- Email: [email protected]
Pediatric oncology enters an era of precision medicine
Author’s Accepted Manuscript Pediatric Oncology Enters the Era of Precision Medicine Nita L. Seibel, Katherine Janeway, Carl E. Allen, Susan N. Chi, Y Jae Cho, Julia L. Glade Bender, AeRang Kim, Theodore W. Laetsch, Meredith S. Irwin, Naoko Takebe, James V. Tricoli, D. Williams Parsons
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S0147-0272(17)30010-7 http://dx.doi.org/10.1016/j.currproblcancer.2017.01.002 YMCN327
To appear in: Current Problems in Cancer Cite this article as: Nita L. Seibel, Katherine Janeway, Carl E. Allen, Susan N. Chi, Y Jae Cho, Julia L. Glade Bender, AeRang Kim, Theodore W. Laetsch, Meredith S. Irwin, Naoko Takebe, James V. Tricoli and D. Williams Parsons, Pediatric Oncology Enters the Era of Precision Medicine, Current Problems in Cancer, http://dx.doi.org/10.1016/j.currproblcancer.2017.01.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pediatric Oncology Enters the Era of Precision Medicine
Nita L. Seibel1, Katherine Janeway2 Carl E. Allen3,4, Susan N. Chi2, Y Jae Cho5,6, Julia L. Glade Bender7, AeRang Kim8, Theodore W. Laetsch9,10, Meredith S. Irwin11, Naoko Takebe12, James V. Tricoli13, and D. Williams Parsons14,15 1
Clinical Investigations Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD 20850 2 Department of Pediatric Oncology, Dana-Farber/Boston Children’s Cancer Center and Blood Disorder Center, Boston, MA, USA 02215 3 Texas Children’s Cancer Center, Texas Children’s Hospital, Houston, TX 77030 4 Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine,TX 77030 Pape´ Family Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97209 6 Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97209 7 Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Department of Pediatrics, Columbia University, New York, NY 10032 8 Division of Oncology, Children’s National Health System, Washington, DC 20010 9 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390 10 Pauline Allen Gill Center for Cancer and Blood Disorders, Children’s Health, Dallas, TX 75235 11 Department of Pediatrics, Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada M5G1X8 12 Investigational Drug Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD 20850 13 Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD 20850 14 Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030 15 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030
Corresponding author: Nita L. Seibel, MD National Institute of Health, National Cancer Institute 9609 Medical Center Drive 5W350 MSC9757 Bethesda, MD USA 240-276-6078 [email protected]
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1
Abstract With the use of high-throughput molecular profiling technologies, precision medicine trials are ongoing for adults with cancer. Similarly, there is interest in how these techniques can be applied to tumors in children and adolescents to expand our understanding of the biology of pediatric cancers and evaluate the clinical implications of genomic testing for these patients. This article will review the early studies in pediatric oncology showing the feasibility of this approach, describe the future plans to evaluate the clinical implications in a multicenter clinical trial and identify the challenges of applying genomics in this patient population. Key words: Genomic profiling, adolescent and young adult cancer; pediatric tumors; whole exome sequencing; RNA sequencing; next generation sequencint
Introduction Improvements in outcomes for children and adolescents with cancer have been seen over the past four decades. Currently 8 out of 10 children diagnosed with cancer will be alive 5 years from the time of diagnosis and most of them much longer.1 Nevertheless, challenges remain in trying to improve the outcomes for all children diagnosed with cancer and particularly in high risk patients. Precision medicine trials are ongoing in a variety of forms for adults with cancer (as detailed in this issue in articles about NCI-MATCH, MPACT, LungMAP, and Alchemist). Similar approaches are being applied to children and adolescents with cancer and are currently under investigation in pediatric oncology. The
3 purpose of this article is to describe how precision medicine is being applied to pediatric oncology and the unique challenges associated with these efforts.
Pilot Studies of Precision Medicine in Pediatric Oncology Although biomarker-driven targeted therapies are not new to pediatric oncology, combining this with individualized genomic analysis is.2-4 Several pediatric oncology studies have explored the feasibility and utility of genomics-driven precision medicine and provided the foundation for pursuing this approach. They cover different aspects of precision medicine and have different study designs, including patient population [solid tumor, central nervous system (CNS) tumors, hematopoietic tumors; age], timing of specimen acquisition (diagnosis or relapse or both), and inclusion of routine germline analysis. Of note, none of the published studies include prospective treatment arms as part of the study, although several of the studies include clinical follow-up to assess whether patients were treated according to genomics-based recommendations and evaluate subsequent outcomes. The Baylor College of Medicine Advancing Sequencing in Childhood Cancer Care (BASIC3) study recently completed enrollment of a primary cohort of 287 newly diagnosed and previously untreated CNS and non-CNS solid tumor patients. 5 Whole exome sequencing (WES) was performed both on tumor samples and peripheral blood. In the report of the first 150 patients (< 18 years of age) of which 121 tumors were sequenced, 33 patients (27%) were found to have somatic mutations of established or potential clinical utility. An additional 24 patients (20%) were found to have mutations in consensus cancer genes that were not classified as targetable. Fewer than half of the somatic mutations identified were in genes known to be recurrently mutated in the tumor type tested. Diagnostic germline findings related to patient phenotype (cancer and/or other diseases) were discovered in 15 (10%) of 150 cases including 13 (8.6%) with pathogenic or likely pathogenic mutations in known cancer susceptibility genes. Treatment decisions or recommendations were not part of this study.
