Search

Top 30 loci associated with metastasis at diagnosis in the discovery set of 541 European osteosarcoma cases.

Relationship of variables to metastasis at diagnosis in the discovery set.

SNPs in the NFIB locus associated with metastasis at diagnosis with P{less than or equal to}1x10-5 in the discovery stage, and functionally annotated with information from the ENCODE and 1000 Genomes Project data.

Associations of the top GWAS and imputed SNP with metastasis at diagnosis in the discovery stage (European ancestry) by inheritance model.

Top genotyped SNP associations with metastasis at diagnosis in the discovery and all replication studies.

Supplementary Figure 1. Manhattan plot of the Discovery stage. SNPs in the NFIB risk locus are highlighted in green. Supplementary Figure 2. LD structure of the NFIB risk locus. Plot was made using the CEU population of the 1000 Genomes Project data with LDlink (ref 54). Supplementary Figure 3. Significant relationship between the genotype of the metastasis associated SNP rs7034162, and expression of NFIB and IGFBP5 in osteosarcoma cell lines and tumors. Significance is based on linear regression comparing the distribution of expression of NFIBbetween the TT homozygous non-risk genotype (combined N=34) of rs7034162 genotypes to the heterozygous risk AT (combined N=10) and the homozygous risk AA genotypes (combined N=2). The green triangle represents the expression levels in the OSA cell line, the blue circle is expression levels in the HOS cell line, and the red square the U2OS cell line expression. These analyses were based on the publically available genotype and expression data from 17 osteosarcoma cell lines and 29 osteosarcoma tumors (ref 20). Supplementary Figure 4. No significant relationship between the genotype of the metastasis associated SNP, rs7034162, and expression of protein-encoding genes FREM1, ZDHHC1, and MPDZ in the neighborhood of NFIB in osteosarcoma cell lines and tumors. Significance is based on linear regression comparing the distribution of expression of FREM1, ZDHHC1, and MPDZ between the TT homozygous non-risk genotype (combined N=34) of rs7034162 genotypes to the heterozygous risk AT (combined N=10) and the homozygous risk AA genotypes (combined N=2). The green triangle represents the expression levels in the OSA cell line, the blue circle is expression levels in the HOS cell line, and the red square the U2OS cell line expression. These analyses were based on the publically available genotype and expression data from 17 osteosarcoma cell lines and 29 osteosarcoma tumors (ref 20). Supplementary Figure 5. The human osteosarcoma cell lines, U2OS and HOS, had higher NFIB protein levels then OSA cells. NFIB levels were determined using immunoblot analysis in the OSA, HOS and U2OS cells both basal (A) and after treatment with siRNA against NFIB (B). Supplementary Figure 6. NFIB expression significantly correlates with IGFBP5 expression in osteosarcoma cell lines and tumors. Significance is based on linear regression comparing the expression levels of NFIB with the corresponding IGFBP5 expression levels. Supplementary Figure 7. Expression levels of IGFBP5 decreases after NFIB suppression of human osteosarcoma cell lines. IGFBP5 expression of OSA, HOS and U2OS cells was determined 48 hours after transfection with control siRNA (si-NEG) or siRNA targeting NFIB (si-NFIB). Graph showing relative expression compared to control treated U2OS cells. Supplementary Figure 8. A model of how the NFIB risk locus leads to changes in NFIB expression and potentially may affect osteosarcoma metastatic potential. The risk allele (right panel) leads to lowered expression of NFIB and NFIB-mediated lower expression of IGFPB5, which then leads to less IGFBP5-mediated inhibition of IGF-1 (right panel, grey arrows), leading to an increase in proliferation, survival and metastasis of osteosarcoma cells (right panel, black arrows). The reference allele (left panel) leads to both higher expression of NFIB and higher expression of NFIB-mediated IGFPB5. In turn, higher IGFBP5 levels leads to increased inhibition of IGF-1 (left panel, black arrows), leading to a decrease in proliferation, survival and metastasis of osteosarcoma cells (left panel, grey arrows). Supplementary Figure 9. Plot of the PCA Eigenvectors of the Discovery stage. Supplementary Figure 10. QQ-plot of the Discovery stage.

Description of participating case studies.

Background: SAR’245 is a clinical-stage site-specific pegylated human IL-2 that blocks IL-2 alpha receptor binding but retains near-native binding affinity for beta/gamma IL-2 receptor subunits. When administered in preclinical models, a unique ‘T-cell remodeling’ MoA characterized by robust increase of CD8+Teff/CD4+Treg coupled with potent NK-cell activation/expansion was observed. Circulating tumor DNA (ctDNA) can be used as a non-invasive biomarker of early clinical response whilst overcoming challenges of obtaining repeat tumor biopsies from patients. Previously, we reported results of the Phase 1 HAMMER study (NCT04009681); herein, we describe an innovative integrative approach that considers peripheral key MoA biomarkers with objective response and dose-limiting toxicity (DLT) rate to help identify the recommended Phase 2 dose (RP2D) for SAR’245. Methods: SAR’245 was given IV as mono Q3W [Cohort B] or Q3W + IV pembro 200 mg Q3W/400 mg Q6W [Cohort C]. Joint modeling was carried out to account for the relationship between dose and 1) MoA biomarkers, and NK cells in blood measured by flow cytometry; 2) response surrogate biomarker: ctDNA measured by Guardant Omni 500 panel; and 3) DLTs. In the model, a latent variable was used to model correlation between DLT and the MoA or response surrogate biomarkers, Bayesian approach was used to derive posterior probabilities (PP) at each dose level of the target region (defined by >20% probability of fold change of biomarker values post-treatment above a predefined threshold and DLT rate Results: Samples from 35 subjects (Cohort B) and 34 subjects (Cohort C) were available. The results from SAR’245 mono suggests that the CD8/CD4 ratio and the concentrations of NK, CD8, and CD4 achieve maximum probability of reaching meaningful modulation (based on pre-defined threshold) around 32 ug/kg. When SAR’245 was combined with pembro, the results with PoM biomarkers showed the best performance at 24-32 µg/kg, while results with ctDNA showed the best results at 16-24 µg/kg. When all parameters were considered, either 24 or 32 µg/kg could serve as an adequate dose at Q3W scheduling. Conclusions: In early oncology studies, joint modeling using non-invasive biomarkers, including MoA and response biomarkers, and a safety profile can inform dose-response relationships and support RP2D selection. This innovative integrative modeling will guide clinical study design. Studies of SAR’245 that further explore the dosing and scheduling are on-going. Disclosures: This study was sponsored by Synthorx, a Sanofi company. Citation Format: Siqing Fu, Gerald S. Falchook, Minal Barve, Meredith McKean, Tira J. Tan, Charlotte Lemech, Cheng E. Chee, Neyssa Marina, Giovanni Abbadessa, Robin Meng, Federico Rotolo, Hong Wang, Jason Deng, Wenting Wang, Rui Wang, Tarek Meniawy. Joint modeling of safety and peripheral mode-of-action (MoA) biomarkers to support RP2D identification in Phase 1 study of SAR444245 (SAR’245) as monotherapy (mono) or combined with pembrolizumab (pembro) in patients with advanced solid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2155.

