Children’s Oncology Group’s 2023 Blueprint for Research: Bone Tumors

Abstract

The Children’s Oncology Group (COG) Bone Tumor Committee is responsible for clinical trials and biologic research on localized, metastatic and recurrent osteosarcoma and Ewing sarcoma (EWS). Results of clinical trials in localized disease completed and published in the past 10 years have led to international standard of care chemotherapy for osteosarcoma and EWS. A recent focus on identifying disease subgroups has led to the identification of biologic features associated with poor outcome including the presence of circulating tumor DNA (ctDNA) at diagnosis, and specific genomic alterations -- MYC amplification for osteosarcoma and STAG2 and TP53 mutation for EWS. Studies validating these potential biomarkers are underway. Clinical trials evaluating the addition of multi-targeted kinase inhibitors, which are active in relapsed bone sarcomas, to standard chemotherapy are underway in osteosarcoma and planned in EWS. In addition, the committee has data analyses and a clinical trial underway to evaluate approaches to local management of the primary tumor and metastatic sites. Given the rarity of bone sarcomas, we have prioritized international interactions and are in the process of forming an international data sharing consortium to facilitate refinement of risk stratification and study of rare disease subtypes.

INTRODUCTION

For osteosarcoma and Ewing sarcoma (EWS), treatment relies on intensive chemotherapy and local control with surgery and/or radiation for both primary and metastatic disease. The COG Bone Tumor Committee (referred to as the Committee hereafter) has conducted pivotal trials establishing current international standards of care. As with other sarcomas, multi-targeted kinase inhibitors (mTKIs) demonstrate activity in relapsed and refractory disease warranting further study. The Committee has clinical trials combining mTKIs and chemotherapy in newly diagnosed osteosarcoma and planned for EWS. Genomic characterization of bone sarcomas has not yet identified opportunities for existing molecularly targeted therapies. Similarly, immunotherapy has yet to make a significant impact in bone sarcomas.

Several outstanding questions significantly impact clinical trial conduct and patient care. Essentially all well-studied cancers have biologic subtypes whose identification explain resistance to upfront therapy, predict recurrence, and identify new potential therapies. The Committee is utilizing available clinical trial data and generating genomic data with the goal to more precisely risk-stratify bone sarcomas beyond the current system whereby the presence or absence of metastatic disease and, for osteosarcoma, pathologic response are used. Drugging the known molecular basis of these diseases – the canonical translocation for EWS and chromosomal instability for osteosarcoma – is an area of active investigation with some promising approaches emerging. To facilitate the investigation of new drugs, the Committee has utilized historical clinical trial data to inform clinical trial design in relapsed/refractory patients facilitating the efficient conduct of phase 2 trials with novel therapies in these populations.

STATE OF THE DISEASE – CLINICAL

Ewing Sarcoma

EWS is a classic translocation-associated sarcoma of bone (approximately 80% of patients) and soft tissues (approximately 20% of patients), with a peak incidence in adolescence and young adults (AYA). With <1,000 new cases per year annually in the United States¹, collaborative research is essential to improve outcomes. As a result of sequential COG clinical trials, outcomes for patients with localized disease were improved (5-year event-free survival (EFS) is 87%) through chemotherapy intensification with every 2 week vincristine/doxorubicin/cyclophosphamide and ifosfamide/etoposide (VDC/IE) chemotherapy(Figure 1).² In contrast, patients with newly diagnosed metastatic or recurrent disease have not seen improvements in outcomes for several decades. For example, on the most recently completed COG trial AEWS1221, the 3-year EFS rate was 38.3%³. Importantly, a range of rational strategies to intensify therapy for these patients have not achieved improved outcomes, highlighting a degree of intrinsic chemotherapy resistance for these patients. Likewise, most patients with recurrent EWS will not survive. COG analyses have provided important outcome data for this population, including a median overall survival (OS) rate of 9 months after first relapse⁴ and a 12.7% EFS rate at 6 months for patients treated on phase 2 trials mainly for multiply recurrent disease⁵. A critical focus for the field therefore is to develop novel strategies for these patients with unsatisfactory survival.