4 The University of Michigan Pediatric Michigan Oncology Sequencing (PEDS-MIONCOSEQ) study is modeled after the sequencing experience in adults with cancer.6 Although the study is ongoing, preliminary results of a cohort of pediatric and young adult participants have been reported. The study population included 102 pediatric and young adult patients (25 years of age and under) with refractory, relapsed cancer as well as newly diagnosed patients (20% of patients) with high-risk or rare cancer types. Patients with both hematopoietic malignancies and solid tumors were included. Ninety-one patients underwent genomic analyses with WES of tumor and germline DNA as well as RNA sequencing of tumor. A multidisciplinary tumor board provided clinical recommendations. They identified 42 patients (46%) with potentially actionable findings that were not identified by standard diagnostic tests that did not include sequencing. Nine of the patients had germline findings, 10 patients had somatic actionable gene fusions found via RNA sequencing, and 2 patients had their diagnosis changed as a result of the analyses. A total of 23 patients had an individualized care decision made based on either tumor or germline sequencing results. Fourteen of the patients had a change in therapy, 9 patients underwent genetic counseling and 1 patient required both. Nine of the 14 patients had a clinical response to the change in therapy lasting more than 6 months. The median turnaround time for return of the results was 54 days. The Individualized Cancer Therapy (iCAT) Study is a multicenter study to assess the feasibility of identifying actionable alterations and making individualized cancer therapy recommendations in pediatric and young adult patients (<30 years of age) with relapsed, refractory or high risk extracranial solid tumors.7 A multidisciplinary expert panel reviewed the profiling results and iCAT recommendations were made if an actionable alteration was present, and an appropriate drug was available. Thirty-one of the 100 participants had tumor submitted only from diagnosis whereas the rest had tumor submitted from recurrence or local control or multiple specimens from recurrence and diagnosis. Tumor profiling was successful in specimens from 89 patients. Overall, 31 (31%) patients received an iCat recommendation and 3 received matched therapy. There were no objective responses.
5 Three patients had a change in their diagnosis based on the tumor profiling. Six patients had an actionable alteration but there was no matching targeted therapy available via a clinical trial or as an FDA-approved therapy with an age-appropriate dose and formulation and so an iCAT recommendation could not be made. Additional alterations with implications for clinical care but not resulting in iCAT recommendations were identified, including mutations indicating the possible presence of a cancer predisposition syndrome. In total, 43 (43%) participants had results with potential clinical significance. The Individualized Therapy for Relapsed Malignancies in Childhood (INFORM) project is a nationwide German program for children with refractory, relapsed malignancies which aims to identify therapeutic targets on an individualized basis.8 In the report of the pilot phase, 57 children, adolescents and young adults, aged 1-40 years with a malignancy including both hematopoietic and solid tumors were enrolled. Seven patients for whom no standard therapy was available were enrolled at the time of primary diagnosis. Tumor specimens were analyzed by whole exome, low-coverage whole genome, and RNA sequencing along with methylation and expression microarray analyses. Alterations were assessed for potential targetability according to a customized seven-step scoring algorithm to prioritize molecular targets and reviewed by an interdisciplinary molecular tumor board prior to returning the results to the treating physician. Germline DNA was screened on each patient for damaging alterations in a predefined list of known cancer predisposition genes. Turnaround time was 28 days. Twenty-six of 52 patients with next-generation sequencing data on their tumors harbored a potentially druggable alteration with a prioritization score of intermediate or higher. Ten patients received targeted therapy based on these results with responses seen in some of the previously treated patients although systematic follow up was not an objective of this study. Underlying cancer predisposition was detected in 2 patients (4%). Comparative primary tumor-relapsed tumor analysis revealed substantial tumor evolution in addition to the detection in one case of an unsuspected secondary malignancy. The Institut Curie reported their 1-year experience of genetic analysis and molecular biology tumor board discussions for targeted therapies in pediatric solid tumors. 9 Tumor tissue from 60
6 pediatric patients (up to age 21.5 years) with poor prognosis or relapsed/refractory solid tumors (including CNS) were analyzed with panel-based next generation sequencing and array comparative genomic hybridization. The most recently available tumor tissue was analyzed but in the case in which there was inadequate material, a new biopsy was not requested and the initial diagnostic biopsy specimen was used. A potentially actionable finding was defined as a molecular alteration in a targetable gene known to be pathogenic. Recommendations from the molecular biology tumor board were given to the treating physicians. The mean turnaround time from the patient referral to the molecular biology tumor board and release of results was 42 +16 days. Of the 58 patients in which molecular profiling was feasible, 23 (40%) had a potentially actionable finding. High grade gliomas had the highest number of targetable alterations. Six of the 23 patients received a matched targeted therapy with 5 being enrolled in a clinical trial and 1 by compassionate use. Two patients had a partial response, 1 with a high grade pelvic sarcoma and the other with a juvenile renal cell carcinoma. Despite having a targetable lesion, 4 patients could not receive therapy due to lack of available clinical trials with the agents. Most of the remaining 13 patients did not receive targeted therapy because of pursuit of conventional chemotherapy or change in health status. The investigators concluded that this approach is feasible but only a small proportion of patients were able to receive the targeted therapy. Future Precision Medicine Trial: NCI Pediatric Molecular Analysis for Therapy Choice (MATCH) The Children’s Oncology Group (COG), the only pediatric oncology cooperative group in the NCI National Clinical Trials Network (NCTN), and in collaboration with and supported by the NCI, is taking the information gained from the above studies one step further by designing a histology agnostic trial in which eligibility to treatment arms is determined based on predefined lists of genomic aberration(s). Tissue from pediatric and adolescent patients with solid tumors will undergo molecular profiling: if an aberration is identified that has been defined as a driver mutation for a Pediatric MATCH study drug targeting the identified aberration, then the patient will have the opportunity to enroll onto the relevant single agent treatment arm. In this way the trial is providing access to the study drug(s) for each
