Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer

Church, Alanna J.; Corson, Laura; Kao, Pei‐Chi; Imamovic-Tuco, Alma; Reidy, Deirdre; Doan, Duong; Kang, Wenjun; Pinto, Navin; Maese, Luke; Laetsch, Theodore W.; Kim, AeRang; Colace, Susan I.; Macy, Margaret E.; Applebaum, Mark A.; Bagatell, Rochelle; Sabnis, Amit J.; Weiser, Daniel A.; Bender, Julia Glade; Homans, Alan C.; Hipps, John; Harris, Haley; Manning, Danielle K.; Al‐Ibraheemi, Alyaa; Li, Yvonne; Gupta, Hersh; Cherniack, Andrew D.; Lo, Ying‐Chun; Strand, Gianna R.; Lee, Lobin A.; Pinches, R. Seth; Vega, Lorena Lazo de la; Harden, Maegan; Lennon, Niall J.; Choi, Seong Ho; Comeau, Hannah; Harris, Marian H.; Forrest, Suzanne J.; Clinton, Catherine; Crompton, Brian D.; Kamihara, Junne; MacConaill, Laura E.; Volchenboum, Samuel L.; Lindeman, Neal I.; Allen, Eliezer M. Van; DuBois, Steven G.; London, Wendy B.; Janeway, Katherine A.

doi:10.1038/s41591-022-01856-6

Cited by 22 publications

(19 citation statements)

References 39 publications

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“…The GAIN Consortium study (ClinicalTrials.gov identifier: NCT02520713 ) is a prospective cohort study enrolling patients age ≤ 30 years with relapsed/refractory and high-risk pediatric extracranial solid tumors at 12 institutions to determine the clinical impact of molecular tumor profiling. 21 The Dana-Farber/Boston Children's Profile Cancer Research Study, offered to all pediatric oncology patients with a variety of solid malignancies and lymphomas since 2013, facilitates research on cancer biology and informs ongoing and potential trials assessing targeted therapies. Patients enrolled on either study were included in this analysis if they had at least one successful targeted DNA sequencing result and a CNS or extracranial solid malignancy.…”

Section: Methodsmentioning

confidence: 99%

Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer

Vega

Comeau

Sallan

et al. 2022

JCO Precision Oncology

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PURPOSE Multiple FGFR inhibitors are currently in clinical trials enrolling adults with different solid tumors, while very few enroll pediatric patients. We determined the types and frequency of FGFR alterations ( FGFR1-4) in pediatric cancers to inform future clinical trial design. METHODS Tumors with FGFR alterations were identified from two large cohorts of pediatric solid tumors subjected to targeted DNA sequencing: The Dana-Farber/Boston Children's Profile Study (n = 888) and the multi-institution GAIN/iCAT2 (Genomic Assessment Improves Novel Therapy) Study (n = 571). Data from the combined patient population of 1,395 cases (64 patients were enrolled in both studies) were reviewed and cases in which an FGFR alteration was identified by OncoPanel sequencing were further assessed. RESULTS We identified 41 patients with tumors harboring an oncogenic FGFR alteration. Median age at diagnosis was 8 years (range, 6 months-26 years). Diagnoses included 11 rhabdomyosarcomas, nine low-grade gliomas, and 17 other tumor types. Alterations included gain-of-function sequence variants (n = 19), amplifications (n = 10), oncogenic fusions ( FGFR3:: TACC3 [n = 3], FGFR1:: TACC1 [n = 1], FGFR1:: EBF2 [n = 1], FGFR1:: CLIP2 [n = 1], and FGFR2:: CTNNA3 [n = 1]), pathogenic-leaning variants of uncertain significance (n = 4), and amplification in combination with a pathogenic-leaning variant of uncertain significance (n = 1). Two novel FGFR1 fusions in two different patients were identified in this cohort, one of whom showed a response to an FGFR inhibitor. CONCLUSION In summary, activating FGFR alterations were found in approximately 3% (41/1,395) of pediatric solid tumors, identifying a population of children with cancer who may be eligible and good candidates for trials evaluating FGFR-targeted therapy. Importantly, the genomic and clinical data from this study can help inform drug development in accordance with the Research to Accelerate Cures and Equity for Children Act.