Figure 1.

Improved outcomes in localized EWS through COG trials of chemotherapy intensification.

EFS=Event-free survival; EWS=Ewing sarcoma; IE=ifosfamide and etoposide; standard timing = every 3 weeks; intensive timing = every 2 weeks

Osteosarcoma

High-grade osteosarcoma has a slightly higher incidence than EWS and is the most common primary bone malignancy with a peak presentation during the pubertal growth spurt⁶. There is a later “second” peak incidence in adults with similar outcomes to AYA patients when treated with cytotoxic chemotherapy treatment⁷. Osteosarcoma can occur after radiation therapy, and it has long been recognized as a malignancy associated with hereditary retinoblastoma and Li Fraumeni syndrome, caused by RB1 and TP53 germline mutations, respectively. A recent study of germline whole exome sequencing of over 1,000 osteosarcoma cases, 40% contributed by COG patients, revealed pathogenic or likely pathogenic germline mutations present in almost 30% of patients⁸.

Outcomes in localized osteosarcoma have plateaued since the early 1980s when the survival benefit of adjuvant systemic therapy in addition to complete surgical resection was demonstrated. The 5-year EFS is 60% (95% CI: 57–62%) and 5-year OS is 76% (95% CI: 74–78%)⁶. In localized osteosarcoma, poor tumor necrosis (≤90%) after neoadjuvant chemotherapy, an axial skeleton tumor site, age >18, and having a large primary tumor (≥1/3 of the involved bone) portend worse outcomes⁹. Prognosis is worse for patients with metastatic disease, with 5-year EFS of 28% (95% CI: 23–33%) and 5-year OS of 45% (95% CI: 39–50%)⁹. The most frequent sites of metastases are the lungs or bone sites distant from the primary tumor¹⁰. The most recent phase 3 trial in newly diagnosed osteosarcoma, an international trial into which COG enrolled the majority of patients, evaluated chemotherapy intensification and immunotherapy but failed to demonstrate improved outcomes with either approach^11,12. Further, there is a significant burden of early and late side effects of treatment. Hence, the major focus of clinical trials in osteosarcoma is on novel therapies. A Committee publication regarding poor outcomes in recurrent disease is frequently utilized to inform clinical trial design¹³.

STATE OF THE DISEASE – BIOLOGICAL

Ewing Sarcoma

EWS is defined by the canonical FET::ETS fusion, most commonly EWSR1::FLI1^14,15. This fusion protein most often joins exon 7 of EWSR1 to either exon 6 (60%) or exon 5 (25%) of FLI1 ¹⁵. Other rare variants involve alternative exons of EWSR1 or FLI1, or alternative fusion partners such as ERG, ETV1, ETV4 or FEV^16–20. Studies by the COG and others showed an absence of prognostic significance of exon 6 vs. exon 5 fusions in spite of a higher proliferative rate in the lab for exon 6 fusions^21,22. The prognostic significance of rarer variant fusions is incompletely investigated.

Like other translocation-positive sarcomas, the genetic background of EWS is characterized by few other recurrent mutations. Copy number alterations (CNAs) are the most common feature with gains of chromosome 8 (50% of cases), chromosome 2 (25% of cases), 1q (25% of cases) and loss of 16q (30%) being the most common^23–26. Mutations in STAG2 (15–20%), TP53 (5–10%), and CDKN2A (10–12%)^24,26 are rare but studies utilizing samples from children on COG trials and a recent international consensus report suggest that they may be prognostically significant^23,27. An additional feature associated with poor outcome, also identified through analysis of samples from Ewing patients enrolled on COG studies, is the detection of circulating tumor DNA (ctDNA) at the time of diagnosis²⁸. If validated, these findings may provide opportunitites to biologically stratify patients based on the combination of clinical and molecular factors. Validation is underway using tissue from patients enrolled on prospective COG clinical trials. Meanwhile, basic biology work continues to better understand how these mutations serve as disease modifiers in the background of a clear oncogenic driver, EWSR1::FLI1 ^29,30.

