Feasibility and clinical integration of molecular profiling for target identification in pediatric solid tumors

Pincez, Thomas; Clément, Nathalie; Lapouble, Eve; Pierron, Gaëlle; Kamal, Maud; Bièche, Ivan; Bernard, Virginie; Fréneaux, Paul; Michon, Jean; Orbach, Daniel; Aerts, Isabelle; Pacquement, Hélène; Bourdeaut, Franck; Jiménez, Irène; Thébaud, Estelle; Oudot, Caroline; Vérité, Cécile; Taque, Sophie; Owens, Cormac; Doz, François; Tourneau, Christophe Le; Delattre, Olivier; Schleiermacher, Gudrun

doi:10.1002/pbc.26365

Cited by 50 publications

(53 citation statements)

References 32 publications

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“…Previous studies with smaller cohorts of patients have also documented frequent potential actionability, with over 90% of patients having at least one potentially actionable alteration [16, 45]. In contrast, other researchers found substantially lower percentages of alterations and potentially actionable alterations [51–54], likely due to smaller panel sizes and interrogation of hot-spot regions, rather than the entire exon of the gene being interrogated. For instance, one large study with 2000 patients found that only 39% had at least one potentially actionable mutation.…”

Section: Discussionmentioning

confidence: 99%

Next-Generation Sequencing in the Clinical Setting Clarifies Patient Characteristics and Potential Actionability

Bieg-Bourne

Millis²,

Piccioni

et al. 2017

Cancer Research

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Enhancements in clinical-grade next-generation sequencing (NGS) have fueled the advancement of precision medicine in the clinical oncology field. Here we survey the molecular profiles of 1,113 patients with diverse malignancies who successfully underwent clinical-grade NGS (236 to 404 genes) in an academic tertiary cancer center. Among the individual tumors examined, the majority showed at least one detectable alteration (97.2%). Amongst 2,045 molecular aberrations was involvement of 302 distinct genes. The most commonly altered genes were TP53 (47.0%), CDKN2A (18.0%), TERT (17.0%), and KRAS (16.0%), and the majority of patients had tumors that harbored multiple alterations. Tumors displayed a median of four alterations (range, 0–29). Most individuals had at least one potentially actionable alteration (94.7%), with the median number of potentially actionable alterations per patient being 2 (range, 0–13). A total of 94.2% patients exhibited a unique molecular profile, with either genes altered or loci within the gene(s) altered being distinct. Approximately 13% of patients displayed a genomic profile identical to at least one other patient; although genes altered were the same, the affected loci may have differed. Overall, our results underscore the complex heterogeneity of malignancies and argue that customized combination therapies will be essential to optimize cancer treatment regimens.

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Section: Discussionmentioning

confidence: 99%

Next-Generation Sequencing in the Clinical Setting Clarifies Patient Characteristics and Potential Actionability

Bieg-Bourne

Millis²,

Piccioni

et al. 2017

Cancer Research

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“…Thus, ALK and BRAF testing in selected tumours at relapse/progression is a standard of care in most pediatric oncology centres. However, consecutive single-marker testing is not compatible with clinical practice because of limited amount of tumour available (mostly diagnostic tru-cut), the intrinsic delays in each analysis and the overall cost [17]. The rapid development of high-throughput technologies and computational frameworks enables the examination of biological systems in unprecedented detail.…”

Section: Discussionmentioning

confidence: 99%

“…The need to explore the usefulness of drugs developed for adult patients arose among pediatric oncologists. The limited number of clinical trials available in children, as well as the lower biological knowledge of pediatric tumors led to the development of important precision medicine projects around the world [11][12][13][14][15][16][17]. In addition, the urgency to transfer biological information to patients in relapse/progression forced to start independent projects.…”

Section: Introductionmentioning

confidence: 99%

Precision medicine in relapsed or refractory pediatric solid tumors: a collaborative Spanish initiative

