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Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer

Nature Medicine volume 28, pages 1581–1589 (2022)Cite this article

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Abstract

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.

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Fig. 1: Relationship between genes containing actionable variants and the drug class of the iCat recommendation.
Fig. 2: Summary infographic of the outcome for the 345 patients in the analytical cohort after return of genomic results with diagnostic or therapeutic significance.
Fig. 3: Swimmer plot of treatment response for 29 patients who received MTT.
Fig. 4

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Data availability

A Supplementary Data file contains all SNVs, CNVs and fusions identified and TMB and mismatch repair status determined by the DNA or RNA panel tests. The Supplementary Data file also includes clinical interpretation of variants determined to have prognostic or diagnostic significance and the associated AMP/CAP/ASCO tier. All iCat recommendations are provided in the Supplementary Data including the iCat tier at the time of the clinical interpretation report and at the time of re-tiering.

Code availability

There is no relevant code provided for this study.

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Acknowledgements

Funding for this study was provided by the Precision For Kids Pan Mass Challenge Team, the 4C’s Fund, Lamb Family Fund, C&S Wholesale Grocers and C&S Charities and Alexandra Simpson Pediatric Research Fund. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript. We also thank the study participants and their families and the research coordinators at each of the study sites.

Author information

Author notes

  1. Laura B. Corson

    Present address: Sema4, Stamford, CT, USA

  2. Deirdre Reidy

    Present address: University of Connecticut School of Medicine, Farmington, CT, USA

  3. Duong Doan

    Present address: University of Massachusetts Medical School, Worcester, MA, USA

  4. Ying-Chun Lo

    Present address: Mayo Clinic, Rochester, MN, USA

  5. Gianna R. Strand

    Present address: Loyola University, Chicago, IL, USA

  6. Lobin A. Lee

    Present address: Children’s Hospital of Philadelphia, Philadelphia, PA, USA

  7. R. Seth Pinches

    Present address: Philadelphia College of Osteopathic Medicine, Philadelphia, PA, USA

  8. These authors contributed equally: Alanna J. Church, Laura B. Corson.

Authors and Affiliations

  1. Boston Children’s Hospital, Boston, MA, USA

    Alanna J. Church, Pei-Chi Kao, Haley Harris, Alyaa Al-Ibraheemi, Ying-Chun Lo, R. Seth Pinches, Marian H. Harris, Catherine M. Clinton & Wendy B. London

  2. Harvard Medical School, Boston, MA, USA

    Alanna J. Church, Alyaa Al-Ibraheemi, Yvonne Li, Hersh Gupta, Andrew D. Cherniack, Marian H. Harris, Suzanne J. Forrest, Brian D. Crompton, Junne Kamihara, Laura E. MacConaill, Neal I. Lindeman, Eliezer Van Allen, Steven G. DuBois, Wendy B. London & Katherine A. Janeway

  3. Dana-Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA

    Laura B. Corson, Alma Imamovic-Tuco, Deirdre Reidy, Duong Doan, Yvonne Li, Hersh Gupta, Andrew D. Cherniack, Gianna R. Strand, Lobin A. Lee, Lorena Lazo De La Vega, Hannah Comeau, Suzanne J. Forrest, Catherine M. Clinton, Brian D. Crompton, Junne Kamihara, Steven G. DuBois & Katherine A. Janeway

  4. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Laura B. Corson, Alma Imamovic-Tuco, Yvonne Li, Hersh Gupta, Andrew D. Cherniack, Maegan V. Harden, Niall J. Lennon & Eliezer Van Allen

  5. University of Chicago, Chicago, IL, USA

    Wenjun Kang, Mark A. Applebaum, Seong Choi & Samuel L. Volchenboum

  6. Seattle Children’s Hospital, Seattle, WA, USA

    Navin Pinto

  7. University of Washington, Seattle, WA, USA

    Navin Pinto

  8. Primary Children’s Hospital, Salt Lake City, UT, USA

    Luke Maese

  9. University of Utah Huntsman Cancer Institute, Salt Lake City, UT, USA

    Luke Maese

  10. University of Texas Southwestern Medical Center, Dallas, TX, USA

    Theodore W. Laetsch

  11. Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Theodore W. Laetsch & Rochelle Bagatell