The dependence of EWS cells on the canonical FET::ETS fusion is quite clear and has been known for more than 25 years, but transcription factors are challenging drug targets particularly for proteins characterized by low complexity domains as found in the 5’ EWSR1 portion of EWSR1::FLI1^31,32. While the initial clinical evaluation of cytarabine, mithramycin, TK216, trabectedin, and seclidemstat (LSD1 inhibitor) have been disappointing, new second generation inhibitors with improved toxicity profiles, the mithramycin analog AIT-102 and lurbinectedin show promise^33–40. These initial negative clinical studies may reflect the need for alternative schedules of administration for transcription factor drug targets, as has been suggested preclinically⁴¹. Emerging data suggest an alternative schedule of trabectedin in combination with low-dose irinotecan may be effective with confirmed partial responses reported ⁴² Finally, immunotherapy has not yet demonstrated robust activity in EWS with active ongoing efforts exploring this potential therapeutic approach^43,44.

Osteosarcoma

The osteosarcoma genome is characterized by copy number gains and losses and mostly non-recurrent fusions suggesting it develops due to chromosomal instability^45–48. TP53 loss is nearly universal as are alterations in cell cycle genes⁴⁶. Recurrent RB1 loss and amplification of CDK4, CCNE1 and 6p21 containing CCND3 have been noted by multiple groups^45–47. Other frequent genomic alterations observed in osteosarcoma include amplification of PDGFRB often with adjacent genes KDR and KIT and loss of ATRX through deletion of inactivating mutations. Emerging approaches to target chromosomal instability through targeting kinases involved in DNA damage repair and exploring strategies related to BRCA1 functional deficiency such as PARP inhibitors⁴⁹ may have relevance in osteosarcoma given the presence of mutational signature 3 in 30% of cases. Data regarding whether the DNA damage leading to the complex osteosarcoma genome is an ongoing process after diagnosis⁵⁰ are emerging as are data regarding epigenetic and metabolic acclimations of metastasis and progression^51,52. Immune therapies have been and are being actively investigated with single agent immune checkpoint inhibitors lacking a clinical signal alone⁵³. A potentially promising approach is antibody-drug conjugates targeting membrane proteins selectively expressed on osteosarcoma cells⁵⁴.

MAJOR RECENT FINDINGS

Ewing Sarcoma

The Committee has four recently reported major findings. First, we completed long-term follow-up of AEWS0031, a phase 3 trial comparing standard timing with vincristine/doxorubicin/cyclophosphamide alternating every three weeks with ifosfamide/etoposide (VDC/IE regimen) to interval compressed VDC/IE given every two weeks⁵⁵. These 10-year follow-up data demonstrate the EFS advantage of interval-compressed chemotherapy is maintained, show an OS advantage with interval compression, and report similar rates of second malignancy with either schedule. AEWS0031 results established a North American standard of care which was extended internationally with the recent EuroEwing2012 trial results demonstrating superiority of interval-compressed VDC/IE regimen compared to a different European standard regimen⁵⁶.

Our successor trial for patients with localized EWS, AEWS1031, evaluated the role of vincristine/topotecan/cyclophosphamide (VTC) in this population². Patients were randomized to interval-compressed VDC/IE regimen or interval-compressed chemotherapy with VDC/IE/VTC. The addition of VTC did not improve 5-year EFS (79%) compared to interval-compressed VDC/IE (78%). The outcomes of patients on AEWS1031 which included adult patients are the best reported by any cooperative group trial for this population further confirming the role of interval-compressed chemotherapy and extending it as a standard beyond pediatrics.

In the newly-diagnosed metastatic setting, we completed the AEWS1221 trial evaluating the role of IGF-1R inhibition³, based upon a large number of phase 1 and 2 trials demonstrating activity of that approach in patients with relapsed EWS. Patients on AEWS1221 were randomized at study entry to interval-compressed VDC/IE vs. that same therapy plus the IGF-1R monoclonal antibody ganitumab. The trial enrolled 298 eligible patients over 4.25 years, demonstrating the ability of the COG to complete a randomized trial in a feasible timeline in this rare subset of a rare disease. Ganitumab did not improve outcomes (3-year EFS 39.1%) compared to interval-compressed chemotherapy (3-year EFS 37.4%) and may have increased toxicity, including pneumonitis. Importantly, AEWS1221 included the option for stereotactic body radiotherapy (SBRT) to sites of bone metastasis and was the first COG trial to evaluate SBRT.