Purpose: The available questionnaires for quality-of-life (QoL) assessments are age-group specific, limiting comparability and impeding longitudinal analyses. The comparability of measurements, however, is a necessary condition for gaining scientific evidence. To overcome this problem, we assessed the viability of harmonising data from paediatric and adult patient-reported outcome (PRO) measures. Method: To this end, we linked physical functioning scores from the Paediatric Quality of Life Inventory (PedsQL) and the Paediatric Quality of Life Questionnaire (PEDQOL) to the European Organisation for Research and Treatment of Cancer Core Questionnaire (EORTC QLQ-C30) for adults. Samples from the EURAMOS-1 QoL sub-study of 75 (PedsQL) and 112 (PEDQOL) adolescent osteosarcoma patients were concurrently administered both paediatric and adult questionnaires on 98 (PedsQL) and 156 (PEDQOL) occasions. We identified corresponding scores using the single-group equipercentile linking method. Results: Linked physical functioning scores showed sufficient concordance to the EORTC QLQ-C30: Lin's r Z 0.74 (PedsQL) and Lin's r Z 0.64 (PEDQOL). Conclusion: Score linking provides clinicians and researchers with a common metric for assessing QoL with PRO measures across the entire lifespan of patients. (C) 2022 The Author(s). Published by Elsevier Ltd.

PURPOSE The primary aim of this phase III randomized trial was to test whether the addition of vincristine, topotecan, and cyclophosphamide (VTC) to interval compressed chemotherapy improved survival outcomes for patients with previously untreated nonmetastatic Ewing sarcoma. METHODS Patients were randomly assigned to receive standard five-drug interval compressed chemotherapy (regimen A) for 17 cycles or experimental therapy with five cycles of VTC within the 17 cycles (regimen B). Patients were stratified by age at diagnosis (< 18 years and ≥18 years) and tumor site (pelvic bone, nonpelvic bone, and extraosseous). Tumor volume at diagnosis was categorized as < 200 mL or ≥ 200 mL. Local control occurred following six cycles. Histologic response was categorized as no viable or any viable tumor. Event-free survival (EFS) and overall survival (OS) were compared between randomized groups with stratified log-rank tests. RESULTS Of 642 enrolled patients, 309 eligible patients received standard and 320 received experimental therapy. The 5-year EFS and OS were 78% and 87%, respectively. There was no difference in survival outcomes between randomized groups (5-year EFS regimen A v regimen B, 78% v 79%; P = .192; 5-year OS 86% v 88%; P = .159). Age and primary site did not affect the risk of an EFS event. However, age ≥ 18 years was associated with an increased risk of death at 5 years (hazard ratio 1.84; 95% CI, 1.15 to 2.96; P = .009). The 5-year EFS rates for patients with pelvic, nonpelvic bone, and extraosseous primary tumors were 75%, 78%, and 85%, respectively. Tumor volume ≥ 200 mL was significantly associated with lower EFS. CONCLUSION While VTC added to five-drug interval compressed chemotherapy did not improve survival, these outcomes represent the best survival estimates to date for patients with previously untreated nonmetastatic Ewing sarcoma.

Background Dexrazoxane protects from lower-cumulative-dose doxorubicin cardiotoxicity, but the effect of dexrazoxane in children with sarcoma treated with higher-cumulative-dose doxorubicin is unknown. Methods We evaluated children with osteosarcoma (OS) on two Children’s Oncology Group trials with higher dose doxorubicin (375–600 mg/m2) preceded by dexrazoxane (10:1 dexrazoxane:doxorubicin dosing). They were evaluated after the minimum expected treatment time (METT), defined as 28 weeks. Cardiotoxicity was identified by echocardiography and serum N-terminal pro-brain natriuretic peptide (NT-proBNP). Second malignant neoplasm (SMN) data was collected. Results All children had normal left ventricular (LV) systolic function as measured by LV fractional shortening and no heart failure. The end-diastolic septal thickness Z-scores (P Z-scores (P Z-scores were significantly smaller for girls (P P = 0.06). Girls had significantly smaller LV end-diastolic dimension Z-scores normalized to BSA (P Conclusions Dexrazoxane prevented LV dysfunction and heart failure in children with OS receiving higher dose doxorubicin. However, LV structural changes were not fully prevented, especially in girls. As a result, hearts become abnormally small for body size, resulting in higher LV stress. Dexrazoxane did not increase the risk of SMN. Dexrazoxane should be used in this population, particularly for girls, to mitigate anthracycline-induced cardiotoxicity. Trial registrations ClinicalTrials.gov: NCT00003937 (P9754) registered 1 Nov 1999, and NCT00023998 (AOST0121) registered 13 Sept 2001.

Background Ewing sarcoma (EWS) and osteosarcoma (OS) require multidisciplinary treatment. Care at specialized cancer centers (SCC: Children's Oncology Group affiliated and/or National Cancer Institute-designated cancer center) has been found to improve outcomes in patients with leukemia, but studies have not considered location of care and outcomes in EWS and OS patients, an ideal group to evaluate given their specialized multidisciplinary treatment needs. Methods Patients hospitalized with primary EWS and OS (2000-2014) were identified using the California Cancer Registry linked with hospitalization data. Patients were divided into age groups (0-18, 19-39, ≥40 years), and classified on whether they received all versus part/none of their inpatient treatment at a SCC within 1 year of diagnosis. Multivariable Cox proportional hazards regression identified factors associated with survival. Results There were 531 ES and 959 OS patients. Five-year overall survival was better for patients with EWS (all: 63% vs. part/none: 42%) and OS (all: 64% vs. part/none: 47%) who received all of their treatment at a SCC. After adjusting for sociodemographic and clinical factors, receiving all inpatient cancer treatment at a SCC was associated with superior overall survival (EWS HR: 0.49, CI 0.37-0.67; OS HR: 0.78, CI 0.63-0.97). Conclusion Our results suggest that treatment for EWS and OS at a SCC is associated with significantly improved survival even after adjustment for known prognostic factors. The superior survival among those treated at SCCs may be due to having greater access to clinical trials and services at SCCs.