  12. University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    Theodore W. Laetsch & Rochelle Bagatell

  13. Children’s National Hospital, Washington, DC, USA

    AeRang Kim

  14. George Washington University School of Medicine and Health Sciences, Washington, DC, USA

    AeRang Kim

  15. Nationwide Children’s Hospital, Columbus, OH, USA

    Susan I. Colace

  16. Ohio State University College of Medicine, Columbus, OH, USA

    Susan I. Colace

  17. Children’s Hospital of Colorado, Aurora, CO, USA

    Margaret E. Macy

  18. University of Colorado School of Medicine, Aurora, CO, USA

    Margaret E. Macy

  19. Comer Children’s Hospital, Chicago, IL, USA

    Mark A. Applebaum

  20. University of California San Francisco Benioff Children’s Hospital, San Francisco, CA, USA

    Amit J. Sabnis

  21. Children’s Hospital at Montefiore, New York, NY, USA

    Daniel A. Weiser

  22. Albert Einstein College of Medicine, New York, NY, USA

    Daniel A. Weiser

  23. Columbia University Irving Medical Center, New York, NY, USA

    Julia L. Glade-Bender

  24. Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Julia L. Glade-Bender

  25. University of Vermont Medical Center, Burlington, VT, USA

    Alan C. Homans

  26. University of Vermont, Burlington, VT, USA

    Alan C. Homans

  27. University of North Carolina Medical Center, Chapel Hill, NC, USA

    John Hipps

  28. University of North Carolina-Chapel Hill School of Medicine, Chapel Hill, NC, USA

    John Hipps

  29. Brigham and Women’s Hospital, Boston, MA, USA

    Danielle Manning, Ying-Chun Lo, Laura E. MacConaill & Neal I. Lindeman

  30. Dana-Farber Cancer Institute, Boston, MA, USA

    Eliezer Van Allen

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Contributions

A.J.C., N.P., L.M., T.W.L., A.K., S.I.C., M.E.M., M.A.A., R.B., A.J.S., D.A.W., M.H.H., J.L.G-B., C.M.C., B.D.C., J.K., L.E.M., S.L.V., N.I.L., E.V.A., S.G.D., W.B.L. and K.A.J. contributed to study design. A.J.C., L.B.C., P-C.K., A.I-T., D.R., D.D., W.K., N.P., L.M., T.W.L., A.K., S.I.C., M.E.M., M.A.A., R.B., A.J.S., D.A.W., J.L.G-B., A.C.H., J.H., H.H., D.M., A.A., G.R.S., L.A.L., R.S.P., L.L., M.V.H., N.J.L., S.C., H.C., M.H.H., S.J.F., C.M.C., B.D.C., J.K., L.E.M., N.I.L., E.V.A., S.G.D. and K.A.J. obtained regulatory approval and performed study conduct, patient recruitment and consent, sequencing, clinical interpretation and clinical data collection. A.J.C., L.B.C., P-C.K., A.I-T., D.D., W.K., H.H., L.L., Y.L., H.G., A.D.C., Y-C.L., H.C., S.J.F., L.E.M., N.I.L., E.V.A., W.B.L. and K.A.J. contributed to data analysis. All authors contributed to manuscript preparation and reviewed and approved the final manuscript.

Corresponding author

Correspondence to Alanna J. Church.