From a biology perspective, we have leveraged our rich biospecimen archive to provide new biological insights in this disease. In the past decade, specimens from patients enrolled on COG tumor banking protocols have been distributed for 23 projects. Analyses of COG specimens have revealed that the presence of ctDNA at the time of diagnosis and loss of STAG2 protein by immunohistochemistry^27,28 are each associated with poorer prognosis. In addition, we determined that translocations are incompletely characterized by local testing ⁵⁷.

Osteosarcoma

COG sites contributed the majority of the 2,260 patients who enrolled on the international collaborative phase 3 EURAMOS1⁵⁸ trial, also known as AOST0331, for newly diagnosed osteosarcoma. Results, published in 2015 and 2016^11,12,58 showed no statistically significant difference in EFS or OS for patients with >90% necrosis to preoperative chemotherapy who were randomized to the addition of IFN-α−2b maintenance following the chemotherapy regimen methotrexate, adriamycin and cisplatin (MAP). Patients with poor response (≤90% necrosis after preoperative chemotherapy) randomization to MAP plus Ifosfamide/Etoposide (IE) compared to those randomized to MAP alone also did not have improved EFS or OS. There was increased toxicity seen in patients receiving MAP/IE. This trial therefore confirmed that ifosfamide/etoposide are not recommended to be added to MAP in upfront treatment of osteosarcoma patients based on necrosis and established MAP as an international standard of care for AYA patients.

The Committee focused its efforts on identifying drugs with signals of activity in the relapsed setting which could be combined with chemotherapy in trials in newly diagnosed patients aiming to improve OS. The approach utilizes a historical benchmark for EFS based on analysis of COG legacy clinical trial data¹³. Osteosarcoma-specific endpoints are required because the tumor has a calcified bone matrix that does not shrink in response to active therapy⁵⁹ and because 25% of the recurrent patient population undergoes, as a standard of care treatment approach, resection of measurable disease. Utilizing this approach, we were able to study four new agents in recurrent osteosarcoma though none of them demonstrated sufficient efficacy for further investigation(Table 1) ^60–63. These studies had rapid patient accrual, including AYA patients, revealing an unmet need for trials in this patient population. In addition, the osteosarcoma-specific endpoints we proposed have been widely adopted, with similar endpoints being adopted for non-COG trials in this patient population and over 120 citations of our original publication. Several industry, collaborative group, and academic trials of multi-targeted kinase inhibitors in recurrent osteosarcoma have been conducted. These have demonstrated consistent class efficacy as measured by improvements in progression-free survival durations and rates compared to the historical benchmark and randomized controls (Table 1)^64–68.

Table 1.

Phase 2 trials of new agents in osteosarcoma conducted by COG and select phase 2 trials of mTKI conducted by other groups

Phase 2 Trial	Drug and mechanism	Relapsed Disease States Included	Target change in % Progression Free	% PF	Accrued (N)	Accrual Duration (mos)
AOST 1322 61	Eribulin (microtubule inhibitor)*	Measurable	20%➔40% @ 4 mos	0%	16	4
AOST 1521 63	Glembatumumab (GPNMB-targeting ADC)*	Measurable	20%➔40% @ 4 mos	13.6% (3/22)	22	6
AOST 1321 60	Denosumab* (RANKL Ab)	Measurable NED	20%➔40% @ 4 mos 30%➔50% @ 12 mos	6.7% (1/15) 26.3% (10/38)	16 38	6 22
AOST 1421 62	Dinutuximab + GM-CSF (GD2 Ab)	NED	30%➔50% @ 12 mos	28.2% (11/39)	39	24
PEPN1924 72	Trastuzumab deruxtecan (ADC)	Measurable	PFS @ 6 mos	11% (1/9)	9	7
Cabozantinib67	mTKI (VEGFR2/MET/AXL)	Measurable	PF @ 4 mos	71%	45 OS	39
Regorafenib68	mTKI (VEGF/PDGFR/FGFR/KIT/RET/RAF)	Measurable	PF @ 4 mos	44.4% Rego vs 0% placebo	43 (38 evaluable)	30

