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Ref Type | Journal Article | ||||||||||||
PMID | (35739269) | ||||||||||||
Authors | Church AJ, Corson LB, Kao PC, Imamovic-Tuco A, Reidy D, Doan D, Kang W, Pinto N, Maese L, Laetsch TW, Kim A, Colace SI, Macy ME, Applebaum MA, Bagatell R, Sabnis AJ, Weiser DA, Glade-Bender JL, Homans AC, Hipps J, Harris H, Manning D, Al-Ibraheemi A, Li Y, Gupta H, Cherniack AD, Lo YC, Strand GR, Lee LA, Pinches RS, Lazo De La Vega L, Harden MV, Lennon NJ, Choi S, Comeau H, Harris MH, Forrest SJ, Clinton CM, Crompton BD, Kamihara J, MacConaill LE, Volchenboum SL, Lindeman NI, Van Allen E, DuBois SG, London WB, Janeway KA | ||||||||||||
Title | Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer. | ||||||||||||
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Abstract Text | To evaluate the clinical impact of molecular tumor profiling (MTP) with targeted sequencing panel tests, pediatric patients with extracranial solid tumors were enrolled in a prospective observational cohort study at 12 institutions. In the 345-patient analytical population, median age at diagnosis was 12 years (range 0-27.5); 298 patients (86%) had 1 or more alterations with potential for impact on care. Genomic alterations with diagnostic, prognostic or therapeutic significance were present in 61, 16 and 65% of patients, respectively. After return of the results, impact on care included 17 patients with a clarified diagnostic classification and 240 patients with an MTP result that could be used to select molecularly targeted therapy matched to identified alterations (MTT). Of the 29 patients who received MTT, 24% had an objective response or experienced durable clinical benefit; all but 1 of these patients received targeted therapy matched to a gene fusion. Of the diagnostic variants identified in 209 patients, 77% were gene fusions. MTP with targeted panel tests that includes fusion detection has a substantial clinical impact for young patients with solid tumors. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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AXL | R229C | missense | unknown | AXL R229C lies within fibronectin type-III domain 1 of the Axl protein (UniProt.org). R229C has been identified in sequencing studies (PMID: 35739269), but has not been biochemically characterized and therefore, its effect on Axl protein function is unknown (PubMed, Jun 2024). | |
MSH6 | A1320Sfs*5 | frameshift | unknown | MSH6 A1320Sfs*5 indicates a shift in the reading frame starting at amino acid 1320 and terminating 5 residues downstream causing a premature truncation of the 1360 amino acid Msh6 protein (UniProt.org). A1320Sfs*5 has been identified in the scientific literature (PMID: 35739269, PMID: 33393477, PMID: 18809606), but has not been biochemically characterized and therefore, its effect on Msh6 protein function is unknown (PubMed, May 2024). | |
MSH6 | Y1256* | nonsense | unknown | MSH6 Y1256* results in a premature truncation of the Msh6 protein at amino acid 1256 of 1360 (UniProt.org). Y1256* has been identified in the scientific literature (PMID: 35739269, PMID: 33393477, PMID: 26552419), but has not been biochemically characterized and therefore, its effect on Msh6 protein function is unknown (PubMed, May 2024). |
Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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MSH6 F1088Lfs*5 MSH6 Y1256* MSH6 A1320Sfs*5 | colorectal carcinoma | predicted - sensitive | Nivolumab | Case Reports/Case Series | Actionable | In a clinical case study, Opdivo (nivolumab) treatment resulted in stable disease lasting four months in a colorectal carcinoma patient harboring MSH6 F1088Lfs*5, Y1256*, and A1320Sfs*5 (PMID: 35739269). | 35739269 |