Ethics declarations

Competing interests

A.J.C. sits on an advisory board for Bayer. L.B.C. is an employee at Sema4 and is a consultant for X-Chem and Biomatics. L.M. is a consultant for Jazz Pharmaceuticals. T.W.L. is an advisory board member for Bayer and has received honoraria from Bayer, Cellectis, Novartis, Deciphera, Jumo Health and Y-mAbs and has received research funding from Pfizer and Bayer. M.A.A. is an advisory board member for Fennec Pharmaceuticals. Y-C.L. is an advisory board member for Takeda Pharmaceutical Company. A.D.C. has received research support from Bayer and his spouse is employed by Labcorp. J.K.’s spouse has received consulting fees from ROME Therapeutics, Foundation Medicine, NanoString, Merck Millipore and Pfizer that are not related to this work. J.K.’s spouse is a founder and has equity in ROME Therapeutics, PanTher Therapeutics and TellBio, which is not related to this work. J.K.’s spouse receives research support from ACD Bio-Techne, PureTech Health and Ribon Therapeutics, which was not used in this work. S.L.V. is a consultant for CVS Accordant. E.V.A. has provided advisory/consulting work for Tango Therapeutics, Genome Medical, Invitae, Enara Bio, Janssen, Manifold Bio and Monte Rosa Therapeutics, has received research support from Novartis and Bristol Myers Squibb, holds equity in Tango Therapeutics, Genome Medical, Syapse, Enara Bio, Manifold Bio, Microsoft and Monte Rosa Therapeutics, has received travel reimbursement from Roche/Genentech and holds institutional patents filed on chromatin mutations and immunotherapy response and methods for clinical interpretation. S.G.D. has consulted for Bayer and received travel expenses from Loxo Oncology, Roche and Salarius. W.B.L. has served on the data safety monitoring boards for Merck Millipore and Jubilant Draximage. K.A.J. has consulted for Ipsen and Bayer, and has received honoraria from Foundation Medicine and Takeda Pharmaceutical Company. The other authors declare no competing interests.

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Nature Medicine thanks Elaine Mardis and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Primary Handling editor: Anna Maria Ranzoni, in collaboration with the Nature Medicine team.

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Extended data

Extended Data Fig. 1 CONSORT diagram.

CONSORT diagram of 389 patients enrolled in the GAIN/iCat2 study between 11/2015 and 12/2018 identifying the analytic cohort. Percentages are based on the analytic population (n = 345).

Extended Data Fig. 2 iCat Recommendations.

Number of genes with iCat recommendations per patient at the time of initial report (February, 2016 to June, 2019) and with updated evidence reviewed between May and June, 2020 (a). Highest tier of iCat therapeutic recommendation for each patient at the time of initial report (February, 2016 to June, 2019) and with updated evidence reviewed between May and June, 2020 (b).

Extended Data Fig. 3 Changes in iCat Recommendations.

Changes in tiering of individual iCat recommendations from the time of initial report (February, 2016 to June, 2019) to re-tiering with updated evidence reviewed between May and June, 2020 upon reevaluation of evidence for expected response to matched targeted therapy.

Extended Data Fig. 4 Genes with iCat Recommendations.

iCat tiers reported according to alteration type (a). Top genes with strong evidence for therapeutic impact (iCat tiers 1-2) at the time of report (February 2016 to June 2019) (b) and with updated evidence reviewed between May and June, 2020 (c).

Extended Data Fig. 5 Responders to Matched Targeted Therapy.

Details of 5 responders to matched targeted therapy. GAIN patient 317 with an ALK fusion in a medullary thyroid carcinoma also responded, with images available in the primary report (Hillier et al., 2019).

Extended Data Fig. 6 Oncoprint for Patients Receiving MTT.

Tumor mutational burden (TMB) and additional alterations in 29 patients who received MTT. Additional alterations are shown if they occurred in >1 case or were potentially targetable. (For the case with high TMB all potentially actionable variants are not shown).

Extended Data Fig. 7 Top Genes with Diagnostic and Prognostic Significance.

All genes or chromosomes arms with tier 1 or 2 AMP/CAP/ASCO guideline evidence for prognostic impact (top; yellow). Top alterations with tier 1 or 2 AMP/CAP/ASCO guideline evidence for diagnostic impact, representing 181 of 227 diagnostically significant alterations (bottom; blue).

Extended Data Fig. 8 Diagnostic Impact Case.

