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  • 1
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    Online Resource
    Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer
    Springer Science and Business Media LLC ; 2022
    In:  Nature Medicine Vol. 28, No. 8 ( 2022-08), p. 1581-1589
    Details
    In: Nature Medicine, Springer Science and Business Media LLC, Vol. 28, No. 8 ( 2022-08), p. 1581-1589
    Type of Medium: Online Resource
    ISSN: 1078-8956 , 1546-170X
    URL: Article
    DOI: 10.1038/s41591-022-01856-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 2
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    Abstract 4268: Protein folding pathway modulation upon Hsp70 inhibition in cancer cells
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4268-4268
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 4268-4268
    Abstract: Cancer cells experience acute stress conditions such as low oxygen and energy, and exposure to toxic agents. To survive proliferate without accumulating toxic misfolded proteins, cancer cells constantly modulate protein homeostasis. Thus, it is not surprising that molecular chaperones, like Hsp70, as well as protein degradation pathways are upregulated in cancer cells compared to their normal counterparts. These data suggest that chaperones are potential targets for cancer therapy. We previously demonstrated the dependence of patient-driven rhabdomyosarcoma cell survival on cytoplasmic Hsp70 activity, thanks to the use of a specific Hsp70 inhibitor, MAL3-101. In particular, we discovered that MAL3-101-mediated Hsp70 inhibition activates the PERK arm of the unfolded protein response (UPR) that results in CHOP-dependent cell death (Sabinis et al., 2016). Moreover, by taking advantage of a MAL3-101-resistant cell line (RMS13-R), we recently determined which compensatory mechanism alters MAL3-101-driven cell death. We found that both endoplasmic reticulum-associated degradation (ERAD) and autophagy are upregulated in RMS13-R cells, underlying increased demand on two protein degradation pathways upon inhibition of Hsp70. However, only autophagy inhibition—but not inhibition of ERAD—re-sensitized RMS13-R cells to Hsp70 inhibition, suggesting that autophagy was the key compensatory mechanism for Hsp70 inhibition. Autophagy was further induced by MAL3-101 treatment in RMS13-R cells, as evidenced by an increase in the messages and proteins corresponding to key autophagy components as well as to the accumulation of autophagic-like structures detected by electron microscopy (Sannino et al., 2018). These data highlight a pro-survival role for autophagy induction upon exposure to an Hsp70 inhibitor in cancer, and provide a link between Hsp70, proteasomal degradation, UPR, and autophagy in rhabdomyosarcoma. We next asked if other cancer types might be sensitive to Hsp70 inhibition, and we investigated the potential benefit of combined treatment with autophagy and/or proteasome inhibitors together with MAL3-101. Specifically, we are investigating the effects of Hsp70 inhibition in breast cancer cells, a cancer type in which higher levels of Hsp70 correlate to increased metastasis and poor prognosis in patients. Our preliminary data suggest that HER2-expressing cells are less sensitive to MAL3-101-mediated Hsp70 inhibition and combinatory treatments including, MAL3-101 and autophagy inhibitors promoted HER2-breast cancer cell death. Further investigations will reveal the potential carcinogenic role of Hsp70 inhibitors in breast cancer treatment and highlight which pathways reduce proteotoxicity in different breast cancer subtypes. Citation Format: Sara Sannino, Christopher J. Guerriero, Amit J. Sabnis, Jeffrey J. Bridsky. Protein folding pathway modulation upon Hsp70 inhibition in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4268.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-4268
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 3
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    Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  JCO Precision Oncology , No. 6 ( 2022-11)
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 6 ( 2022-11)
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.22.00390
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 4
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    Clinical Targeted Next-Generation Panel Sequencing Reveals MYC Amplification Is a Poor Prognostic Factor in Osteosarcoma
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  JCO Precision Oncology , No. 7 ( 2023-03)
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 7 ( 2023-03)