Osteosarcoma is the most common type of bone cancer in children and young adults with a peak incidence in adolescents. It has a propensity for lung metastases and is a prime example of a cancer where cure will only be achieved if many specialities closely cooperate within a dedicated multidisciplinary environment. Neither surgery nor chemotherapy alone will cure many patients, but their combination can lead to long-term, disease-free survival in 60–70%.

PURPOSE To evaluate the safety, pharmacokinetics, and preliminary activity of bemarituzumab in patients with FGFR2b-overexpressing gastric and gastroesophageal junction adenocarcinoma (GEA). PATIENTS AND METHODS FPA144-001 was a phase I, open-label, multicenter trial consisting of the following 3 parts: part 1a involved dose escalation in patients with recurrent solid tumors at doses ranging from 0.3 to 15 mg/kg; part 1b involved dose escalation in patients with advanced-stage GEA; and part 2 involved dose expansion in patients with advanced-stage GEA that overexpressed FGFR2b at various levels (4 cohorts; high, medium, low, and no FGFR2b overexpression) and 1 cohort of patients with FGFR2b-overexpressing advanced-stage bladder cancer. RESULTS Seventy-nine patients were enrolled; 19 were enrolled in part 1a, 8 in part 1b, and 52 in part 2. No dose-limiting toxicities were reported, and the recommended dose was identified as 15 mg/kg every 2 weeks based on safety, tolerability, pharmacokinetic parameters, and clinical activity. The most frequent treatment-related adverse events (TRAEs) were fatigue (17.7%), nausea (11.4%), and dry eye (10.1%). Grade 3 TRAEs included nausea (2 patients) and anemia, neutropenia, increased AST, increased alkaline phosphatase, vomiting, and an infusion reaction (1 patient each). Three (10.7%) of 28 patients assigned to a cohort receiving a dose of ≥ 10 mg/kg every 2 weeks for ≥ 70 days reported reversible grade 2 corneal TRAEs. No TRAEs of grade ≥ 4 were reported. Five (17.9%; 95% CI, 6.1% to 36.9%) of 28 patients with high FGFR2b-overexpressing GEA had a confirmed partial response. CONCLUSION Overall, bemarituzumab seems to be well tolerated and demonstrated single-agent activity as late-line therapy in patients with advanced-stage GEA. Bemarituzumab is currently being evaluated in combination with chemotherapy in a phase III trial as front-line therapy for patients with high FGFR2b-overexpressing advanced-stage GEA.

BackgroundTHOR-707 (SAR444245) is a recombinant human IL-2 molecule irreversibly bound to a PEG chain to block alpha-binding while retaining near-native affinity for beta/gamma IL-2 receptor subunits. We report updated results from the ongoing HAMMER phase 1/2 trial.MethodsSAR444245 was given via IV infusion as monotherapy Q2W [A] or Q3W [B], with pembrolizumab 200mg IV Q3W [C], or Q3W with cetuximab 400mg/m2 IV on D1 then 250mg/m2 IV QW [D] after pre-medication and peri-infusion hydration. A 3+3 design was used to identify the MTD/RP2D in pts with advanced solid tumors. Key objectives included assessments of safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD).Results68 pts, median age 61.5 (37–78) yrs with median 3 (1–10) prior therapies enrolled. Most common tumors: melanoma (n=10), colorectal (n=11). Doses tested by cohort: [A]: 8–16 µg/kg (n=9); [B]: 8–40 µg/kg (n=29); [C]: 8–32 µg/kg (n=20); [D]: 16–24 µg/kg (n=10). The most common (>30%) AEs included pyrexia (52.5%), nausea (50.0%), flu-like symptoms (44.1%), vomiting (36.8%), chills (32.4%), fatigue (32.4%), AST elevation (30.9%). AEs generally resolved promptly with supportive care. Grade(G) 3/4 (>5%) related AEs included ALT/AST elevation (5.9%), and decreased lymphocyte count (26.5% within first 24 hrs, recovering by 48–72 hrs, this lymphocyte migration is mechanistically consistent with immune cell margination). G3/4 CRS was observed in 2 pts. Two DLTs occurred: G3 infusion reaction (32 µg/kg [B]) and G3 AST/ALT/G2 bilirubin elevation with G2 CRS (24 µg/kg [C]). No vascular leak syndrome, QTc prolongation, cardiac, or end organ toxicity was observed. Half-life was ~10 h. Sustained increases in CD8 T and NK cells were observed (fold relative to baseline): monotherapy (1–9.4x and 2–43.3x); with pembrolizumab (0.5–5.78x and 1.5–26.9x); with cetuximab (1.3–7.57x and 3.6–45.4x). Max CD4 and eosinophils increased to 136 cell/µL and 1078 cell/µL. No IL-5 elevation or ADAs were observed. Transient IL-6 increases in 4 pts (500, 627, 1000, 1100 pg/mL) were not associated with AEs. Four pts had confirmed PRs (1 PD1-treated SCC, unknown primary [B]; 2 PD1-naïve BCC and 1 PD1-treated HNSCC [C]); 3 pts had minor responses -- prostate (-24%) and PD1-treated melanoma (-17%) [B]; PD1-treated NSCLC (¬-29%) [C] -- after ≥2 scans. 23 pts completed ≥5 cycles.ConclusionsSAR444245 was well tolerated and demonstrated antitumor activity in heavily pretreated patients, including prior checkpoint inhibitor therapy. Clinical safety, efficacy and PD suggest a wide therapeutic window. Combination with pembrolizumab and cetuximab leveraged SAR44245’s effects on CD8 T and NK cells.Trial RegistrationNCT04009681Ethics ApprovalThe clinical trial was approved by each institutions ethics’ and review board prior to beginning study enrollment.