7 patient in addition to genomic tumor analysis and treatment assignment. This trial will screen large numbers of patients for multiple targets and evaluate for clinical activity in patients carrying specific mutations that can inform future trials. This would be the first pediatric oncology trial for all solid tumors to identify the molecular aberration(s) in the tumor and provide the investigational agent for treatment of the identified molecular aberrations within the same trial. Similar to the NCI MATCH study, NCI Pediatric MATCH will employ an analytically validated next-generation sequencing targeted assay of more than 4,000 different mutations (SNVs, indels, copy number alterations, and gene fusions) across more than 140 genes.10 This type of basket/umbrella hybrid trial will utilize a rules-based treatment assignment which has not been used in the other pediatric trials.11 This offers the advantage of predefining treatment based on the presence of a molecular aberration, ensures availability of agents within the context of a trial, and negates assignment bias because all patients with a predefined actionable mutation of interest (aMOI) are assigned a given treatment. NCI Pediatric MATCH will be a national trial under a single IND. (see Figure 1) The trial will be run by COG (APEC1621 NCI-COG Pediatric MATCH) and available to all children and adolescents from 1 to 21 years of age who are treated or evaluated at approximately 200 COG institutions in the U.S. Patients with recurrent or refractory solid tumors including CNS tumors, as well as lymphomas and histiocytoses with measurable disease and who do not have any therapeutic options available are eligible for the study. A tumor specimen must be submitted from relapse or progression except in the case of patients with brain stem gliomas in which tissue from a diagnostic biopsy may be submitted for molecular characterization. Treatment will be offered to participants in whose tumor specimen a molecular aberration is detected that is addressed by a treatment included in the trial. The primary aims of the study are to determine the objective response rate in pediatric patients with advanced solid tumors and lymphomas harboring a priori specified genomic alterations treated with pathway-targeting agents and to determine the proportion of pediatric patients whose tumors have pathway alterations that can be targeted by existing anti-cancer drugs. Approximately 300 children and
8 adolescent tumor specimens will be screened each year in order to accumulate data on 1000 pediatric tumors. The anticipated turnaround time from receiving the tumor specimen until the return of the results to the treating physician is approximately 2-3 weeks. A total of 20 patients will be enrolled per treatment arm (or stratum within the arm) depending on the aMOIs and the agent will be considered of interest for further development if 3 or more patients out of 20 show a response. The arms may be expanded in the trial to enroll additional patients if activity is seen for a particular agent. The study will have the flexibility to open and close arms. A patient’s tumor that progresses while on treatment will be eligible to go on another treatment arm, if the tumor has additional genetic aberrations that are being targeted with another NCI Pediatric MATCH agent. The molecular targets and study drugs selected for the trial were identified and prioritized by the Pediatric MATCH Target and Agent Prioritization (TAP) Committee consisting of representatives from COG disease committees from 10 children’s hospitals, the NCI, and the Food and Drug Administration (FDA). The TAP committee systematically reviewed target and agent pairs for inclusion in Pediatric MATCH Trial. Criteria used to prioritize the target and agent pairs included the frequency of the alterations in the target in pediatric malignancies, strength of the evidence linking the target to activity of the agent, whether the target can be detected with the testing platform, clinical and preclinical evidence for the specific agent, and other ongoing or planned biomarker defined clinical studies. Fifteen drugtarget pairs were reviewed by the TAP committee, with seven recommended for further development as initial arms of the Pediatric MATCH Trial. Details of this process have been described previously.12 The two criteria established for identifying specific agents to be considered for inclusion in NCI Pediatric MATCH were demonstrated activity against tumors with a particular genomic alteration and the establishment of the an adult recommended phase 2 dose.
Individual meetings were held with different
pharmaceutical companies for agents of interest within a targeted drug class in order to gain additional knowledge about the strength of the biomarker in predicting those patients who may benefit from the agent and to discuss any experience in pediatrics. The same levels of evidence for drug selection used in
9 Adult MATCH were applied for Pediatric MATCH.10 Neither a completed pediatric phase 1 study nor pediatric formulation was required in order to be considered for NCI Pediatric MATCH. However, in the case of an oral agent, appropriately sized capsules or tablets were required in order to dose pediatric patients.
NCI Pediatric MATCH will open with at least 8 treatment arms with plans to add additional
arms based upon ongoing review of new data and as agents become available based on the identified targets. The plan is to investigate 15 to 20 single agents. Unique Aspects of NCI Pediatric MATCH There are some noteworthy differences for NCI Pediatric MATCH as compared to NCI-MATCH or similar precision medicine protocols. The number of molecular aberrations seen in pediatric tumors is much less than identified in tumors occurring in adults. 13,14 Therefore the anticipated match rate is expected to be lower than the experience with tumors occurring in adults.
Currently in NCI-MATCH,
the rate of matching is approximately 20-25%, however, in pediatrics it is projected to be around 10%. One way to increase the chances of finding a targetable abnormality in a patient’s tumor is to make sure the biopsy is done after recurrence/progression and as close to the time of analysis.15-18 In fact, in some studies in adults, it is recommended that a metastatic (as opposed to primary) lesion is biopsied. 19,20 In Pediatric MATCH in order to provide access for as many children and adolescents as possible and because the risks associated with biopsies in children differ from adults, there is more flexibility with the timing of the biopsy (need not be obtained just prior to study enrollment as long as is from a recurrence) or in the case of brain stem gliomas from the time of diagnosis. The types of targetable abnormalities identified in tumors occurring in pediatrics are also somewhat different from those seen in tumors occurring in adults. For example, frequent targetable kinase alterations seen in lung cancer and breast cancer such as EGFR and HER2, respectively, rarely occur in pediatric tumors. Therefore, it is hard to justify including inhibitors of these abnormalities as treatment arms in Pediatric MATCH. Drug availability is another challenge since agents are not yet available to target many of the recurrent aberrations identified in pediatric tumors. Based on the small number of pediatric cancers and even
10 smaller subgroups of molecular aberrations identified in the tumors, agents have not been developed to target some of the detectable molecular aberrations. Different from Adult MATCH but similar to 3 of the 5 pediatric studies described above, germline DNA will be collected and analyzed on all patients enrolled on NCI Pediatric MATCH. By including germline analysis using the same panel as for tumor sequencing, it will be possible to determine which mutations of interest and actionable mutations of interest represent germline variants in cancer susceptibility genes. Clinical genomics labs will interpret the germline findings and provide a report back to the treating oncologist identifying whether any of the MOIs or aMOIs included in the tumor sequencing report represent pathogenic or likely pathogenic germline variants in cancer susceptibility genes. The results of the germline analysis will not be used for treatment assignment and are not meant to provide a comprehensive cancer susceptibility evaluation. Adolescent and Young Adults Oncology Patients Adolescent and young adult (AYA) oncology patients up to age 21 will be eligible to enroll on NCI Pediatric MATCH. COG is participating in NCI MATCH which allows adolescent patients 18 years of age and older to enroll. Hopefully this will translate into broader access for this group of patients to precision medicine trials. In addition, if a patient on Pediatric MATCH has an aMOI for which there is no treatment arm on Pediatric MATCH, but one exists on Adult MATCH, steps will be taken to make the treatment available for the patient. Conclusion In the past, diagnosis, classification and management of cancer was largely directed by the site of tumor origin. In the era of precision medicine, this paradigm is being re-evaluated.
