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Purpose: Molecular tumor profiling is becoming a routine part of clinical cancer care, typically involving tumor-only panel testing without matched germline. We hypothesized that integrated germline sequencing could improve clinical interpretation and enhance the identification of germline variants with significant hereditary risks., Materials and Methods: Tumors from pediatric patients with high-risk, extracranial solid malignancies were sequenced with a targeted panel of cancer-associated genes. Later, germline DNA was analyzed for a subset of these genes. We performed a post hoc analysis to identify how an integrated analysis of tumor and germline data would improve clinical interpretation., Results: One hundred sixty participants with both tumor-only and germline sequencing reports were eligible for this analysis. Germline sequencing identified 38 pathogenic or likely pathogenic variants among 35 (22%) patients. Twenty-five (66%) of these were included in the tumor sequencing report. The remaining germline pathogenic or likely pathogenic variants were single-nucleotide variants filtered out of tumor-only analysis because of population frequency or copy-number variation masked by additional copy-number changes in the tumor. In tumor-only sequencing, 308 of 434 (71%) single-nucleotide variants reported were present in the germline, including 31% with suggested clinical utility. Finally, we provide further evidence that the variant allele fraction from tumor-only sequencing is insufficient to differentiate somatic from germline events., Conclusion: A paired approach to analyzing tumor and germline sequencing data would be expected to improve the efficiency and accuracy of distinguishing somatic mutations and germline variants, thereby facilitating the process of variant curation and therapeutic interpretation for somatic reports, as well as the identification of variants associated with germline cancer predisposition., Competing Interests: Alanna J. Church Honoraria: The Jackson Laboratory Consulting or Advisory Role: AlphaSights, The Jackson Laboratory, Bayer Travel, Accommodations, Expenses: Bayer Laura B. Corson Employment: Sema4 Stock and Other Ownership Interests: Alnylam, Inovio Pharmaceuticals, Agios Consulting or Advisory Role: Biomatics Patents, Royalties, Other Intellectual Property: Patent from work done at H3 Biomedicine before 2016 Brennan Decker Employment: Foundation Medicine Stock and Other Ownership Interests: Avidea Technologies, Roche Consulting or Advisory Role: Foundation Medicine, Avidea Technologies Catherine M. Clinton Employment: Helix OpCo LLC Mark A. Applebaum Consulting or Advisory Role: Fennec Pharma Rochelle Bagatell Uncompensated Relationships: Ymabs Therapeutics Inc Steven G. DuBois Consulting or Advisory Role: Bayer, Amgen Research Funding: Merck (Inst), Roche/Genentech (Inst), Lilly (Inst), Curis (Inst), Loxo (Inst), BMS (Inst), Eisai (Inst), Pfizer (Inst), Turning Point Therapeutics (Inst), Bayer (Inst), Salarius Pharmaceuticals (Inst) Travel, Accommodations, Expenses: Roche/Genentech, Salarius Pharmaceuticals Uncompensated Relationships: Ymabs Therapeutics Inc Julia L. Glade-Bender Research Funding: Eisai (Inst), Lilly (Inst), Loxo (Inst), Roche/Genentech (Inst), Bayer (Inst) Patents, Royalties, Other Intellectual Property: Patent on a T lympboblastic lymphoma cell line, CUTLL1 Travel, Accommodations, Expenses: Amgen (Inst) Uncompensated Relationships: SpringWorks Therapeutics, Bristol Myers Squibb, Merck, Eisai Open Payments Link: https://openpaymentsdata.cms.gov/physician/708514 AeRang Kim Research Funding: Esai (Inst); AstraZeneca (Inst); Oncternal (Inst); Ascentage (Inst); BioAlta (Inst). Theodore W. Laetsch Consulting or Advisory Role: Novartis, Bayer, Cellectis, Aptitude Health, Clinical Education Alliance, Deciphera, Jumo Health, Massive Bio, Med Learning Group, Medscape, Physicans' Education Resource, Y-mAbs Therapeutics Research Funding: Pfizer (Inst), Novartis (Inst), Bayer (Inst), AbbVie (Inst), Amgen (Inst), Atara Biotherapeutics (Inst), Bristol Myers Squibb (Inst), Lilly (Inst), Epizyme (Inst), GlaxoSmithKline (Inst), Janssen (Inst), Jubilant Pharmaceuticals (Inst), Novella Clinical (Inst), Servier (Inst), Foundation Medicine (Inst), Merck Sharp & Dohme (Inst) Margaret E. Macy Stock and Other Ownership Interests: Johnson & Johnson, GE Healthcare, Varian Medical Systems Consulting or Advisory Role: Ymabs Therapeutics Inc Research Funding: Bayer (Inst), Ignyta (Inst), Roche (Inst), Lilly (Inst), Merck (Inst), Oncternal Therapeutics Inc (Inst), AbbVie (Inst), Jubilant DraxImage (Inst), Actuate Therapeutics (Inst) Patents, Royalties, Other Intellectual Property: Patent for non-invasive methods of leukemia cell detection with MRI/MRS—Patent No. 8894975 Luke Maese Honoraria: Jazz Pharmaceuticals Consulting or Advisory Role: Jazz Pharmaceuticals Amit J. Sabnis Consulting or Advisory Role: Cardinal Health Joshua D. Schiffman Employment: PEEL Therapeutics Leadership: PEEL Therapeutics Stock and Other Ownership Interests: ItRunsInMyFamily.com, PEEL Therapeutics Honoraria: Affymetrix Consulting or Advisory Role: N-of-One, Fabric Genomics Samuel L. Volchenboum Stock and Other Ownership Interests: Litmus Health Consulting or Advisory Role: Accordant Travel, Accommodations, Expenses: Sanford Health Daniel A. Weiser Consulting or Advisory Role: Illumina Radiopharmaceuticals Jonathan A. Nowak Research Funding: NanoString Technologies, Illumina Katherine A. Janeway Honoraria: Foundation Medicine, Takeda Consulting or Advisory Role: Bayer, Ipsen Travel, Accommodations, Expenses: Bayer Brian D. Crompton Employment: Acceleron Pharma (I) Stock and Other Ownership Interests: Acceleron Pharma (I) Research Funding: Gradalis Junne Kamihara Stock and Other Ownership Interests: PanTher Therapeutics (I), ROME Therapeutics (I), TellBio (I) Honoraria: Pfizer (I), NanoString Technologies (I), Foundation Medicine (I), Ikena Oncology (I) Consulting or Advisory Role: ROME Therapeutics (I), Third Rock Ventures (I), Tekla Capital Management (I) Research Funding: PureTech (I), Ribon Therapeutics (I), ACD Biotechne (I) Patents, Royalties, Other Intellectual Property: Patent on drug delivery device licensed to PanTher Therapeutics (I), Patents on Repeat RNA biomarkers and therapeutics licensed to Rome Therapeutics (I), Patents on Circulating Tumor Cell Biomarkers Licensed to TellBio Inc (I) No other potential conflicts of interest were reported. Alanna J. Church Honoraria: The Jackson Laboratory Consulting or Advisory Role: AlphaSights, The Jackson Laboratory, Bayer Travel, Accommodations, Expenses: Bayer Laura B. Corson Employment: Sema4 Stock and Other Ownership Interests: Alnylam, Inovio Pharmaceuticals, Agios Consulting or Advisory Role: Biomatics Patents, Royalties, Other Intellectual Property: Patent from work done at H3 Biomedicine before 2016 Brennan Decker Employment: Foundation Medicine Stock and Other Ownership Interests: Avidea Technologies, Roche Consulting or Advisory Role: Foundation Medicine, Avidea Technologies Catherine M. Clinton Employment: Helix OpCo LLC Mark A. Applebaum Consulting or Advisory Role: Fennec Pharma Rochelle Bagatell Uncompensated Relationships: Ymabs Therapeutics Inc Steven G. DuBois Consulting or Advisory Role: Bayer, Amgen Research Funding: Merck (Inst), Roche/Genentech (Inst), Lilly (Inst), Curis (Inst), Loxo (Inst), BMS (Inst), Eisai (Inst), Pfizer (Inst), Turning Point Therapeutics (Inst), Bayer (Inst), Salarius Pharmaceuticals (Inst) Travel, Accommodations, Expenses: Roche/Genentech, Salarius Pharmaceuticals Uncompensated Relationships: Ymabs Therapeutics Inc Julia L. Glade-Bender Research Funding: Eisai (Inst), Lilly (Inst), Loxo (Inst), Roche/Genentech (Inst), Bayer (Inst) Patents, Royalties, Other Intellectual Property: Patent on a T lympboblastic lymphoma cell line, CUTLL1 Travel, Accommodations, Expenses: Amgen (Inst) Uncompensated Relationships: SpringWorks Therapeutics, Bristol Myers Squibb, Merck, Eisai Open Payments Link: https://openpaymentsdata.cms.gov/physician/708514 AeRang Kim Research Funding: Esai (Inst); AstraZeneca (Inst); Oncternal (Inst); Ascentage (Inst); BioAlta (Inst). Theodore W. Laetsch Consulting or Advisory Role: Novartis, Bayer, Cellectis, Aptitude Health, Clinical Education Alliance, Deciphera, Jumo Health, Massive Bio, Med Learning Group, Medscape, Physicans' Education Resource, Y-mAbs Therapeutics Research Funding: Pfizer (Inst), Novartis (Inst), Bayer (Inst), AbbVie (Inst), Amgen (Inst), Atara Biotherapeutics (Inst), Bristol Myers Squibb (Inst), Lilly (Inst), Epizyme (Inst), GlaxoSmithKline (Inst), Janssen (Inst), Jubilant Pharmaceuticals (Inst), Novella Clinical (Inst), Servier (Inst), Foundation Medicine (Inst), Merck Sharp & Dohme (Inst) Margaret E. Macy Stock and Other Ownership Interests: Johnson & Johnson, GE Healthcare, Varian Medical Systems Consulting or Advisory Role: Ymabs Therapeutics Inc Research Funding: Bayer (Inst), Ignyta (Inst), Roche (Inst), Lilly (Inst), Merck (Inst), Oncternal Therapeutics Inc (Inst), AbbVie (Inst), Jubilant DraxImage (Inst), Actuate Therapeutics (Inst) Patents, Royalties, Other Intellectual Property: Patent for non-invasive methods of leukemia cell detection with MRI/MRS—Patent No. 8894975 Luke Maese Honoraria: Jazz Pharmaceuticals Consulting