PF = progression free; NED=no evidence of disease; Ab=Antibody; ADC=Antibody-drug conjugate; mTKI=multi-targeted tyrosine kinase inhibitors; mos=months; GPNMB=glycoprotein non-metastatic protein B; RANKL=Receptor activator of nuclear factor kappa-Β ligand; GM-CSF=granulocyte-macrophage colony-stimulating factor; PF=Progression-free; OS=osteosarcoma

^*First clinical trial in children

To address some of the high-priority biology questions, emphasis has been placed on supporting basic science investigation in osteosarcoma. There were 939 distinct patients with specimens banked through protocol AOST06B1 and stored at the Biopathology Center. With the opening of Project:EveryChild (APEC14B1) in October 2015, AOST06B1 closed to enrollment in December 2017. In the last decade, biospecimens have been distributed to 26 projects. Results of these studies have provided proof of principle for biologic subtypes associated with treatment response and resistance such MYC amplification and the presence of ctDNA at diagnosis with poor outcome^28,69.

STRATEGIC APPROACH

The primary focus of the Committee continues to be to design and conduct clinical trials leading to improved patient outcomes and decreased toxicity. In patients with relapsed/refractory disease, the Committee prioritizes clinical trials focusing on determining whether new agents with pre-clinical activity have clinical activity. In newly diagnosed patients, we focus on assessing the impact of adding to chemotherapy novel agents which, when given to relapsed patients, show a clinical signal of activity. Clinical trials to be pursued are discussed further below.

Moreover, we employ a multidisciplinary therapeutic approach to trial design as well investigating novel local control approaches to disease management at primary and metastatic sites with surgery and radiation. In osteosarcoma, the COG Surgery Committee identified the approach to resection of lung metastasis in osteosarcoma as the highest priority surgical local control question leading to the design of AOST2031 discussed below. We are similarly evaluating local control outcomes on our most recent trials for patients with EWS in order to determine risk factors for local recurrence which can then be addressed with improvement in local control approaches in subsequent trials.

Additional strategic priorities are those that will prepare the Committee to design the next generation of clinical trials in EWS and osteosarcoma. Our approach has been to organize and harmonize clinical data and investigate associated biospecimens to further develop and validate clinical-biological subtyping of bone sarcomas. For example, preliminary data suggest that osteosarcoma may be divided into unique biologic subtypes with distinct prognostic implications^45,70 based on the presence of MYC amplification. The Committee is a third of the way done with a case-control study using COG banked samples to validate this observation⁷¹. In an analysis of samples from patients enrolled on COG banking studies, the detection of ctDNA at the time of diagnosis has been associated with poor outcome in both EWS and osteosarcoma.²⁸ COG is contributing samples to a prospective study validation of these findings regarding ctDNA and outcome which will also assess changes in ctDNA over time. Other examples of studies underway within the committee utilizing banked samples include AEWS18B1, aimed at validating the reported association between STAG2 and TP53 outcome in a 350-patient cohort who received treatment with interval compressed VDC/IE on COG trials.

The Committee has embarked on an international data-sharing effort to facilitate refinement of risk prediction and study rare subtypes. The Harmonization International Bone Sarcoma Consortium (HIBiSCus), memorandum of understanding was signed in April 2021 and data contributor agreements are in process. The Data for the Common Good (D4CG) will host the aggregated data, making it available for use.

The Committee further facilitates biologic discovery by supporting scientists requesting samples. We provide detailed sample acquisition guidance in AOST2031 and have embedded a patient-derived xenograft study into this protocol. We continue efforts to improve the utility of banked specimens by incentivizing submission of frozen samples and samples from metastatic sites with ongoing pathology review and nucleic acid extraction of specimens {Sonja Chen, 2022 #57}.