Numerous pediatric
oncology investigators have demonstrated that it is feasible to analyze tissue from pediatric solid tumors for molecular aberrations in a timely manner with clinical implications. It is now time to test the hypothesis that assigning treatment based on the presence of specific targets in tumors will provide
11 clinical benefit.21 The NCI Pediatric MATCH study represents a first step in exploring this application of genomics for the treatment of childhood cancer patients. Although there are still many obstacles remaining as precision medicine is applied to pediatric oncology, these trials mark the beginning of the era incorporating these advances into clinical practice.
The Children’s Oncology Group has been awarded a grant by the National Cancer Institute (NCI;1U10CA180886) as a member of the NCI National Clinical Trials Network that will support the NCI-Pediatric MATCH Trial. References: 1. Howlader N, Noone AM, Krapcho M, (eds) et al. SEER Cancer Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016. 2. Mosse YP, Lim MS, Voss SD, et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: Children’s Oncology Group phase 1 consortium study. Lancet Oncol 2013;14:472-480. 3. Schultz KA, Carroll A, Heerema NA, et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children's Oncology Group study AALL0031. Leukemia 2014;28: 1467-71. 4. Schultz KA, Bowman WP, Alero A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol 2009;27: 5175-81. 5. Parsons DW, Roy A, Yang Y, et al. Diagnostic yield of clinical tumor and germline whole-exome sequencing for children with solid tumors. JAMA Oncol 2016;2: 616-624.
12 6.
Mody RJ, Wu YM, Lonigro RJ, et al. Integrative clinical sequencing in the management of refractory or relapsed cancer in youth. J Am Med Assoc 2015;314: 913-925.
7.
Harris MH, DuBois SG, Glade Bender JL, et al. Multicenter feasibility study of tumor molecular profiling to inform therapeutic decisions in advanced pediatric solid tumors: the Individualized Cancer Therapy (iCat)Study. JAMA Oncol 2016;2: 608-615.
8. Worst BC, van Tilburg CM, Balasubramanian GP, et al. Next-generation personalized medicine for high-risk paediatric cancer patients-the INFORM pilot study. Eur J Cancer 2016;65: 91-101. 9. Pincez T, Clement N, Lapouble E, et al. Feasibility and clinical integration of molecular profiling for target identification in pediatric solid tumors. Pediatr Blood Cancer DOI:10:1002/pbc.26365 (2016). 10. Conley BA, Gray R, Chen A et al. NCI-molecular analysis for therapy choice (NCI-MATCH) clinical trial: interim analysis. Cancer Res 206:76(14 suppl#CT101). 11. Takebe N, YAP TA. Editorial - precision medicine in oncology. Curr Probl Cancer 12. Allen CE, Laetsch TW, Mody R, et al. Precision pediatric oncology: review of agents, targets and rationale for the COG-NCI Pediatric MATCH. J Natl Cancer Inst 2016:djw274.DOI:10.1093/jnci/djw274. 13. Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013;499: 214-8. 14. Vogelstein B, Papadopoulos N, Velculescu VE et al. Cancer genome landscapes. Science 2013;399: 1546-58. 15. Padovan-Merhar OM, Raman P, Ostrovnaya I et al. Enrichment of targetable mutations in the relapsed neuroblastoma genome. PLoS Genet 12 (2016):e1006501.doi:10.1371/journal. Pgen.1006501 16. Eleveld TF, Oldridge DA, Bernard V et al. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet 2015;47: 864-71.
13 17. Schramm A, Koster J, Assenov Y et al. Mutational dynamics between primary and relapse neuroblastomas. Nat Genet 2015;47:872-7. 18. Schleiemacher G, Javanmardi N, Bernard V et al. Emergence of new ALK mutations at relapse of neuroblastoma. J Clin Oncol 2014;32: 2727-34. 19. Gerlinger M., Rowan A.J., Horswell S., et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366: 883-892. 20. Le Tourneau C, Kamal M., Tsimberidou A-M., et al. Treatment algorithms based on tumor molecular profiling: the essence of precision medicine trials. J Natl Cancer Inst. 2016;108: djv362. 21. Kummar S., Williams P.M., Lih C-J. et al. Application of molecular profiling in clinical trials for advanced metastatic cancers. J Natl Cancer Inst (2015;107: djv003. Figure 1. NCI-Pediatric Molecular Analysis for Therapeutic Choice (MATCH) Trial Schema. TRK, tyrosine receptor kinase; FGFR, fibroblast growth factor receptor; EZH2, enhancer of zeste homolog 2; PI3K/mTOR, phosphoinositide 3-kinase/mammalian target of rapamycin; ALK, anaplastic lymphoma kinase; PARP, poly ADP ribose polymerase.