    Abstract: Osteosarcoma risk stratification, on the basis of the presence of metastatic disease at diagnosis and histologic response to chemotherapy, has remained unchanged for four decades, does not include genomic features, and has not facilitated treatment advances. We report on the genomic features of advanced osteosarcoma and provide evidence that genomic alterations can be used for risk stratification. MATERIALS AND METHODS In a primary analytic patient cohort, 113 tumor and 69 normal samples from 92 patients with high-grade osteosarcoma were sequenced with OncoPanel, a targeted next-generation sequencing assay. In this primary cohort, we assessed the genomic landscape of advanced disease and evaluated the correlation between recurrent genomic events and outcome. We assessed whether prognostic associations identified in the primary cohort were maintained in a validation cohort of 86 patients with localized osteosarcoma tested with MSK-IMPACT. RESULTS In the primary cohort, 3-year overall survival (OS) was 65%. Metastatic disease, present in 33% of patients at diagnosis, was associated with poor OS ( P = .04). The most frequently altered genes in the primary cohort were TP 53, RB1, MYC, CCNE1, CCND3, CDKN2A/B, and ATRX. Mutational signature 3 was present in 28% of samples. MYC amplification was associated with a worse 3-year OS in both the primary cohort ( P = .015) and the validation cohort ( P = .012). CONCLUSION The most frequently occurring genomic events in advanced osteosarcoma were similar to those described in prior reports. MYC amplification, detected with clinical targeted next-generation sequencing panel tests, is associated with poorer outcomes in two independent cohorts.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.22.00334
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 5
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    Synthetic Essentiality of Metabolic Regulator PDHK1 in PTEN-Deficient Cells and Cancers
    Elsevier BV ; 2019
    In:  Cell Reports Vol. 28, No. 9 ( 2019-08), p. 2317-2330.e8
    Details
    In: Cell Reports, Elsevier BV, Vol. 28, No. 9 ( 2019-08), p. 2317-2330.e8
    Type of Medium: Online Resource
    ISSN: 2211-1247
    URL: Article
    DOI: 10.1016/j.celrep.2019.07.063
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2019
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  • 6
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    Combined chemical–genetic approach identifies cytosolic HSP70 dependence in rhabdomyosarcoma
    Proceedings of the National Academy of Sciences ; 2016
    In:  Proceedings of the National Academy of Sciences Vol. 113, No. 32 ( 2016-08-09), p. 9015-9020
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 113, No. 32 ( 2016-08-09), p. 9015-9020
    Abstract: Cytosolic and organelle-based heat-shock protein (HSP) chaperones ensure proper folding and function of nascent and injured polypeptides to support cell growth. Under conditions of cellular stress, including oncogenic transformation, proteostasis components maintain homeostasis and prevent apoptosis. Although this cancer-relevant function has provided a rationale for therapeutically targeting proteostasis regulators (e.g., HSP90), cancer-subtype dependencies upon particular proteostasis components are relatively undefined. Here, we show that human rhabdomyosarcoma (RMS) cells, but not several other cancer cell types, depend upon heat-shock protein 70 kDA (HSP70) for survival. HSP70-targeted therapy (but not chemotherapeutic agents) promoted apoptosis in RMS cells by triggering an unfolded protein response (UPR) that induced PRKR-like endoplasmic reticulum kinase (PERK)–eukaryotic translation initiation factor α (eIF2α)–CEBP homologous protein (CHOP) signaling and CHOP-mediated cell death. Intriguingly, inhibition of only cytosolic HSP70 induced the UPR, suggesting that the essential activity of HSP70 in RMS cells lies at the endoplasmic reticulum–cytosol interface. We also found that increased CHOP mRNA in clinical specimens was a biomarker for poor outcomes in chemotherapy-treated RMS patients. The data suggest that, like human epidermal growth factor receptor 2 ( HER2 ) amplification in breast cancer, increased CHOP in RMS is a biomarker of decreased response to chemotherapy but enhanced response to targeted therapy. Our findings identify the cytosolic HSP70–UPR axis as an unexpected regulator of RMS pathogenesis, revealing HSP70-targeted therapy as a promising strategy to engage CHOP-mediated apoptosis and improve RMS treatment. Our study highlights the utility of dissecting cancer subtype-specific dependencies on proteostasis networks to uncover unanticipated cancer vulnerabilities.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.1603883113
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2016
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    SSG: 11
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  • 7