Gargallo¹,

Mora²,

Berlanga

et al. 2019

transl med commun

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Background: Understanding pediatric cancer biology is a huge challenge in continuous development that is currently being implemented into the clinical practice thanks to the new high throughput technologies integrated by personalized medicine. We present the results of the Precision Medicine program for children and adolescents with solid tumors in relapse/progression carried out in University La Fe Hospital (Valencia) from 2014. This is the first Spanish experience in precision medicine published in pediatric oncology. Methods: Study enrollment was offered to all patients having a refractory or relapsed solid tumor and an available biopsy treated in La Fe Hospital (Valencia, Spain) or in other Spanish pediatric oncologic center. Eighty four patients were finally studied. The commercial Human Comprehensive Cancer GeneReadDNAseq Targeted genes Panel (Qiagen©) was sequenced in fresh/frozen samples. Variants considered pathogenic or likely pathogenic were classified using the algorithm published by Parsons et al. based on perceived clinical utility. Results: Thirteen of 84 patients (15%) received therapeutic recommendations due to an actionable variant detected and three patients received prognosis information based on sequencing results. Conclusions: Precision medicine projects based on targetable gene panel approximations can obtain translatable information to pediatric patients with reasonable efforts. This approach lowers economic expenses and reduces time of response with respect to whole exome sequencing. Since the translation to the clinical practice is the main objective of these projects, limiting the number of relatively well-known biological markers will allow us to transfer similar amount of information with less economic and human effort.

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“…These initiatives have demonstrated the feasibility of such strategies at a single site or across multiple sites. 17 , 18 , 19 , 20 , 21 , 22 They have reported many genomic biomarkers or oncogenic drivers that have been proven useful to tailored patient management.…”

Section: Introductionmentioning

confidence: 99%

Molecular Profiling of Hard-to-Treat Childhood and Adolescent Cancers

et al. 2019

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IMPORTANCE Little progress in pediatric cancer treatment has been noted in the past decade, urging the development of novel therapeutic strategies for adolescents and children with hard-totreat cancers. Use of comprehensive molecular profiling in the clinical management of children and adolescents with cancer appears a suitable approach to improve patient care and outcomes, particularly for hard-to-treat cases. OBJECTIVE To assess the feasibility of identifying potentially actionable mutations using nextgeneration sequencing-based assays in a clinically relevant time frame. DESIGN, SETTING, AND PARTICIPANTS This diagnostic study reports the results of the TRICEPS study, a prospective genome sequencing study conducted in Québec, Canada. Participants, aged 18 years or younger at diagnosis, with refractory or relapsed childhood and adolescent cancers were enrolled from April 2014 through January 2018. Whole-exome sequencing (WES) of matched tumor normal samples and RNA sequencing of tumor were performed to identify single-nucleotide variants, fusion transcripts, differential gene expression, and copy number alterations. Results reviewed by a team of experts were further annotated, synthesized into a report, and subsequently discussed in a multidisciplinary molecular tumor board. MAIN OUTCOMES AND MEASURES Molecular profiling of pediatric patients with hard-to-treat cancer, identification of actionable and targetable alteration needed for the management of these patients, and proposition of targeted and personalized novel therapeutic strategies. RESULTS A total of 84 patients with hard-to-treat cancers were included in the analysis. These patients had a mean (range) age of 10.1 (1-21) years and a similar proportion of male (45 [54%]) and female (39 [46%]). Sixty-two patients (74%) had suitable tissues for multimodal molecular profiling (WES and RNA sequencing). The process from DNA or RNA isolation to genomic sequencing and data analysis steps took a median (range) of 24 (4-41) days. Potentially actionable alterations were identified in 54 of 62 patients (87%). Actions were taken in 22 of 54 patients (41%), and 18 (33%) either were on a second or third line of treatment, were in remission, or had stable disease and thus no actions were taken. CONCLUSIONS AND RELEVANCE Incorporating genomic sequencing into the management of hard-to-treat childhood and adolescent cancers appeared feasible; molecular profiling may enable the identification of potentially actionable alterations with clinical implications for most patients, (continued) Key Points Question Can genome sequencing facilitate the molecular profiling of the patient's tumor to identify actionable and targetable alterations? Findings In this diagnostic study of 62 consecutive pediatric patients with hard-to-treat cancer who were enrolled in the TRICEPS study, incorporating multimodal genomic sequencing, including RNA sequencing, into the management of refractory or relapsed childhood and adolescent cancers identified potentially actionable alterations in 54 (87%)...

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Feasibility and clinical integration of molecular profiling for target identification in pediatric solid tumors

Abstract: Pediatric molecular profiling is feasible, with more than a third of patients being eligible to receive targeted therapy, yet only a small proportion were treated with these therapies. Analysis at diagnosis may be useful for children with very poor prognosis tumsors.

Cited by 50 publications

References 32 publications

Next-Generation Sequencing in the Clinical Setting Clarifies Patient Characteristics and Potential Actionability

Next-Generation Sequencing in the Clinical Setting Clarifies Patient Characteristics and Potential Actionability

Precision medicine in relapsed or refractory pediatric solid tumors: a collaborative Spanish initiative

Molecular Profiling of Hard-to-Treat Childhood and Adolescent Cancers

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