14
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www.elsevier.com/locate/cpcancerv
S0147-0272(17)30010-7 http://dx.doi.org/10.1016/j.currproblcancer.2017.01.002 YMCN327
To appear in: Current Problems in Cancer Cite this article as: Nita L. Seibel, Katherine Janeway, Carl E. Allen, Susan N. Chi, Y Jae Cho, Julia L. Glade Bender, AeRang Kim, Theodore W. Laetsch, Meredith S. Irwin, Naoko Takebe, James V. Tricoli and D. Williams Parsons, Pediatric Oncology Enters the Era of Precision Medicine, Current Problems in Cancer, http://dx.doi.org/10.1016/j.currproblcancer.2017.01.002 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Pediatric Oncology Enters the Era of Precision Medicine
Nita L. Seibel1, Katherine Janeway2 Carl E. Allen3,4, Susan N. Chi2, Y Jae Cho5,6, Julia L. Glade Bender7, AeRang Kim8, Theodore W. Laetsch9,10, Meredith S. Irwin11, Naoko Takebe12, James V. Tricoli13, and D. Williams Parsons14,15 1
Clinical Investigations Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD 20850 2 Department of Pediatric Oncology, Dana-Farber/Boston Children’s Cancer Center and Blood Disorder Center, Boston, MA, USA 02215 3 Texas Children’s Cancer Center, Texas Children’s Hospital, Houston, TX 77030 4 Division of Pediatric Hematology-Oncology, Department of Pediatrics, Baylor College of Medicine,TX 77030 Pape´ Family Research Institute, Department of Pediatrics, Oregon Health & Science University, Portland, OR 97209 6 Knight Cancer Institute, Oregon Health & Science University, Portland, OR 97209 7 Division of Pediatric Hematology, Oncology and Stem Cell Transplantation, Department of Pediatrics, Columbia University, New York, NY 10032 8 Division of Oncology, Children’s National Health System, Washington, DC 20010 9 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390 10 Pauline Allen Gill Center for Cancer and Blood Disorders, Children’s Health, Dallas, TX 75235 11 Department of Pediatrics, Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON, Canada M5G1X8 12 Investigational Drug Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD 20850 13 Cancer Diagnosis Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute, Rockville, MD 20850 14 Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030 15 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030
Corresponding author: Nita L. Seibel, MD National Institute of Health, National Cancer Institute 9609 Medical Center Drive 5W350 MSC9757 Bethesda, MD USA 240-276-6078 [email protected]
2
1
Abstract With the use of high-throughput molecular profiling technologies, precision medicine trials are ongoing for adults with cancer. Similarly, there is interest in how these techniques can be applied to tumors in children and adolescents to expand our understanding of the biology of pediatric cancers and evaluate the clinical implications of genomic testing for these patients. This article will review the early studies in pediatric oncology showing the feasibility of this approach, describe the future plans to evaluate the clinical implications in a multicenter clinical trial and identify the challenges of applying genomics in this patient population. Key words: Genomic profiling, adolescent and young adult cancer; pediatric tumors; whole exome sequencing; RNA sequencing; next generation sequencint
Introduction Improvements in outcomes for children and adolescents with cancer have been seen over the past four decades. Currently 8 out of 10 children diagnosed with cancer will be alive 5 years from the time of diagnosis and most of them much longer.1 Nevertheless, challenges remain in trying to improve the outcomes for all children diagnosed with cancer and particularly in high risk patients. Precision medicine trials are ongoing in a variety of forms for adults with cancer (as detailed in this issue in articles about NCI-MATCH, MPACT, LungMAP, and Alchemist). Similar approaches are being applied to children and adolescents with cancer and are currently under investigation in pediatric oncology. The
3 purpose of this article is to describe how precision medicine is being applied to pediatric oncology and the unique challenges associated with these efforts.
Pilot Studies of Precision Medicine in Pediatric Oncology Although biomarker-driven targeted therapies are not new to pediatric oncology, combining this with individualized genomic analysis is.2-4 Several pediatric oncology studies have explored the feasibility and utility of genomics-driven precision medicine and provided the foundation for pursuing this approach. They cover different aspects of precision medicine and have different study designs, including patient population [solid tumor, central nervous system (CNS) tumors, hematopoietic tumors; age], timing of specimen acquisition (diagnosis or relapse or both), and inclusion of routine germline analysis. Of note, none of the published studies include prospective treatment arms as part of the study, although several of the studies include clinical follow-up to assess whether patients were treated according to genomics-based recommendations and evaluate subsequent outcomes. The Baylor College of Medicine Advancing Sequencing in Childhood Cancer Care (BASIC3) study recently completed enrollment of a primary cohort of 287 newly diagnosed and previously untreated CNS and non-CNS solid tumor patients. 5 Whole exome sequencing (WES) was performed both on tumor samples and peripheral blood. In the report of the first 150 patients (< 18 years of age) of which 121 tumors were sequenced, 33 patients (27%) were found to have somatic mutations of established or potential clinical utility. An additional 24 patients (20%) were found to have mutations in consensus cancer genes that were not classified as targetable. Fewer than half of the somatic mutations identified were in genes known to be recurrently mutated in the tumor type tested. Diagnostic germline findings related to patient phenotype (cancer and/or other diseases) were discovered in 15 (10%) of 150 cases including 13 (8.6%) with pathogenic or likely pathogenic mutations in known cancer susceptibility genes. Treatment decisions or recommendations were not part of this study.