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    Abstract A06: The added value of examining germline variants in a precision cancer therapy study
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 14_Supplement ( 2020-07-15), p. A06-A06
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 14_Supplement ( 2020-07-15), p. A06-A06
    Abstract: Introduction: Tumor profiling is becoming a more routine part of clinical care. Many academic centers and commercial entities offer tumor sequencing of cancer-related genes without matched germline profiling. We hypothesize that tumor-only sequencing may limit full clinical interpretation and have decreased sensitivity to identify significant germline variants. Methods: The Genomic Assessment Improves Novel Therapy (GAIN) Consortium is a clinical cancer genomics study for patients with high-risk solid malignancies. Patients in this study were selected for subanalysis if panel sequencing of 447 genes was performed on a tumor and interpreted by an expert panel prior to the availability of matched germline sequencing. Interpretation of tumor sequencing included both therapeutic recommendations and a curation of cancer-related variants of potential clinical significance if present in the germline. Germline sequencing was separately performed targeting 147 genes (a subset of the somatic panel) and analyzed with a germline-specific pipeline to identify and filter variants. We examined clinical recommendations in the somatic reports that were based on single-nucleotide variants identified from the 147 overlapping genes. We compared these interpretations with results from the matched germline data. Results: We identified 159 participants with somatic and germline sequencing reports meeting the eligibility criteria. Germline sequencing identified 38 pathogenic or likely pathogenic (P/LP) germline variants in 35 of 159 patients (22%). Of those 35 patients, 17 (49%) had a P/LP variant in an autosomal dominant cancer predisposition gene, 19 (54%) in an autosomal recessive gene, and 1 (2.9%) in a noncancer gene. Of the 38 total variants, 21 (55%) were identified by the analytic pipeline used for somatic sequencing and noted as potential germline variants in the somatic reports. Forty treatment recommendations were made from the somatic data within the overlapping genes. Ten (25%) treatment recommendations were based on variants that were later determined to be germline. These included variants in TP53, SDHA, SMARCA4, TSC2, FAM175A, CHEK2, and AKT1, many of which were noted in the somatic reports to be variants of uncertain significance or possibly germline. Conclusions: In this study, we found that clinically actionable germline variants were under-reported when relying on analytical pipelines and clinical interpretations developed for the analysis of tumor samples. In the absence of germline sequencing, we also found that cancer treatment recommendations can be made based on mutations identified from tumor sequencing that are germline variants. In many cases, these recommendations remain appropriate (e.g., PARP inhibitors for BRCA1/2) while in other cases germline data facilitated a more nuanced interpretation of actionability. These findings support the use of germline genetic testing and paired tumor-germline analysis in precision cancer medicine studies. Citation Format: Jaclyn Schienda, Catherine M. Clinton, Laura B. Corson, Alma Imamovic-Tuco, Navin Pinto, Luke Maese, Theodore W. Laetsch, AeRang Kim, Susan I. Vear, Margaret E. Macy, Mark A. Applebaum, Rochelle Bagatell, Amit J. Sabnis, Daniel A. Weiser, Julia L. Glade-Bender, Samuel L. Volchenboum, Wenjun Kang, Danielle Manning, Jonathan Nowak, Joshua Schiffman, Neal I. Lindeman, Alanna J. Church, Katherine A. Janeway, Brian D. Crompton, Junne Kamihara. The added value of examining germline variants in a precision cancer therapy study [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A06.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PEDCA19-A06
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    Abstract B13: Leveraging cloud-based computational resources for gene fusion discovery with potential clinical implications for pediatric solid tumor patients
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 14_Supplement ( 2020-07-15), p. B13-B13
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 14_Supplement ( 2020-07-15), p. B13-B13