or Advisory Role: Jazz Pharmaceuticals Amit J. Sabnis Consulting or Advisory Role: Cardinal Health Joshua D. Schiffman Employment: PEEL Therapeutics Leadership: PEEL Therapeutics Stock and Other Ownership Interests: ItRunsInMyFamily.com, PEEL Therapeutics Honoraria: Affymetrix Consulting or Advisory Role: N-of-One, Fabric Genomics Samuel L. Volchenboum Stock and Other Ownership Interests: Litmus Health Consulting or Advisory Role: Accordant Travel, Accommodations, Expenses: Sanford Health Daniel A. Weiser Consulting or Advisory Role: Illumina Radiopharmaceuticals Jonathan A. Nowak Research Funding: NanoString Technologies, Illumina Katherine A. Janeway Honoraria: Foundation Medicine, Takeda Consulting or Advisory Role: Bayer, Ipsen Travel, Accommodations, Expenses: Bayer Brian D. Crompton Employment: Acceleron Pharma (I) Stock and Other Ownership Interests: Acceleron Pharma (I) Research Funding: Gradalis Junne Kamihara Stock and Other Ownership Interests: PanTher Therapeutics (I), ROME Therapeutics (I), TellBio (I) Honoraria: Pfizer (I), NanoString Technologies (I), Foundation Medicine (I), Ikena Oncology (I) Consulting or Advisory Role: ROME Therapeutics (I), Third Rock Ventures (I), Tekla Capital Management (I) Research Funding: PureTech (I), Ribon Therapeutics (I), ACD Biotechne (I) Patents, Royalties, Other Intellectual Property: Patent on drug delivery device licensed to PanTher Therapeutics (I), Patents on Repeat RNA biomarkers and therapeutics licensed to Rome Therapeutics (I), Patents on Circulating Tumor Cell Biomarkers Licensed to TellBio Inc (I) No other potential conflicts of interest were reported., (© 2021 by American Society of Clinical Oncology.)

Purpose: The complexity of results generated from whole-genome sequencing (WGS) and whole-exome sequencing (WES) adds challenges to obtaining informed consent in pediatric oncology. Little is known about knowledge of WGS and WES in this population, and no validated tools exist in pediatric oncology., Methods: We developed and psychometrically evaluated a novel WGS and WES knowledge questionnaire, the Precision in Pediatric Sequencing Knowledge Questionnaire (PIPseqKQ), to identify levels of understanding among parents and young adult cancer survivors (≥ 18 years old), off therapy for at least 1 year from a single-institution pediatric oncology outpatient clinic. Participants also completed health literacy and numeracy questionnaires. All participants provided written informed consent., Results: One hundred eleven participants were enrolled: 76 were parents, and 35 were young adults. Of the total cohort, 77 (69%) were female, 63 (57%) self-identified as white, and 74 (67%) self-identified as non-Hispanic. Sixty-six (59%) had less than a college degree. Adequate health literacy (n = 87; 80%) and numeracy (n = 89; 80%) were demonstrated. Internal consistency was high (Cronbach's α = .88), and test-retest reliability was greater than the 0.7 minimum requirement. Scores were highest for genetic concepts related to health and cancer and lowest for WGS and WES concepts. Health literacy and educational attainment were significantly associated with PIPseqKQ scores. Overall, participants felt the benefits of WGS and WES outweighed the potential risks., Conclusion: Parents and young adult cancer survivors have some genetics knowledge, but they lack knowledge about WGS and WES. The PIPseqKQ is a reliable tool that can identify deficits in knowledge, identify perceptions of risks and benefits of WGS and WES, and help clinicians tailor their consent discussions to best fit families. The PIPseqKQ also may inform the development of educational tools to better facilitate the informed consent process in pediatric oncology., Competing Interests: The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center. Jennifer A. ObergNo relationship to discloseJenny RuizNo relationship to discloseTrisha Ali-ShawNo relationship to discloseKathryn A. SchlechtwegNo relationship to discloseAngela RicciNo relationship to discloseAndrew L. KungConsulting or Advisory Role: Darwin Health, MI Bioresearch, Imago Bioscience Patents, Royalties, Other Intellectual Property: Royalty from licensing agreements with MI BioresearchWendy K. ChungConsulting or Advisory Role: Regeneron Genetics Center Research Funding: BiogenPaul S. AppelbaumNo relationship to discloseJulia L. Glade BenderResearch Funding: Bristol-Myers Squibb (Inst), Pfizer (Inst), Novartis (Inst), Ignyta (Inst), Amgen (Inst), Celgene (Inst), Eisai (Inst), Lilly (Inst), Merck (Inst) Travel, Accommodations, Expenses: Novartis, Amgen, MerckJennifer M. LevineNo relationship to disclose, (© 2018 by American Society of Clinical Oncology.)