4 The University of Michigan Pediatric Michigan Oncology Sequencing (PEDS-MIONCOSEQ) study is modeled after the sequencing experience in adults with cancer.6 Although the study is ongoing, preliminary results of a cohort of pediatric and young adult participants have been reported. The study population included 102 pediatric and young adult patients (25 years of age and under) with refractory, relapsed cancer as well as newly diagnosed patients (20% of patients) with high-risk or rare cancer types. Patients with both hematopoietic malignancies and solid tumors were included. Ninety-one patients underwent genomic analyses with WES of tumor and germline DNA as well as RNA sequencing of tumor. A multidisciplinary tumor board provided clinical recommendations. They identified 42 patients (46%) with potentially actionable findings that were not identified by standard diagnostic tests that did not include sequencing. Nine of the patients had germline findings, 10 patients had somatic actionable gene fusions found via RNA sequencing, and 2 patients had their diagnosis changed as a result of the analyses. A total of 23 patients had an individualized care decision made based on either tumor or germline sequencing results. Fourteen of the patients had a change in therapy, 9 patients underwent genetic counseling and 1 patient required both. Nine of the 14 patients had a clinical response to the change in therapy lasting more than 6 months. The median turnaround time for return of the results was 54 days. The Individualized Cancer Therapy (iCAT) Study is a multicenter study to assess the feasibility of identifying actionable alterations and making individualized cancer therapy recommendations in pediatric and young adult patients (<30 years of age) with relapsed, refractory or high risk extracranial solid tumors.7 A multidisciplinary expert panel reviewed the profiling results and iCAT recommendations were made if an actionable alteration was present, and an appropriate drug was available. Thirty-one of the 100 participants had tumor submitted only from diagnosis whereas the rest had tumor submitted from recurrence or local control or multiple specimens from recurrence and diagnosis. Tumor profiling was successful in specimens from 89 patients. Overall, 31 (31%) patients received an iCat recommendation and 3 received matched therapy. There were no objective responses.
5 Three patients had a change in their diagnosis based on the tumor profiling. Six patients had an actionable alteration but there was no matching targeted therapy available via a clinical trial or as an FDA-approved therapy with an age-appropriate dose and formulation and so an iCAT recommendation could not be made. Additional alterations with implications for clinical care but not resulting in iCAT recommendations were identified, including mutations indicating the possible presence of a cancer predisposition syndrome. In total, 43 (43%) participants had results with potential clinical significance. The Individualized Therapy for Relapsed Malignancies in Childhood (INFORM) project is a nationwide German program for children with refractory, relapsed malignancies which aims to identify therapeutic targets on an individualized basis.8 In the report of the pilot phase, 57 children, adolescents and young adults, aged 1-40 years with a malignancy including both hematopoietic and solid tumors were enrolled. Seven patients for whom no standard therapy was available were enrolled at the time of primary diagnosis. Tumor specimens were analyzed by whole exome, low-coverage whole genome, and RNA sequencing along with methylation and expression microarray analyses. Alterations were assessed for potential targetability according to a customized seven-step scoring algorithm to prioritize molecular targets and reviewed by an interdisciplinary molecular tumor board prior to returning the results to the treating physician. Germline DNA was screened on each patient for damaging alterations in a predefined list of known cancer predisposition genes. Turnaround time was 28 days. Twenty-six of 52 patients with next-generation sequencing data on their tumors harbored a potentially druggable alteration with a prioritization score of intermediate or higher. Ten patients received targeted therapy based on these results with responses seen in some of the previously treated patients although systematic follow up was not an objective of this study. Underlying cancer predisposition was detected in 2 patients (4%). Comparative primary tumor-relapsed tumor analysis revealed substantial tumor evolution in addition to the detection in one case of an unsuspected secondary malignancy. The Institut Curie reported their 1-year experience of genetic analysis and molecular biology tumor board discussions for targeted therapies in pediatric solid tumors. 9 Tumor tissue from 60
6 pediatric patients (up to age 21.5 years) with poor prognosis or relapsed/refractory solid tumors (including CNS) were analyzed with panel-based next generation sequencing and array comparative genomic hybridization. The most recently available tumor tissue was analyzed but in the case in which there was inadequate material, a new biopsy was not requested and the initial diagnostic biopsy specimen was used. A potentially actionable finding was defined as a molecular alteration in a targetable gene known to be pathogenic. Recommendations from the molecular biology tumor board were given to the treating physicians. The mean turnaround time from the patient referral to the molecular biology tumor board and release of results was 42 +16 days. Of the 58 patients in which molecular profiling was feasible, 23 (40%) had a potentially actionable finding. High grade gliomas had the highest number of targetable alterations. Six of the 23 patients received a matched targeted therapy with 5 being enrolled in a clinical trial and 1 by compassionate use. Two patients had a partial response, 1 with a high grade pelvic sarcoma and the other with a juvenile renal cell carcinoma. Despite having a targetable lesion, 4 patients could not receive therapy due to lack of available clinical trials with the agents. Most of the remaining 13 patients did not receive targeted therapy because of pursuit of conventional chemotherapy or change in health status. The investigators concluded that this approach is feasible but only a small proportion of patients were able to receive the targeted therapy. Future Precision Medicine Trial: NCI Pediatric Molecular Analysis for Therapy Choice (MATCH) The Children’s Oncology Group (COG), the only pediatric oncology cooperative group in the NCI National Clinical Trials Network (NCTN), and in collaboration with and supported by the NCI, is taking the information gained from the above studies one step further by designing a histology agnostic trial in which eligibility to treatment arms is determined based on predefined lists of genomic aberration(s). Tissue from pediatric and adolescent patients with solid tumors will undergo molecular profiling: if an aberration is identified that has been defined as a driver mutation for a Pediatric MATCH study drug targeting the identified aberration, then the patient will have the opportunity to enroll onto the relevant single agent treatment arm. In this way the trial is providing access to the study drug(s) for each