THOR-707 (SAR444245) is a recombinant human IL-2 molecule that includes a PEG moiety irreversibly bound to a novel amino acid via click chemistry to block the alpha-binding domain while retaining near-native affinity for the beta/gamma subunits. In animal models, THOR-707 improved the anti-tumor benefits of aldesleukin, but without its severe side effects, both as single agent and combined with anti-PD1. Here we report safety, PK/PD, and preliminary anti-tumor activity for THOR-707 as monotherapy and combined with pembrolizumab in the ongoing HAMMER Phase 1/2 trial. THOR-707 was administered via IV infusion as monotherapy Q2W (Cohort A), Q3W (Cohort B), or combined with pembrolizumab 200 mg IV Q3W (Cohort C); escalation follows a 3 + 3 schema to identify the maximum tolerated dose and/or the recommended Phase 2 dose. As of 16 November 2020, 28 pts were enrolled: ECOG 0-1; median age 62 (37-76) yrs; median lines of prior therapies were 3 (1-9; 11 pts had prior anti-PD1). Most common tumor types: colorectal (n=5), melanoma (n=4). Cohort enrollment was A: 8 µg/kg (n=4); B: 8 µg/kg (n=4), 16 µg/kg (n=6), 24 µg/kg (n=7); C: 8 µg/kg (n=4), 16 µg/kg (n=3). No dose-limiting toxicity (DLT) or vascular leak syndrome (VLS) was observed. Most common treatment-emergent adverse events (TEAEs) were flu-like symptoms (46.4%), fever (46.4%), vomiting/nausea (35.7%), chills (32.1%), following the first dose and resolved with standard supportive care. No cumulative toxicity, end organ toxicity, QTc prolongation, or other cardiac toxicity was observed. Grade (G) 3-4 related toxicities in B: 1 G3 rash (8 µg/kg); 1 G4 AST increase, 2 G3 increase in AST/ALT & 1 G4 decrease in lymphocytes (16 µg/kg); 2 G4 decrease in lymphocytes, 1 G4 CRS with G3 hypertension (led to discontinuation), and 1 G3 acute kidney injury (24 µg/kg); C: 1 G3 & 1G4 decrease in lymphocytes (16 µg/kg). CD8 cells (effector & memory) and NK cells increased in Cycle 1 by a median (range) respectively of 3.1 (1.04 - 5.91) and 7.93 (1.71 - 26.85) fold and were sustained until next cycle. There was no meaningful increase in CD4 Tregs or eosinophil counts (a marker of potential VLS), 1.89 (0.86- 5.36) and 1.77 (0.47- 3.65) fold. No anti-drug antibodies (IL-2 or PEG) and no meaningful IL-5 elevations were found. One IL-6 increase at 24 hrs (to 1,000 pg/mL) was observed. Half-life is ~ 10 hours. Three pts have confirmed partial responses: 1 PD-1-naïve basal cell carcinoma; 1 head & neck squamous cell carcinoma with progression after a prior anti-PD-1, ongoing for 9+ mos in C (8 µg/kg); 1 squamous cellular carcinoma of unknown origin, unresponsive to prior anti-PD-1, ongoing for 3+ mos in B (24 µg/kg). Two pts had stable disease for 9 and 6 mos, respectively, with pancreatic (in A, 8 µg/kg) and prostate cancer (in B, 16 µg/kg); 11 pts remained on treatment for ≥5 cycles. Preliminary encouraging results with THOR-707 monotherapy and in combination with pembrolizumab support IL-2 not-alpha preferential activity, validating preclinical models, with initial efficacy and a tolerable safety profile. Dose escalation continues. NCT04009681 Citation Format: Filip Janku, Raghad Abdul-Karim, Arun Azad, Johanna Bendell, Gerald Falchook, Hui K. Gan, Tira Tan, Judy S. Wang, Cheng Ean CHEE, Lina Ma, Jill Mooney, Neyssa Marina, Giovanni Abbadessa, Marcos Milla, Tarek Meniawy. THOR-707 (SAR444245), a novel not-alpha IL-2 as monotherapy and in combination with pembrolizumab in advanced/metastatic solid tumors: Interim results from HAMMER, an open-label, multicenter phase 1/2 Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB041.

PURPOSE: To provide clinically useful gadolinium-free whole-body cancer staging of children and young adults with integrated positron emission tomography / magnetic resonance (PET/MR) imaging in less than 1 h. PROCEDURES: In this prospective clinical trial, 20 children and young adults (11–30 years old, 6 male, 14 female) with solid tumors underwent 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) PET/MR on a 3T PET/MR scanner after intravenous injection of ferumoxytol (5mg Fe/kg) and [(18)F]FDG (2–3 MBq/kg). Time needed for patient preparation, PET/MR image acquisition and data processing was compared before (n = 5) and after (n = 15) time-saving interventions, using a Wilcoxon test. The ferumoxytol-enhanced PET/MR images were compared with clinical standard staging tests regarding radiation exposure and tumor staging results, using Fisher's exact tests. RESULTS: Tailored workflows significantly reduced scan times from 36 to 24 min for head to mid thigh scans (p < 0.001). These streamlined PET/MR scans were obtained with significantly reduced radiation exposure (mean 3.4 mSv) compared to PET/CT with diagnostic CT (mean 13.1 mSv; p = 0.003). Using the iron supplement ferumoxytol “off label” as an MR contrast agent avoided gadolinium chelate administration. The ferumoxytol-enhanced PET/MR scans provided equal or superior tumor staging results compared to clinical standard tests in 17 out of 20 patients. PET/MR had comparable detection rates for pulmonary nodules equal or greater 5 mm (94% vs. 100%), yet detected significantly fewer lung nodules compared to PET/CT for smaller nodules (20% vs 100%) (p = 0.03). [(18)F]FDG-avid nodules were detected with slightly higher sensitivity on the PET of the PET/MR compared to the PET of the PET/CT (59% vs 49%). CONCLUSION: Our streamlined ferumoxytol-enhanced PET/MR protocol provided cancer staging of children and young adults in less than 1 h with equivalent or superior clinical information compared to clinical standard staging tests. The detection of small pulmonary nodules with PET/MR needs to be improved.