    Abstract: Introduction: Gene fusions are important oncogenic drivers with significant clinical impact in some cancer types. This is particularly true in pediatric cancers that often have low mutational burden and lack other diagnostic markers and therapeutic targets. Many gene fusions are rare or private to the individual patient and can be difficult to detect with methods optimized for common fusions. Unbiased sequencing methods and expansive computational resources are needed for expanding our ability to characterize fusions. Building a comprehensive catalog of oncogenic gene fusions will improve our understanding of their diversity and fully harness their potential for clinical impact. Methods: Patients are eligible for the GAIN/iCat2 study if they have been diagnosed with high-risk or recurrent/refractory extracranial solid tumor at age 30 or less and have a sample available for sequencing. Enrolled patients with an unclear diagnosis after standard clinical testing are nominated for transcriptome sequencing by the study investigators. We developed a computational pipeline in Google Cloud for gene fusion discovery utilizing paired end Illumina RNA-Seq data, multiple fusion callers, and a custom algorithm for integrative data analysis. The multicaller fusion detection approach enables us to address the high false-positive rate typical for gene fusion calling in transcriptomic data while improving the sensitivity to detect the more challenging fusions. After filtering, the fusions are annotated using the databases of known fusions and cancer genes. The predicted fusion transcripts are inspected visually, and the fusions are selected based on relevance to diagnostic classification or therapy to be validated by an orthogonal method. Results: 41 tumor samples were sequenced and analyzed for gene fusions. A total of 203 candidate fusions were detected by two or more fusion callers. Based on functional annotations and potential impact on diagnosis or therapeutic approaches, 12 fusion transcripts of interest were identified, 10 of which were validated by either pre-enrollment testing or an orthogonal method. Of 16 mesenchymal cases, 6 validated fusions had diagnostic relevance and 3 validated fusions had therapeutic implications (ERC1-BRAF, RBPMS-NTRK2, and VCAN-IL23R). Two patients responded to matched targeted therapy. In one case, diagnostic classification was revised. Conclusions: Whole-transcriptome sequencing in this selected patient population identified some fusion transcripts with clinical relevance. Determining the biologic significance of previously unreported fusions will require orthogonal sequencing such as whole genome, functional studies, and analysis of larger patient populations. Improved accuracy and scalability of methods for large-scale gene fusion analysis in the growing public datasets are likely to expand the landscape of gene fusions in cancer. Citation Format: Alma Imamovic, Alanna J. Church, Laura B. Corson, Deirdre Reidy, Navin Pinto, Luke Maese, Theodore W. Laetsch, AeRang Kim, Susan I. Vear, Margaret E. Macy, Mark A. Applebaum, Rochelle Bagatell, Amit J. Sabnis, Daniel A. Weiser, Julia L. Glade-Bender, Gianna R. Strand, Lobin A. Lee, R. Seth Pinches, Catherine M. Clinton, Brian D. Crompton, Neal I. Lindeman, Steven G. DuBois, Katherine A. Janeway, Eliezer M. Van Allen. Leveraging cloud-based computational resources for gene fusion discovery with potential clinical implications for pediatric solid tumor patients [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B13.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PEDCA19-B13
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 9
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    Abstract A59: Sequencing identifies diagnostically relevant alterations in pediatric solid tumor patients
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 14_Supplement ( 2020-07-15), p. A59-A59
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 14_Supplement ( 2020-07-15), p. A59-A59
    Abstract: Introduction: Molecular techniques have been incorporated into the diagnostic algorithms for many specific tumors, but the diagnostic role of next-generation sequencing has not been described at a population level. We report diagnostically relevant alterations identified by large-scale sequencing in a prospective cohort of pediatric solid tumors. Methods and Objectives: Patients are eligible for the GAIN / iCat2 study if they have a high-risk, recurrent, or refractory extracranial solid tumor diagnosed at age 30 or less and have an adequate sample for sequencing available. After informed consent, tumor was sequenced using a next-generation sequencing assay that evaluates 447 genes and includes data about sequence variants, copy number alterations, and, in selected genes, translocations. Some cases received additional sequencing via RNASeq or targeted RNA sequencing for further evaluation of fusions. Diagnostic relevance was determined according to AMP/ASCO/CAP standards and guidelines for the reporting of sequence variants in cancer. Results: 349 patients were enrolled as of December 31, 2018, and had tumor tissue successfully sequenced. These