7 patient in addition to genomic tumor analysis and treatment assignment. This trial will screen large numbers of patients for multiple targets and evaluate for clinical activity in patients carrying specific mutations that can inform future trials. This would be the first pediatric oncology trial for all solid tumors to identify the molecular aberration(s) in the tumor and provide the investigational agent for treatment of the identified molecular aberrations within the same trial. Similar to the NCI MATCH study, NCI Pediatric MATCH will employ an analytically validated next-generation sequencing targeted assay of more than 4,000 different mutations (SNVs, indels, copy number alterations, and gene fusions) across more than 140 genes.10 This type of basket/umbrella hybrid trial will utilize a rules-based treatment assignment which has not been used in the other pediatric trials.11 This offers the advantage of predefining treatment based on the presence of a molecular aberration, ensures availability of agents within the context of a trial, and negates assignment bias because all patients with a predefined actionable mutation of interest (aMOI) are assigned a given treatment. NCI Pediatric MATCH will be a national trial under a single IND. (see Figure 1) The trial will be run by COG (APEC1621 NCI-COG Pediatric MATCH) and available to all children and adolescents from 1 to 21 years of age who are treated or evaluated at approximately 200 COG institutions in the U.S. Patients with recurrent or refractory solid tumors including CNS tumors, as well as lymphomas and histiocytoses with measurable disease and who do not have any therapeutic options available are eligible for the study. A tumor specimen must be submitted from relapse or progression except in the case of patients with brain stem gliomas in which tissue from a diagnostic biopsy may be submitted for molecular characterization. Treatment will be offered to participants in whose tumor specimen a molecular aberration is detected that is addressed by a treatment included in the trial. The primary aims of the study are to determine the objective response rate in pediatric patients with advanced solid tumors and lymphomas harboring a priori specified genomic alterations treated with pathway-targeting agents and to determine the proportion of pediatric patients whose tumors have pathway alterations that can be targeted by existing anti-cancer drugs. Approximately 300 children and
8 adolescent tumor specimens will be screened each year in order to accumulate data on 1000 pediatric tumors. The anticipated turnaround time from receiving the tumor specimen until the return of the results to the treating physician is approximately 2-3 weeks. A total of 20 patients will be enrolled per treatment arm (or stratum within the arm) depending on the aMOIs and the agent will be considered of interest for further development if 3 or more patients out of 20 show a response. The arms may be expanded in the trial to enroll additional patients if activity is seen for a particular agent. The study will have the flexibility to open and close arms. A patient’s tumor that progresses while on treatment will be eligible to go on another treatment arm, if the tumor has additional genetic aberrations that are being targeted with another NCI Pediatric MATCH agent. The molecular targets and study drugs selected for the trial were identified and prioritized by the Pediatric MATCH Target and Agent Prioritization (TAP) Committee consisting of representatives from COG disease committees from 10 children’s hospitals, the NCI, and the Food and Drug Administration (FDA). The TAP committee systematically reviewed target and agent pairs for inclusion in Pediatric MATCH Trial. Criteria used to prioritize the target and agent pairs included the frequency of the alterations in the target in pediatric malignancies, strength of the evidence linking the target to activity of the agent, whether the target can be detected with the testing platform, clinical and preclinical evidence for the specific agent, and other ongoing or planned biomarker defined clinical studies. Fifteen drugtarget pairs were reviewed by the TAP committee, with seven recommended for further development as initial arms of the Pediatric MATCH Trial. Details of this process have been described previously.12 The two criteria established for identifying specific agents to be considered for inclusion in NCI Pediatric MATCH were demonstrated activity against tumors with a particular genomic alteration and the establishment of the an adult recommended phase 2 dose.
Individual meetings were held with different
pharmaceutical companies for agents of interest within a targeted drug class in order to gain additional knowledge about the strength of the biomarker in predicting those patients who may benefit from the agent and to discuss any experience in pediatrics. The same levels of evidence for drug selection used in
9 Adult MATCH were applied for Pediatric MATCH.10 Neither a completed pediatric phase 1 study nor pediatric formulation was required in order to be considered for NCI Pediatric MATCH. However, in the case of an oral agent, appropriately sized capsules or tablets were required in order to dose pediatric patients.
NCI Pediatric MATCH will open with at least 8 treatment arms with plans to add additional
arms based upon ongoing review of new data and as agents become available based on the identified targets. The plan is to investigate 15 to 20 single agents. Unique Aspects of NCI Pediatric MATCH There are some noteworthy differences for NCI Pediatric MATCH as compared to NCI-MATCH or similar precision medicine protocols. The number of molecular aberrations seen in pediatric tumors is much less than identified in tumors occurring in adults. 13,14 Therefore the anticipated match rate is expected to be lower than the experience with tumors occurring in adults.
Currently in NCI-MATCH,
the rate of matching is approximately 20-25%, however, in pediatrics it is projected to be around 10%. One way to increase the chances of finding a targetable abnormality in a patient’s tumor is to make sure the biopsy is done after recurrence/progression and as close to the time of analysis.15-18 In fact, in some studies in adults, it is recommended that a metastatic (as opposed to primary) lesion is biopsied. 19,20 In Pediatric MATCH in order to provide access for as many children and adolescents as possible and because the risks associated with biopsies in children differ from adults, there is more flexibility with the timing of the biopsy (need not be obtained just prior to study enrollment as long as is from a recurrence) or in the case of brain stem gliomas from the time of diagnosis. The types of targetable abnormalities identified in tumors occurring in pediatrics are also somewhat different from those seen in tumors occurring in adults. For example, frequent targetable kinase alterations seen in lung cancer and breast cancer such as EGFR and HER2, respectively, rarely occur in pediatric tumors. Therefore, it is hard to justify including inhibitors of these abnormalities as treatment arms in Pediatric MATCH. Drug availability is another challenge since agents are not yet available to target many of the recurrent aberrations identified in pediatric tumors. Based on the small number of pediatric cancers and even
10 smaller subgroups of molecular aberrations identified in the tumors, agents have not been developed to target some of the detectable molecular aberrations. Different from Adult MATCH but similar to 3 of the 5 pediatric studies described above, germline DNA will be collected and analyzed on all patients enrolled on NCI Pediatric MATCH. By including germline analysis using the same panel as for tumor sequencing, it will be possible to determine which mutations of interest and actionable mutations of interest represent germline variants in cancer susceptibility genes. Clinical genomics labs will interpret the germline findings and provide a report back to the treating oncologist identifying whether any of the MOIs or aMOIs included in the tumor sequencing report represent pathogenic or likely pathogenic germline variants in cancer susceptibility genes. The results of the germline analysis will not be used for treatment assignment and are not meant to provide a comprehensive cancer susceptibility evaluation. Adolescent and Young Adults Oncology Patients Adolescent and young adult (AYA) oncology patients up to age 21 will be eligible to enroll on NCI Pediatric MATCH. COG is participating in NCI MATCH which allows adolescent patients 18 years of age and older to enroll. Hopefully this will translate into broader access for this group of patients to precision medicine trials. In addition, if a patient on Pediatric MATCH has an aMOI for which there is no treatment arm on Pediatric MATCH, but one exists on Adult MATCH, steps will be taken to make the treatment available for the patient. Conclusion In the past, diagnosis, classification and management of cancer was largely directed by the site of tumor origin. In the era of precision medicine, this paradigm is being re-evaluated.