BACKGROUND Ewing sarcoma survivors (ESSs) are at increased risk for treatment-related complications. The incidence of treatment-related morbidity and late mortality with aging is unknown. METHODS This study reports survival probabilities, estimated with the Kaplan-Meier method, and the cumulative incidence of cause-specific mortality and chronic conditions among ESSs in the Childhood Cancer Survivor Study who were treated between 1970 and 1986. Piecewise exponential models were used to estimate relative rates (RRs) and 95% confidence intervals (CIs) for these outcomes. Chronic conditions were graded with the Common Terminology Criteria for Adverse Events (version 4.03). RESULTS Among 404 5-year ESSs (median age at last follow-up, 34.8 years; range, 9.1-54.8 years), the 35-year survival rate was 70% (95% CI, 66%-74%). Late recurrence (cumulative incidence at 35 years, 15.1%) was the most common cause of death, and it was followed by treatment-related causes (11.2%). There were 53 patients with subsequent neoplasms (SNs; cumulative incidence at 35 years, 24.0%), and 38 were malignant (14.3% at 35 years). The standardized incidence ratios were 377.1 (95% CI, 172.1-715.9) for osteosarcoma, 28.9 (95% CI, 3.2-104.2) for acute myeloid leukemia, 14.9 (95% CI, 7.9-25.5) for breast cancer, and 13.1 (95% CI, 4.8-28.5) for thyroid cancer. Rates of chronic conditions were highest for musculoskeletal (RR, 18.1; 95% CI, 12.8-25.7) and cardiac complications (RR, 1.8; 95% CI, 1.4-2.3). Thirty-five years after the diagnosis, the cumulative incidences of any chronic conditions and 2 or more chronic conditions were 84.6% (95% CI, 80.4%-88.8%) and 73.8% (95% CI, 67.8%-79.9%), respectively. CONCLUSIONS With extended follow-up, ESSs' risk for late mortality and SNs does not plateau. Treatment-related chronic conditions develop years after therapy, and this supports the need for lifelong follow-up. Cancer 2017;123:2551–60. © 2017 American Cancer Society.

Bemarituzumab is an afucosylated monoclonal antibody against FGFR2b (a FGF receptor) with demonstrated monotherapy clinical activity in patients with late-line gastric cancer whose tumors overexpress FGFR2b (NCT02318329). We describe the rationale and design of the FIGHT trial (NCT03343301), a global, randomized, double-blind, placebo-controlled Phase III study evaluating the role of bemarituzumab in patients with previously untreated, FGFR2b-overexpressing advanced gastroesophageal cancer. Patients are randomized in a blinded fashion to the combination of mFOLFOX6 and bemarituzumab or mFOLFOX6 and placebo. Eligible patients are selected based on the presence of either FGFR2b protein overexpression determined by immunohistochemistry or FGFR2 gene amplification determined by circulating tumor DNA. The primary end point is overall survival, and secondary end points include progression-free survival, objective response rate and safety.

Background The quality of life (QoL) of patients with osteosarcoma (OS) may be adversely affected by the disease or its treatment. Therefore, it is important to understand the QoL of patients undergoing treatment for OS to improve the QoL. We report on the first prospective international QoL study that was embedded within a large randomized clinical trial from 4 national study groups. Objective This paper aimed to describe the QoL study development, methodology, accrual details, and characteristics of the QoL cohort. Methods A total of 2260 patients registered in the EURopean AMerican Osteosarcoma Study-1 (EURAMOS-1), of whom 97.92% (2213/2260) were eligible for the optional QoL assessment and could participate in terms of questionnaire availability. Overall, 61.86% (1369/2213) of patients and/or proxies completed the QoL evaluation at the first assessment time point (E1) after the start of preoperative treatment. The QoL measures used (self- and/or proxy reports) depending on the patient’s age and national study group. Participants and nonparticipants in the ancillary QoL study were compared regarding relevant demographic and disease-related characteristics at registration in the trial. Results The participation rate at time point E1 did not differ with regard to age, gender, the occurrence of pathological fracture, or the presence of any metastases at diagnosis. No differences were found regarding the primary tumor site. Only the national study group affiliation had an influence on participation. Participation decreased linearly with trial progress up to 20% at the final time point of QoL assessment. Conclusions This study demonstrates the feasibility of international cooperation for the purpose of assessing and understanding the QoL of pediatric and adolescent/young adult patients with cancer. Future outcomes of this QoL substudy will help to adapt interventions to improve QoL.

PURPOSE The R2Pulm trial was conducted to evaluate the effect of busulfan-melphalan high-dose chemotherapy with autologous stem-cell rescue (BuMel) without whole-lung irradiation (WLI) on event-free survival (main end point) and overall survival, compared with standard chemotherapy with WLI in Ewing sarcoma (ES) presenting with pulmonary and/or pleural metastases. METHODS From 2000 to 2015, we enrolled patients younger than 50 years of age with newly diagnosed ES and with only pulmonary or pleural metastases. Patients received chemotherapy with six courses of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) and one course of vincristine, dactinomycin, and ifosfamide (VAI) before either BuMel or seven courses of VAI and WLI (VAI plus WLI) by randomized assignment. The analysis was conducted as intention to treat. The estimates of the hazard ratio (HR), 95% CI, and P value were corrected for the three previous interim analyses by the inverse normal method. RESULTS Of 543 potentially eligible patients, 287 were randomly assigned to VAI plus WLI (n = 143) or BuMel (n = 144). Selected patients requiring radiotherapy to an axial primary site were excluded from randomization to avoid excess organ toxicity from interaction between radiotherapy and busulfan. Median follow-up was 8.1 years. We did not observe any significant difference in survival outcomes between treatment groups. Event-free survival was 50.6% versus 56.6% at 3 years and 43.1% versus 52.9% at 8 years, for VAI plus WLI and BuMel patients, respectively, resulting in an HR of 0.79 (95% CI, 0.56 to 1.10; P = .16). For overall survival, the HR was 1.00 (95% CI, 0.70 to 1.44; P = .99). Four patients died as a result of BuMel-related toxicity, and none died after VAI plus WLI. Significantly more patients in the BuMel arm experienced severe acute toxicities than in the VAI plus WLI arm. CONCLUSION In ES with pulmonary or pleural metastases, there is no clear benefit from BuMel compared with conventional VAI plus WLI.