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Section: Methodsmentioning

confidence: 99%

Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer

Vega

Comeau

Sallan

et al. 2022

JCO Precision Oncology

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“…One case (Case 1,2) have been previously reported in the literature. 34,37,40 Representative haematoxylin and eosin-stained slides of whole tissue sections for each case were reviewed by three pathologists (E.B., A.A., and J.L.D.) to confirm the diagnoses.…”

Section: Methodsmentioning

confidence: 99%

Histologic characterization of paediatric mesenchymal neoplasms treated with kinase‐targeted therapy

et al. 2022

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Aims Recurrent alterations involving receptor tyrosine or cytoplasmic kinase genes have been described in soft‐tissue neoplasms such as infantile fibrosarcoma (IFS) and inflammatory myofibroblastic tumour (IMT). Recent trials and regulatory approvals for targeted inhibitors against the kinase domains of these oncoproteins have allowed for increased use of targeted therapies. We aimed to characterize the histologic features of paediatric mesenchymal neoplasms with kinase alterations treated with targeted inhibitors. Methods and results Eight patients with tyrosine kinase‐altered mesenchymal neoplasms with pre‐ and posttreatment samples were identified. Tumours occurred in five females and three males with a median age at presentation of 6.5 years. Tumour sites were bone/somatic soft‐tissue (n = 5) and viscera (n = 3). Pretreatment diagnoses were: IMT (n = 3), epithelioid inflammatory myofibroblastic sarcoma (n = 1), and descriptive diagnoses (n = 4) such as “kinase‐driven spindle cell tumor.” Fusions identified were ETV6::NTRK3 (n = 2), TPM3::NTRK1, SEPT7::BRAF, TFG::ROS1, KLC1::ALK, RANBP2::ALK, and MAP4::RAF1. Patients were treated with larotrectinib (n = 3), ALK or ALK/ROS1 inhibitors (n = 3), and MEK inhibitors (n = 2). Posttreatment tumours exhibited a striking decrease in cellularity (7/8) and the presence of collagenous stroma (7/8) with extensive glassy hyalinization (5/8). In two cases, abundant coarse or psammomatous calcifications were seen and in one case prominent perivascular hyalinization was noted. Residual viable tumour was seen in 3/8 cases (<5% in one case, and >75% in 2/8 cases). Conclusion Mesenchymal neoplasms with tyrosine kinase alterations treated with targeted inhibitors show a pathologic response, which includes decreased cellularity and stromal hyalinization. The presence of these features may be helpful in assessing tumour response after targeted therapy.

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“…The patient underwent gross total surgical resection of the CNS tumor. Targeted sequencing panel tests demonstrated the relapsed neuroblastoma was MYCN amplified with wild‐type ALK 9 . No other sites of disease were detected.…”

Section: Case Reportsmentioning

confidence: 99%

Multimodality treatment for recurrent neuroblastoma in the central nervous system

Desai

Elmuti

Cahaney

et al. 2023

Pediatric Blood & Cancer

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Survival for patients with recurrent central nervous system (CNS) neuroblastoma remains poor. A single‐institutional study demonstrated the potential of multimodality therapy, including compartmental intrathecal radioimmunotherapy (cRIT) with 131I‐3F8 or 131I‐8H9 to increase the survival of neuroblastoma patients with CNS relapse. However, not all patients are able to receive this therapy. We report three patients with CNS neuroblastoma who remain disease‐free 3–9 years after receiving multimodality treatment without cRIT. Additional studies to identify patients most likely to benefit from cRIT are warranted.

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Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer

Cited by 22 publications

References 39 publications

Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer

Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer

Histologic characterization of paediatric mesenchymal neoplasms treated with kinase‐targeted therapy

Multimodality treatment for recurrent neuroblastoma in the central nervous system

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