patients represent 60 unique diagnoses according to the WHO ICD-O classification. The most common single diagnoses were osteosarcoma (n=64), Ewing sarcoma (n=44), and alveolar rhabdomyosarcoma (n=32). For 349 patients, 184 (53%) had one or more genetic alterations that were diagnostically relevant, of which 159 (86%) were structural variants, 16 (8%) were sequence variants, and 9 (5%) were copy number variations. Alterations of high diagnostic relevance include CIC-DUX4 fusions in sarcoma (n=8), TP53 intron 1 rearrangements in osteosarcoma (n=26), DICER1 sequence variants in various tumors (n=7), and BCOR internal tandem duplications in clear-cell sarcoma of kidney and primitive myxoid mesenchymal tumor of infancy (n=3). Conclusions: Diagnostically relevant alterations were identified in over half of pediatric solid tumor patients evaluated. Gene fusions are particularly prevalent. These results support a role for sequencing that includes robust fusion assessment to inform diagnosis in patients with pediatric solid tumors. Citation Format: Alanna J. Church, Laura B. Corson, Alma Imamovic-Tuco, Gianna R. Strand, Dierdre Reidy, Duong Doan, Robert S. Pinches, Mark A. Applebaum, Rochelle Bagatell, Brian D. Crompton, Steven G. DuBois, Julia L. Glade Bender, Theodore W. Laetsch, Lobin A. Lee, Neal I. Lindeman, Marian H. Harris, Margaret E. Macy, Luke Maese, Navin Pinto, Amit J. Sabnis, Eliezer M. Van Allen, Susan I. Vear, Daniel A. Weiser, Catherine M. Clinton, Katherine A. Janeway. Sequencing identifies diagnostically relevant alterations in pediatric solid tumor patients [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr A59.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.PEDCA19-A59
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 10
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    Clinical impact of molecular tumor profiling in pediatric, adolescent, and young adult patients with extra-cranial solid malignancies: An interim report from the GAIN/iCat2 study.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 10005-10005
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 10005-10005
    Abstract: 10005 Background: Next generation sequencing (NGS) assays are now a standard part of clinical care for many adult solid cancers. The significance of molecular tumor profiling for the care of children with cancer is not well understood.We aimed to determine the clinical impact of identifying genomic alterations by NGS for young patients with relapsed, refractory, or high-risk extracranial solid tumors. Methods: We report on the first 389 participants in a prospective cohort study enrolling patients at 12 institutions with extracranial solid tumors diagnosed at age 30 years or less. Targeted DNA NGS was performed on one or more tumor samples from each patient. Selected patients also had tumors subjected to RNA sequencing. Test results were returned to the treating oncologist and follow-up treatment and response data were collected.Identified genomic alterations were classified according to evidence of impact on diagnosis, prognosis or response to targeted therapy matched to an identified alteration (matched targeted therapy, MTT) using established guidelines. Response to MTT was determined and reported as a response if either there was radiographic response according to RECIST or the duration of therapy was 〉 4 months. Results: Molecular tumor profiling (MTP) was successful in 345 (89%) patients (mean age 11 years at diagnosis; 65% with sarcoma). Two hundred and ninety-nine patients with MTP results (87%) had one or more alterations of clinical significance. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 208 (60%), 51 (15%) and 240 (70%) patients, respectively. Of the 240 patients with tumors harboring genomic alterations designated as having therapeutic impact, 23 (11%) had Tier 1 molecular findings. 205 patients were eligible to receive MTT based on having a molecular alteration with therapeutic significance and sufficient follow-up; 31 of these patients (15%) received MTT. Seven patients (23%) receiving MTT responded, 6 of these were kinase fusions. All of the responders received targeted therapy matched to a fusion and 78% of diagnostically significant alterations were fusions. Conclusions: Molecular tumor profiling has a significant impact on diagnosis and treatment recommendations for young patients with extracranial solid tumors. These results emphasize the importance of fusion detection for patients with sarcomas and rare tumors. Clinical trial information: NCT02520713.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.10005
    RVK:
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    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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