Background The prognostic significance of having extraskeletal (EES) versus skeletal Ewing sarcoma (ES) in the setting of modern chemotherapy protocols is unknown. The purpose of this study was to compare the clinical characteristics, biologic features, and outcomes for patients with EES and skeletal ES. Methods Patients had localized ES and were treated on two consecutive protocols using five-drug chemotherapy (INT-0154 and AEWS0031). Patients were analyzed based on having an extraskeletal (n = 213) or skeletal (n = 826) site of tumor origin. Event-free survival (EFS) was estimated using the Kaplan–Meier method, compared using the log-rank test, and modeled using Cox multivariate regression. Results Patients with extraskeletal ES (EES) were more likely to have axial tumors (72% vs. 55%; P 8 cm (9% vs. 17%; P < 0.01), and less likely to be white (81% vs. 87%; P < 0.001) compared to patients with skeletal ES. There was no difference in key genomic features (type of EWSR1 translocation, TP53 mutation, CDKN2A mutation/loss) between groups. After controlling for age, race, and primary site, EES was associated with superior EFS (hazard ratio = 0.69; 95% confidence interval: 0.50–0.95; P = 0.02). Among patients with EES, age ≥18, nonwhite race, and elevated baseline erythrocyte sedimentation rate were independently associated with inferior EFS. Conclusion Clinical characteristics, but not key tumor genomic features, differ between EES and skeletal ES. Extraskeletal origin is a favorable prognostic factor, independent of age, race, and primary site.

BackgroundThe choice of a local control (LC) modality for Ewing sarcoma (EWS) of the femur is controversial. This study aimed to determine the effect of LC modality on tumor LC and patient outcomes.MethodsThe study reviewed the treatment and outcomes for 115 patients who had EWS of the femur treated with similar chemotherapy in three cooperative group trials. Patient outcomes were analyzed according to the LC modality using the log-rank test and the cumulative incidence of local or distant failure using competing risks regression.ResultsThe median age of the patients was 13 years. The most common tumor location was the proximal femur followed by the mid femur. For 55 patients with available data, the tumor was larger than 8 cm in 29 patients and 8 cm or smaller in 26 patients. For 84 patients (73 %), surgery only was performed, whereas 17 patients (15 %) had surgery plus radiation, and 14 patients (12 %) had radiation only. The 5-year event-free survival (EFS) rate was 65 % (95 % confidence interval [CI], 55-73 %), and the 5-year overall survival (OS) rate was 70 % (95 % CI, 61-78 %). Patient outcomes did not differ significantly according to tumor location within the femur (proximal, mid or distal) or tumor size (

Background The prognostic value of histologic response for osteosarcoma may have changed with induction chemotherapy schedules over time. We hypothesized that the increased intensity of induction therapy provided on INT0133 compared to the Children's Cancer Group study CCG-782 would diminish the impact of histologic response on the risk of events after definitive surgery. Methods Retrospective analysis was performed for patients aged

Background Complete surgical resection of primary tumors is critical for long-term control of high-grade osteosarcoma. Uniform assessment of the extent of surgical resection is important in clinical trials, though the accuracy of this reporting has been poorly studied. Methods We conducted a retrospective cohort study of patients 5–40 years of age with newly diagnosed high-grade resectable osteosarcoma treated as part of the AOST0331 clinical trial at Children's Oncology Group institutions. The extent of surgical resection of the primary tumor was graded as wide or radical by the treating institution. Central assessment of the extent of resection by two orthopedic oncologists was compared with institutional assessment by reviewing pathology and operative reports. Results We included 956 patients who had data available for central review. The extent of resection reported by treating institutions was 536/956 (56%) radical and 420/956 (44%) wide. The extent of resection assessed by central review was 162/956 (17%) radical and 794/956 (83%) wide. The overall discordance rate for the cohort was 43%. Conclusions Institutional reports of radical resection in high-grade osteosarcoma significantly over-estimate the proportion of patients undergoing radical resection. This highlights the need for centralized review and improved accuracy of reporting of the extent of resection. J. Surg. Oncol. 2016;113:351–354. © 2016 Wiley Periodicals, Inc.

11529 Background: Maximum tumor dimension > 8 cm. and large tumor volume have been reported to be adverse prognostic factors in patients with ES but have not been prospectively evaluated in the context of a phase 3 clinical trial with interval compressed chemotherapy. Methods: COG AEWS1031 (NCT01231906) was a randomized phase 3 clinical trial comparing interval compressed chemotherapy regimens in patients with newly diagnosed localized ES of bone and soft tissue. A correlative objective of AEWS1031 was to evaluate tumor size and volume as prognostic factors. Institution-reported dimensions of the primary tumor from baseline imaging were prospectively collected. For inclusion in this analysis, patients had to have at least 1 tumor dimension reported for tumor size analyses and dimensions in 3 axes for tumor volume analyses. Maximum dimension was dichotomized as less than vs. > / = 8cm. Tumor volume was dichotomized as less than vs. > / = 200 mL. Event-free (EFS) and overall survival (OS) from enrollment were calculated using Kaplan-Meier methods and compared between groups using a two-sided log-rank test. Hazard ratios (HR) and confidence intervals (CI) were calculated using the Cox model. Results: The 5-year EFS and OS of the 629 eligible patients was 78% (95% CI: 75-81%) and 87% (95% CI: 84-90%) respectively and there was no significant difference in both EFS and OS between the randomized interval compressed chemotherapy arms of AEWS1031. 590 of 629 (94%) patients were evaluable for maximum tumor dimension and 307 (52%) had tumors > / = 8 cm. Patients with tumors > / = 8 cm were at significantly increased risk for EFS events (p = 0.016) with estimated 5-year EFS of 73.7% (95% CI: 68.1 vs.78.4%) vs. 82.9% (95% CI 77.7-87.1%) for patients with tumors < 8 cm [HR: 1.53 (1.08-2.17)]. For tumor volume, 586 of 629 patients (93%) were evaluable and 180 (31%) had tumors > / = 200 mL. Patients with tumor volume > / = 200 mL were at significantly increased risk for EFS events (p = 0.003) with estimated 5-year EFS of 70% (95% CI: 62.3-76.4%) vs. 81.6% (95% CI: 77.2-85.2%) for patients with tumors < 200 mL [HR: 1.69 (1.2-2.39)]. Conclusions: Maximum tumor dimension and tumor volume as defined are both prognostic in patients with newly diagnosed localized ES treated with interval compressed chemotherapy. Clinical trial information: NCT01231906 .