Details of an illustrative case (GAIN318) of diagnostic impact: MRI (sagittal short inversion time inversion recovery (STIR) sequence) of a distal tibia tumor at diagnosis (a) and one year later at recurrence (b). The diagnosis rendered in the pathology report at initial diagnosis was aneurysmal bone cyst (ABC) while biopsy of the recurrence demonstrated osteogenic cells with pleomorphism and atypical mitotic figures (c, H&E stain, single experiment, not repeated). p53 IHC (d) shows loss of p53 expression in tumor but not normal cells (single experiment, not repeated). GAIN sequencing identified a novel TP53::USP6 fusion connecting TP53 intron 1 to USP6 intron 7, supporting a diagnosis of osteosarcoma in which TP53 rearrangements are common (e, created with Biorender.com). RNA analysis shows high expression of USP6, as measured by the number of unique RNA reads across 4 USP6 target regions [chr17:5031701, chr17:5033235, chr17:5033666, chr17:5033937], shown in the context of 12 cases with USP6 fusions (left, average read count 1552 reads) compared to 20 control cases with no USP6 fusions (right, average read count 8.0). This represents a significant difference in expression (unpaired two-tail t-test, p = 6.3e-10). Box plots represent maximum and minimum values (whiskers), first and third quartiles (bounds of box) and median (center line) (f).

Extended Data Fig. 9 Overview of the iCat2/GAIN Study.

Overview of the iCat2/GAIN study (a, created with Biorender.com). Targeted DNA NGS is performed on one or more tumor samples from each patient. Selected patients also have tumors subjected to RNA sequencing. Test results are returned to the treating oncologist and follow-up treatment and response data are collected. Details of clinical interpretation of test reports including molecular tumor board are shown in extended data Fig. 3. Testing strategy (b) to select patients for additional sequencing with either whole transcriptome sequencing or targeted RNA fusion panel testing (RNASeq). RNASeq was not performed if it was unlikely to contribute to research findings or clinical care. In this study, transcriptome sequencing was analyzed only for structural variants (SVs) and OncoPanel detects rearrangements in 60 genes (c). The testing triage is based on several assumptions: 1) False positives for SV detection OncoPanel are uncommon; 2) If oncogenic fusions have not been described in a particular solid tumor in previous studies and typical oncogenic events for that diagnosis are present then novel oncogenic fusions are unlikely; and 3) very rare pediatric solid malignancies might harbor previously undescribed fusions because they are understudied.

Extended Data Fig. 10 Details of Clinical Interpretation.

Details of clinical interpretation of test reports. A knowledgebase and report generation tool, iCatalog, was developed specifically for this study. iCatalog contains pediatric cancer specific knowledge on the gene and variant level including associated references (stored with PMID) and clinical trials (stored by NCT number). iCatalog knowledge is maintained by a staff scientist and research coordinator both at several scheduled times and when interpreting cases. iCatalog uses API to annotate variants. Resources available to the iCatalog user are shown below. Cases with Tier 5 iCat recommendations, previously undiscussed evidence or conflicting evidence are discussed at the molecular tumor board. Clinical interpretation reports are returned to the lead site investigator or enrolling oncologist.

Supplementary information

Supplementary Information

Study Protocol

Reporting Summary

Supplementary Data

Description of each tab of the supplementary data file: genes targeted for exonic sequence variants by the DNA sequencing panel; genes targeted for rearrangements by the DNA sequencing panel; gene list for the LaMPP solid and brain tumor fusion panel; table of single nucleotide variants (SNVs) identified by OncoPanel sequencing; table of copy number variants (CNVs) identified by OncoPanel sequencing; table of structural variants (SVs) identified by OncoPanel sequencing; table of tumor mutational burden (TMB) and mismatch repair (MMR) status identified by OncoPanel sequencing; table of diagnostic, prognostic and therapeutic alterations; list of iCat recommendations for therapeutically actionable alterations; detection of Genome4Kids solid tumor (ST) patient actionable variants by GAIN sequencing; Genomes4Kids solid tumor (ST) patient actionable variants annotated with detected or not detected by GAIN sequencing; Genomes4Kids solid tumor (ST) patient actionable variants annotated not detected by GAIN sequencing.

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Church, A.J., Corson, L.B., Kao, PC. et al. Molecular profiling identifies targeted therapy opportunities in pediatric solid cancer. Nat Med 28, 1581–1589 (2022). https://doi.org/10.1038/s41591-022-01856-6

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