Numerous pediatric
oncology investigators have demonstrated that it is feasible to analyze tissue from pediatric solid tumors for molecular aberrations in a timely manner with clinical implications. It is now time to test the hypothesis that assigning treatment based on the presence of specific targets in tumors will provide
11 clinical benefit.21 The NCI Pediatric MATCH study represents a first step in exploring this application of genomics for the treatment of childhood cancer patients. Although there are still many obstacles remaining as precision medicine is applied to pediatric oncology, these trials mark the beginning of the era incorporating these advances into clinical practice.
The Children’s Oncology Group has been awarded a grant by the National Cancer Institute (NCI;1U10CA180886) as a member of the NCI National Clinical Trials Network that will support the NCI-Pediatric MATCH Trial. References: 1. Howlader N, Noone AM, Krapcho M, (eds) et al. SEER Cancer Statistics Review, 1975-2013, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2013/, based on November 2015 SEER data submission, posted to the SEER web site, April 2016. 2. Mosse YP, Lim MS, Voss SD, et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: Children’s Oncology Group phase 1 consortium study. Lancet Oncol 2013;14:472-480. 3. Schultz KA, Carroll A, Heerema NA, et al. Long-term follow-up of imatinib in pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia: Children's Oncology Group study AALL0031. Leukemia 2014;28: 1467-71. 4. Schultz KA, Bowman WP, Alero A, et al. Improved early event-free survival with imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a children's oncology group study. J Clin Oncol 2009;27: 5175-81. 5. Parsons DW, Roy A, Yang Y, et al. Diagnostic yield of clinical tumor and germline whole-exome sequencing for children with solid tumors. JAMA Oncol 2016;2: 616-624.
12 6.
Mody RJ, Wu YM, Lonigro RJ, et al. Integrative clinical sequencing in the management of refractory or relapsed cancer in youth. J Am Med Assoc 2015;314: 913-925.
7.
Harris MH, DuBois SG, Glade Bender JL, et al. Multicenter feasibility study of tumor molecular profiling to inform therapeutic decisions in advanced pediatric solid tumors: the Individualized Cancer Therapy (iCat)Study. JAMA Oncol 2016;2: 608-615.
8. Worst BC, van Tilburg CM, Balasubramanian GP, et al. Next-generation personalized medicine for high-risk paediatric cancer patients-the INFORM pilot study. Eur J Cancer 2016;65: 91-101. 9. Pincez T, Clement N, Lapouble E, et al. Feasibility and clinical integration of molecular profiling for target identification in pediatric solid tumors. Pediatr Blood Cancer DOI:10:1002/pbc.26365 (2016). 10. Conley BA, Gray R, Chen A et al. NCI-molecular analysis for therapy choice (NCI-MATCH) clinical trial: interim analysis. Cancer Res 206:76(14 suppl#CT101). 11. Takebe N, YAP TA. Editorial - precision medicine in oncology. Curr Probl Cancer 12. Allen CE, Laetsch TW, Mody R, et al. Precision pediatric oncology: review of agents, targets and rationale for the COG-NCI Pediatric MATCH. J Natl Cancer Inst 2016:djw274.DOI:10.1093/jnci/djw274. 13. Lawrence MS, Stojanov P, Polak P, et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 2013;499: 214-8. 14. Vogelstein B, Papadopoulos N, Velculescu VE et al. Cancer genome landscapes. Science 2013;399: 1546-58. 15. Padovan-Merhar OM, Raman P, Ostrovnaya I et al. Enrichment of targetable mutations in the relapsed neuroblastoma genome. PLoS Genet 12 (2016):e1006501.doi:10.1371/journal. Pgen.1006501 16. Eleveld TF, Oldridge DA, Bernard V et al. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet 2015;47: 864-71.
13 17. Schramm A, Koster J, Assenov Y et al. Mutational dynamics between primary and relapse neuroblastomas. Nat Genet 2015;47:872-7. 18. Schleiemacher G, Javanmardi N, Bernard V et al. Emergence of new ALK mutations at relapse of neuroblastoma. J Clin Oncol 2014;32: 2727-34. 19. Gerlinger M., Rowan A.J., Horswell S., et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012;366: 883-892. 20. Le Tourneau C, Kamal M., Tsimberidou A-M., et al. Treatment algorithms based on tumor molecular profiling: the essence of precision medicine trials. J Natl Cancer Inst. 2016;108: djv362. 21. Kummar S., Williams P.M., Lih C-J. et al. Application of molecular profiling in clinical trials for advanced metastatic cancers. J Natl Cancer Inst (2015;107: djv003. Figure 1. NCI-Pediatric Molecular Analysis for Therapeutic Choice (MATCH) Trial Schema. TRK, tyrosine receptor kinase; FGFR, fibroblast growth factor receptor; EZH2, enhancer of zeste homolog 2; PI3K/mTOR, phosphoinositide 3-kinase/mammalian target of rapamycin; ALK, anaplastic lymphoma kinase; PARP, poly ADP ribose polymerase.
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