Purpose: Pazopanib, an oral multikinase angiogenesis inhibitor, prolongs progression-free survival in adults with soft tissue sarcoma (STS). A phase I pharmacokinetic and pharmacodynamic study of two formulations of pazopanib was performed in children with STS or other refractory solid tumors., Patients and Methods: Pazopanib (tablet formulation) was administered once daily in 28-day cycles at four dose levels (275 to 600 mg/m(2)) using the rolling-six design. Dose determination for a powder suspension was initiated at 50% of the maximum-tolerated dose (MTD) for the intact tablet. Ten patients with STS underwent dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) scanning at baseline and 15 ± 2 days after initiation of pazopanib at the tablet MTD., Results: Fifty-three patients were enrolled; 51 were eligible (26 males; median age, 12.9 years; range, 3.8 to 23.9 years). Hematologic and nonhematologic toxicities were generally mild, with dose-limiting lipase, amylase, and ALT elevation, proteinuria, and hypertension. One patient with occult brain metastasis had grade 4 intracranial hemorrhage. The MTD was 450 mg/m(2) for tablet and 160 mg/m(2) for suspension. Steady-state trough concentrations were reached by day 15 and did not seem to be dose dependent. One patient each with hepatoblastoma or desmoplastic small round cell tumor achieved a partial response; eight patients had stable disease for ≥ six cycles, seven of whom had sarcoma. All patients with evaluable DCE-MRI (n = 8) experienced decreases in tumor blood volume and permeability (P < .01). Placental growth factor increased, whereas endoglin and soluble vascular endothelial growth factor receptor-2 decreased (P < .01; n = 41)., Conclusion: Pazopanib is well tolerated in children, with evidence of antiangiogenic effect and potential clinical benefit in pediatric sarcoma.

Purpose: We conducted a pediatric phase I trial of the vascular endothelial growth factor (VEGF)-neutralizing antibody bevacizumab (BV). Primary aims included estimating the maximum-tolerated dose (MTD) and determining the dose-limiting toxicities (DLTs), pharmacokinetics, and biologic effects of BV in children with cancer., Patients and Methods: BV (5, 10, 15 mg/kg) was administered intravenously every 2 weeks in 28-day courses to children with refractory solid tumors., Results: Twenty-one patients enrolled, 20 (median age, 13 years) were eligible, and 18 completed one course and were fully assessable for toxicity. A total of 67 courses were administered (median, three courses per patient; range, one to 16 courses). Treatment was well tolerated with no DLTs observed. Non-DLTs included infusional reaction, rash, mucositis, proteinuria, and lymphopenia. Increases in systolic and diastolic blood pressure not meeting Common Terminology Criteria for Adverse Events (CTCAEv3) pediatric-specific criteria for hypertension were observed. There was no hemorrhage or thrombosis. Growth perturbation was not detected in a limited sample over the first course. The serum exposure to BV as measured by area under the concentration-time curve (AUC) seemed to increase in proportion to dose. The median clearance of BV was 4.1 mL/d/kg (range, 3.1 to 15.5 mL/d/kg), and the median half-life was 11.8 days (range, 4.4 to 14.6 days). No objective responses were observed. Exploratory analyses on circulating endothelial mobilization and viability are consistent with the available adult data., Conclusion: BV is well tolerated in children. Phase II pediatric studies of BV in combination with chemotherapy in dosing schedules similar to adults are planned.