shift towards precision medicine, the therapeutic framework of targeting the individual oncogenic changes each tumor harbors. The success of precision medicine therapies, such as targeted kinase inhibitors and immunotherapies, in other cancers have motivated studies in brain cancers. The high specificity and cost of these therapies also encourage a shift in clinical trial design away from randomized control trials towards smaller, more exclusive early phase clinical trials. While these new trials advance the clinical application of increasingly precise and individualized therapies, their design brings ethical challenges . We review the pertinent ethical considerations for clinical trials of precision medicine in neuro-oncology and discuss methods to protect patients in this new era of trial design.
| S-EPMC5543186 | biostudies-other
Project description:PurposeThe National Cancer Institute-Children's Oncology Group Pediatric MATCH trial aimed to facilitate evaluation of molecular-targeted therapies in biomarker-selected cohorts of childhood and young adult patients with cancer by screening tumors for actionable alterations.Patients and methodsTumors from patients age 1-21 years with refractory solid tumors, lymphomas, or histiocytic disorders were subjected to cancer gene panel sequencing and limited immunohistochemistry to identify actionable alterations for assignment to phase II treatment arms. The rates of treatment arm assignment and enrollment were compared between clinical and demographic groups.ResultsTesting was completed for 94.7% of tumors submitted. Actionable alterations were detected in 31.5% of the first 1,000 tumors screened, with treatment arm assignment and enrollment occurring in 28.4% and 13.1% of patients, respectively. Assignment rates varied by tumor histology and were higher for patients with CNS tumors or enrolled at Pediatric Early Phase Clinical Trials Network sites. A reported history of prior clinical molecular testing was associated with higher assignment and enrollment rates. Actionable alterations in the mitogen-activated protein kinase signaling pathway were most frequent (11.2%). The most common reasons provided for not enrolling on treatment arms were patients receiving other treatment or poor clinical status.ConclusionThe Pediatric MATCH trial has proven the feasibility of a nationwide screening Protocol for identification of actionable genetic alterations and assignment of pediatric and young adult patients with refractory cancers to trials of molecularly targeted therapies. These data support the early use of tumor molecular screening for childhood patients with cancer whose tumors have not responded to standard treatments.
| S-EPMC9273376 | biostudies-literature
Project description:Fusion genes represent a class of attractive therapeutic targets. Thousands of fusion genes have been identified in patients with cancer, but the functional consequences and therapeutic implications of most of these remain largely unknown. Here, we develop a functional genomic approach that consists of efficient fusion reconstruction and sensitive cell viability and drug response assays. Applying this approach, we characterize ~100 fusion genes detected in patient samples of The Cancer Genome Atlas, revealing a notable fraction of low-frequency fusions with activating effects on tumor growth. Focusing on those in the RTK-RAS pathway, we identify a number of activating fusions that can markedly affect sensitivity to relevant drugs. Last, we propose an integrated, level-of-evidence classification system to prioritize gene fusions systematically. Our study reiterates the urgent clinical need to incorporate similar functional genomic approaches to characterize gene fusions, thereby maximizing the utility of gene fusions for precision oncology.
| S-EPMC8827659 | biostudies-literature
Project description:BackgroundFrequency of clinically relevant mutations in solid tumors by targeted and whole-exome sequencing is ∼30%. Transcriptome analysis complements detection of actionable gene fusions in advanced cancer patients. Goal of this study was to determine the added value of anchored multiplex PCR (AMP)-based next-generation sequencing (NGS) assay to identify further potential drug targets, when coupled with whole-exome sequencing (WES).MethodsSelected series of fifty-six samples from 55 patients enrolled in our precision medicine study were interrogated by WES and AMP-based NGS. RNA-seq was performed in 19 cases. Clinically relevant and actionable alterations detected by three methods were integrated and analyzed.ResultsAMP-based NGS detected 48 fusions in 31 samples (55.4%); 31.25% (15/48) were classified as targetable based on published literature. WES revealed 29 samples (51.8%) harbored targetable alterations. TMB-high and MSI-high status were observed in 12.7% and 1.8% of cases. RNA-seq from 19 samples identified 8 targetable fusions (42.1%), also captured by AMP-based NGS. When number of actionable fusions detected by AMP-based NGS were added to WES targetable alterations, 66.1% of samples had potential drug targets. When both WES and RNA-seq were analyzed, 57.8% of samples had targetable alterations.ConclusionsThis study highlights importance of an integrative genomic approach for precision oncology, including use of different NGS platforms with complementary features. Integrating RNA data (whole transcriptome or AMP-based NGS) significantly enhances detection of potential targets in cancer patients. In absence of fresh frozen tissue, AMP-based NGS is a robust method to detect actionable fusions using low-input RNA from archival tissue.
| S-EPMC7674614 | biostudies-literature
Project description:Precision oncology, where patients are given therapies based on their genomic profile and disease trajectory, is rapidly evolving to become a pivotal part of cancer management, supported by regulatory approvals of biomarker-matched targeted therapies and cancer immunotherapies. However, next-generation sequencing (NGS)-based technologies have revealed an increasing number of molecular-based cancer subtypes with rare patient populations, leading to difficulties in executing/recruiting for traditional clinical trials. Therefore, approval of novel therapeutics based on traditional interventional studies may be difficult and time consuming, with delayed access to innovative therapies. Real-world data (RWD) that describe the patient journey in routine clinical practice can help elucidate the clinical utility of NGS-based genomic profiling, multidisciplinary case discussions, and targeted therapies. We describe key learnings from the setup of WAYFIND-R (NCT04529122), a first-of-its-kind global cancer registry collecting RWD from patients with solid tumors who have undergone NGS-based genomic profiling. The meaning of 'generalizability' and 'high quality' for RWD across different geographic areas was revisited, together with patient recruitment processes, and data sharing and privacy. Inspired by these learnings, WAYFIND-R's design will help physicians discuss patient treatment plans with their colleagues, improve understanding of the impact of treatment decisions/cancer care processes on patient outcomes, and provide a platform to support the design and conduct of further clinical/epidemiologic research. WAYFIND-R demonstrates user-friendly, electronic case report forms, standardized collection of molecular tumor board-based decisions, and a dashboard providing investigators with access to local cohort-level data and the ability to interact with colleagues or search the entire registry to find rare populations. Overall, WAYFIND-R will inform on best practice for NGS-based treatment decisions by clinicians, foster global collaborations between cancer centers and enable robust conclusions regarding outcome data to be drawn, improve understanding of disparities in patients' access to advanced diagnostics and therapies, and ultimately drive advances in precision oncology.
| S-EPMC9384950 | biostudies-literature