KEY TRIALS TO BE PURSUED

Ewing Sarcoma

The committee has plans to pursue trials in all three clinical groups: newly diagnosed localized disease; newly diagnosed metastatic disease; and recurrent disease (Table 2). In the newly diagnosed localized population, we are validating clinical and molecular factors to inform a future risk-stratified trial. Guiding principles will be therapy reduction (e.g., fewer cycles of VDC/IE) for patients with defined low risk localized tumors and addition of targeted therapies for patients with defined high-risk localized tumors. Candidate biomarkers include STAG2 mutation and protein expression status, TP53 mutation status, baseline ctDNA burden, and response to therapy.

Table 2.

Ongoing and Planned Clinical Trials in Ewing Sarcoma and Osteosarcoma

Trial Number	Patient population	Phase	Intervention	Primary outcome measure	Status
Ewing Sarcoma
AEWS2231	Newly dx, metastatic	3	VDC and either VIR or IE	EFS	In development
ADVL1921	Recurrent	2	irinotecan/temozolomide alone or with palbociclib	EFS	Active
Pending assigned study number; Newly Diagnosed Task Force	Newly dx, localized	Unk	Risk-based therapy	Unk	In development
Osteosarcoma
AOST2032	Newly dx	Feasibility, 2/3	Cabozantinib + MAP	EFS	Active
AOST2031	Lung only metastatic (newly diagnosed and recurrent)	3	Randomized: thoracotomy or thoracoscopy	Pulmonary EFS	Active
AOST2121	Recurrent, fully resected	2	OST31–164 Her2-targeting Listeria	EFS	Active
PEPN1924	Recurrent	2	Trastuzumab Deruxtecan	EFS	Active
AOST2221	Recurrent, fully resected	2	Regorafenib	EFS	In development

VDC=vincristine/doxorubicin/cyclophosphamide; VIR=vincristine/irinotecan/regorafenib; EFS=event-free survival; MAP=methotrexate/adriamycin/cisplatin; Unk=Unknown; HER2=human erythroblastic oncogene B

In the newly-diagnosed metastatic population, we are pursuing the combination of vincristine/irinotecan/regorafenib (VIR) added to VDC in a randomized phase 3 trial compared to VDC/IE. Patients on the VIR arm will also receive maintenance regorafenib. This proposed trial will be the first in COG to include central molecular confirmation of EWS translocation status and the first to include patients with molecularly-defined other round cell sarcomas in a parallel cohort.

In the relapse population, we are contributing to an ongoing international randomized evaluation of irinotecan/temozolomide with or without palbociclib (NCT03709680). In addition, we work closely with COG’s Developmental Therapeutics Committee to monitor for signals of activity emerging from PEP-CTN studies that might inform a phase 2 trial for patients with relapsed EWS. Drugs currently being evaluated in EWS include the Beta-catenin pathway inhibitor tegavivint and the ATR inhibitor BAY1895344.

Osteosarcoma

As stated above, the class effect of angiogenesis-inhibiting mTKIs have clear signal of activity in relapsed osteosarcoma patients. Thus, our approach in the frontline is a feasibility (to optimize dose and schedule and evaluate safety of this novel combination) followed by a phase 2/3 randomized controlled clinical trial investigating to MAP with or without the addition of cabozantinib in both the localized and metastatic populations (NCT05691478). This opened to enrollment in 2023 and includes six months of cabozantinib as maintenance for those randomized to receive it (Table 2).

While chemotherapy and surgery often address the primary site of osteosarcoma, pulmonary recurrence is the most likely route of failure for initially localized disease and the most common site of metastases at presentation. The optimal approach to the surgical management of pulmonary metastases is not clear. The Surgery and Bone Tumor Committees developed AOST2031 to address this critical surgical question by randomizing the surgical approach in a phase 3 study (Figure 2, NCT05235165). This trial is designed to determine if open thoracotomy is superior to thoracoscopic resection for thoracic EFS in patients with oligometastatic pulmonary osteosarcoma. Secondary aims include quality of life assessments utilizing patient reported outcomes. Biology and pathology correlative aims will leverage resected specimens to generate multi-omic data and well-characterized, clinically annotated models of metastatic osteosarcoma.