Background The combination of topotecan and cyclophosphamide is active in relapsed Ewing sarcoma family of tumors (ESFT). The feasibility of adding these agents combined with vincristine (vincristine–topotecan–cyclophosphamide [VTc]) to standard five-drug chemotherapy with vincristine–doxorubicin–cyclophosphamide (VDC) and ifosfamide–etoposide (IE) administered in an interval-compressed (2-week instead of 3-week intervals) schedule was investigated. Procedure Newly diagnosed patients with localized ESFT < 31 years, with good performance status and adequate organ function were eligible. Seventeen alternating cycles of chemotherapy with VTc, VDC, and IE were administered at 2-week intervals. Local control (LC) of the primary tumor occurred following six cycles. Primary endpoints were the ability to deliver chemotherapy in an interval-compressed schedule, and the rate of grade 3 or greater nonhematologic toxicity and grade 4 hematologic toxicity, which delayed chemotherapy by ≥2 weeks. Secondary endpoints were event-free survival (EFS) and overall survival (OS). Results Thirty-five patients with a median age of 11 years were enrolled. The mean time to last dose of chemotherapy prior to LC was 12.6 ± 1.4 weeks and 45.5% of patients received intended chemotherapy without any delay prior to LC. There were no toxic deaths or unexpected toxicities. Five-year EFS was 79.6% (95% confidence interval [CI]: 61.8–89.7%) and 5-year OS was 88% (95% CI: 71.4–95.3%). Conclusions The addition of VTc to standard therapy was tolerable with sufficient interval compression compared to historical standard 3-week cycles.

Cushing’s syndrome (CS) in the pediatric population is challenging to diagnose and treat. Although next-generation medical therapies are emerging for adults with CS, none are currently approved or used in children. Here we describe the first use of mifepristone, a glucocorticoid receptor antagonist, to treat CS in a pediatric subject. The patient, a 14-year-old girl with an 18-month history of metastatic neuroendocrine carcinoma, suffered from fatigue, profound myopathy, irritability, and depression. She was found to have hypertension, hypokalemia, and worsening control of her preexisting type 1 diabetes. In this report, we detail our clinical evaluation that confirmed CS caused by an ectopic adrenocorticotropic hormone secreting tumor. Surgical and radiation therapies were not pursued because of her poor functional status and limited life expectancy, and medical treatment of CS was indicated for symptom relief. Mifepristone treatment provided rapid improvement in glycemic control, insulin resistance, and hypertension as well as significant diminishment of her myopathy and fatigue. Hypokalemia was managed with an oral potassium replacement and dose escalation of spironolactone; no other significant adverse effects were observed. Despite successful palliation of Cushing’s signs and symptoms, the patient died of progression of her cancer. This case demonstrates the safety and efficacy of mifepristone treatment in a pediatric patient with symptomatic, ectopic CS. We conclude that, in appropriate pediatric patients with CS, glucocorticoid receptor antagonism with mifepristone should be considered to control the effects of hypercortisolism and to improve quality of life.

Metastasis is the leading cause of death in patients with osteosarcoma, the most common pediatric bone malignancy. We conducted a multistage genome-wide association study of osteosarcoma metastasis at diagnosis in 935 osteosarcoma patients to determine whether germline genetic variation contributes to risk of metastasis. We identified an SNP, rs7034162, in NFIB significantly associated with metastasis in European osteosarcoma cases, as well as in cases of African and Brazilian ancestry (meta-analysis of all cases: P = 1.2 × 10−9; OR, 2.43; 95% confidence interval, 1.83–3.24). The risk allele was significantly associated with lowered NFIB expression, which led to increased osteosarcoma cell migration, proliferation, and colony formation. In addition, a transposon screen in mice identified a significant proportion of osteosarcomas harboring inactivating insertions in Nfib and with lowered NFIB expression. These data suggest that germline genetic variation at rs7034162 is important in osteosarcoma metastasis and that NFIB is an osteosarcoma metastasis susceptibility gene. Significance: Metastasis at diagnosis in osteosarcoma is the leading cause of death in these patients. Here we show data that are supportive for the NFIB locus as associated with metastatic potential in osteosarcoma. Cancer Discov; 5(9); 920–31. ©2015 AACR. This article is highlighted in the In This Issue feature, p. 893

Background Although multiple prognostic variables have been proposed for Ewing sarcoma (EWS), little work has been done to further categorize these variables into prognostic groups for risk classification. Procedure We derived initial prognostic groups from 2,124 patients with EWS in the SEER database. We constructed a multivariable recursive partitioning model of overall survival using the following covariates: age; stage; race/ethnicity; sex; axial primary; pelvic primary; and bone or soft tissue primary. Based on this model, we identified risk groups and estimated 5-year overall survival for each group using Kaplan–Meier methods. We then applied these groups to 1,680 patients enrolled on COG clinical trials. Results A multivariable model identified five prognostic groups with significantly different overall survival: (i) localized, age

BACKGROUND: Despite advances in treatment, survival from acute lymphoblastic leukemia (ALL) remains lower among non-White children than White children in the US. We investigated the association of race/ethnicity and socioeconomic status (SES) with survival. PROCEDURES: We analyzed 9,295 Californian children (3,251 Whites, 4,890 Hispanics, 796 Asians, and 358 Blacks) aged ≤ 19 years diagnosed with a first primary ALL during 1988-2011. We used the Kaplan-Meier method to estimate survival at 1, 5, and 10 years after diagnosis for three calendar periods. Hazard ratios of death for race/ethnicity, SES, and clinical factors were estimated by Cox regression models. RESULTS: Median follow-up time was 7.4 years (range 0-25 years). Over time, survival after ALL improved steadily, but inequalities persisted across races/ethnicities. Five-year survival (95% confidence interval) was 85.0% (83.6-86.2) for White, 81.4% (78.3-84.0) for Asian, 79.0% (77.8-80.2) for Hispanic, and 74.4% (69.4-78.8) for Black children. In multivariable-adjusted models, the hazard of death was increased by 57% among Black, 38% among Hispanic, and 33% among Asian children compared with White children. Patients residing in the lowest SES neighborhoods at diagnosis had a 39% increased risk of death relative to those living in higher SES neighborhoods. CONCLUSION: Despite significant improvements in survival, non-White children and children residing in low SES neighborhoods experienced worse survival even after adjusting for potential confounders. Our findings highlight the need to capture specific information on disease biology, treatment, and treatment adherence to better understand the predictors of lower survival in minority and low SES groups.