Figure 2.

AOST2031

In the relapse setting, we continue to pursue clinical trials to assess new drugs for osteosarcoma. An industry-partnered phase 2 trial, AOST2121 launched in 2021 is examining OST31–164, a live-attenuated Listeria bacterial vector and plasmid system coupled with internal and external epitopes of the Her2 receptor, as adjuvant therapy after surgical remission in pulmonary-only relapse. The trial is ongoing with swift accrual. A study of adjuvant regorafenib after resection of pulmonary metastatic disease is in development.

CONCLUSIONS

Over the past 10 years, the Committee’s clinical trials have contributed significantly to harmonization of standard of care chemotherapy for localized disease across the young adult age spectrum and internationally. While we lack an agreed upon risk stratification in localized disease, the Committee activities dedicated to clinical data harmonization efforts and analysis of associated biospecimens hold the promise for identifying subgroups groups in bone sarcomas. Metastatic bone sarcomas continue to be challenging without survival improvements, with ongoing Committee efforts focused on an important local control question in osteosarcoma and addition of mTKIs to chemotherapy in both EWS and osteosarcoma. New strategies including biologic insights and novel agents will be needed to improve outcomes in relapse bone sarcoma patients. We have a clearly delineated strategy for the study of new agents with agents targeting disease specific surface antigens prioritized for study in osteosarcoma and agents affecting the characteristic translocation such as alternative dose trabectidin prioritized for EWS.

Abbreviation Key:

ATR

Ataxia telangiectasia and Rad3 related

ATRX

alpha-thalassemia/mental retardation, X-linked

AYA(s)

Adolescents and young adult(s)

BRCA1

Breast cancer type 1 susceptibility

CCND3

Cyclin D3

CCNE1

Cyclin E1

CDK4

Cyclin-dependent kinase 4

CDKN2A

Cyclin-dependent kinase inhibitor 2A

CI

Confidence Interval

CNA

Copy Number Alterations

COG

Children’s Oncology Group

ctDNA

Circulating tumor DNA

D4CG

Data for the Common Good

DFS

Disease-free survival

DNA

Deoxyribonucleic acid

EFS

Event-free survival

ERG

ETS-related gene

ETS

erythroblast transformation-specific

ETV

E twenty-six

EURAMOS

European and American Osteosarcoma Study group

EWS

Ewing sarcoma

EWSR1

Ewing Sarcoma ribonucleic acid binding protein 1

FDA

Food and Drug Administration

FET

Female Expressed Transcript

FEV

Fifth Ewing Variant

FLI/FLI1

Friend Leukemia Integration 1

HIBiSCus

Harmonization International Bone Sarcoma Consortium

JCO

Journal of Clinical Oncology

KDR

Kinase Insert Domain Receptor

KIT

receptor tyrosine kinase that responds to stem cell factor

LSD1

Lysine-specific demethylase 1

MAP

Methotrexate, Adriamycin (Doxorubicin) and Cisplatin

mTKIs

multi-targeted kinase inhibitors

MYC

myelocytomatosis

NCI

National Cancer Institute

NIH

National Institute of Health

PARP

Poly (ADP-ribose) polymerase

PEP-CTN

Pediatric Early Phase Clinical Trials Network

PGDFRB

Platelet derived growth factor receptor beta

OS

Overall survival

RB1

Retinoblastoma 1

SBRT

Stereotactic Body Radiation Therapy

SES

Socioeconomic status

STAG2

Stromal Antigen 2

TP53

Tumor protein P53 or transformation-related protein 53

VDC/IE

Vincristine, Doxorubicin, Cyclophosphamide alternating with Ifosfamide and Etoposide

VIR

Vincristine, Irinotecan and Regorafenib

VTC

Vincristine, Topotecan and Cyclophosphamide