Purpose. To associate baseline patient characteristics and relapse across consecutive COG studies.Methods. We analyzed risk factors for LESFT patients in three randomized COG trials. We evaluated age at enrollment, primary site, gender, tumor size, and treatment (as randomized). We estimated event-free survival (EFS, Kaplan-Meier) and compared risk across groups (log-rank test). Characteristics were assessed by proportional hazards regression with the characteristic of interest as the only component. Confidence intervals (CI) for RR were derived. Factors related to outcome at level 0.05 were included in a multivariate regression model.Results. Between 12/1988 and 8/2005, 1444 patients were enrolled and data current to 2001, 2004, or 2008 were used. Patients were with a median age of 12 years (0–45), 55% male and 88% Caucasian. The 5-year EFS was 68.3% ± 1.3%. In univariate analysis age, treatment, and tumor location were identified for inclusion in the multivariate model, and all remained significant (p< 0.01). Since tumor size was not collected in the last study, the other two were reanalyzed. This model identified age, treatment, tumor location, and tumor size as significant predictors.Conclusion. Age > 18 years, pelvic tumor, size > 8 cms, and chemotherapy without ifosfamide/etoposide significantly predict worse outcome. AEWS0031 isNCT00006734, INT0091 and INT0054 designed before 1993 (unregistered).

Background Survival rates of patients with osteosarcoma have remained stagnant over the last thirty years. Better understanding of biology, new therapeutics, and improved biomarkers are needed. The Children's Oncology Group (COG) addressed this need by developing one of the largest osteosarcoma biorepositories ever, containing over 15,000 tumor and tissue samples from over 1,500 patients. Procedure The biology study P9851 and the banking study AOST06B1 has enrolled 1,787 patients (as of September, 2013). Clinical information was lacking on 510 patients on P9851, who were not enrolled on a concurrent therapeutic trial. The value of these specimens was diminished. The lack of statistical support available for biology projects slowed the analysis of several critical studies. The QuadW Foundation, CureSearch, and the COG formed the Childhood Sarcoma Biostatistics and Annotation Office (CSBAO) to provide the infrastructure and address these needs by linking clinically annotated patient data to archived tissue samples and to develop biostatistical support for childhood sarcoma research. Results Originally 5.3% of samples from the 510 patients on P9851 not enrolled on a therapeutic study had full clinical annotation. The efforts of the CSBAO have linked clinical annotation to 90.8% of those specimens and provided statistical analyses to several studies that had used COG samples. As a result, 24 biology studies in osteosarcoma have been completed and published in peer-reviewed journals. Conclusions These samples and in-silico data are available to the research community for basic and translational science projects to improve the biological understanding and treatment of patients affected by osteosarcoma. Pediatr Blood Cancer 2015;62:450–455. © 2014 Wiley Periodicals, Inc.

Background A growing collection of retrospective studies have suggested that TP53 mutations and/or CDKN2A deletions have prognostic significance in Ewing sarcoma. We sought to evaluate these variables in patients with localized disease treated prospectively on a single Children’s Oncology Group protocol.

Osteosarcoma is a highly aggressive cancer for which treatment has remained essentially unchanged for more than 30 years. Osteosarcoma is characterized by widespread and recurrent somatic copy-number alterations (SCNA) and structural rearrangements. In contrast, few recurrent point mutations in protein-coding genes have been identified, suggesting that genes within SCNAs are key oncogenic drivers in this disease. SCNAs and structural rearrangements are highly heterogeneous across osteosarcoma cases, suggesting the need for a genome-informed approach to targeted therapy. To identify patient-specific candidate drivers, we used a simple heuristic based on degree and rank order of copy-number amplification (identified by whole-genome sequencing) and changes in gene expression as identified by RNA sequencing. Using patient-derived tumor xenografts, we demonstrate that targeting of patient-specific SCNAs leads to significant decrease in tumor burden, providing a road map for genome-informed treatment of osteosarcoma. Significance: Osteosarcoma is treated with a chemotherapy regimen established 30 years ago. Although osteosarcoma is genomically complex, we hypothesized that tumor-specific dependencies could be identified within SCNAs. Using patient-derived tumor xenografts, we found a high degree of response for “genome-matched” therapies, demonstrating the utility of a targeted genome-informed approach. This article is highlighted in the In This Issue feature, p. 1

Background Patients with Ewing sarcoma require local primary tumor control with surgery, radiation, or both. Optimal choice of local control for overall and local disease control remains unclear.

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 x 10(-39); Region 3: rs2853677, P = 3.30 x 10(-36) and PConditional = 2.36 x 10(-8); Region 4: rs2736098, P = 3.87 x 10(-12) and PConditional = 5.19 x 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 x 10(-6); and Region 6: rs10069690, P = 7.49 x 10(-15) and PConditional = 5.35 x 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 x 10(-18) and PConditional = 7.06 x 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

Background Since the initial reports of human epidermal growth factor receptor 2 (HER-2) expression as being prognostic in osteosarcoma, numerous small studies varying in the interpretation of the immunohistochemical (IHC) staining patterns have produced conflicting results. The Children's Oncology Group therefore embarked on a prospective biology study in a larger sample of patients to define in osteosarcoma the prognostic value of HER-2 expression using the methodology employed in the initial North American study describing an association between HER-2 expression and outcome. Procedure The analytic patient population was comprised of 149 patients with newly diagnosed osteosarcoma, 135 with localized disease and 14 with metastatic disease, all of whom had follow up clinical data. Paraffin embedded material from the diagnostic biopsy was stained with CB11 antibody and scored by two independent observers. Correlation of HER-2 IHC score and demographic variables was analyzed using a Fisher's exact test and correlation with survival using a Kaplan–Meier analysis. Results No association was found with HER-2 status and any of the demographic variables tested including the presence or absence of metastatic disease at diagnosis. No association was found between HER-2 status and either event free survival or overall survival in the patients with localized disease. Conclusion HER-2 expression is not prognostic in osteosarcoma in the context of this large prospective study. HER-2 expression cannot be used as a basis for stratification of therapy. Identification of potential prognostic factors should occur in the context of large multi-institutional biology studies. Pediatr Blood Cancer 2014;61:1558–1564. © 2014 Wiley Periodicals, Inc.

Background FPA150 is a fully human antibody against B7-H4 (a transmembrane protein of the B7 family) blocking negative regulatory function in T cells. FPA150 additionally exhibits enhanced antibody-dependent cell-mediated cytotoxicity and in vivo synergizes with anti-PD1 agents. We initiated a phase Ia/Ib evaluation of safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and activity in monotherapy (mono) and with anti-PD1 (combo). A current update of this ongoing trial is provided. Methods Trial design (see table).Table1198PTablePhasePatientsDesignDosesObjectiveStatus1aDose EscalationAdvanced solid tumorsAccelerated Titration; 3+3 escalation0.01-0.3mg/kg; 1-20mg/kgSafety, tolerability & PKComplete; recommended dose (RD) identifiedDose ExplorationB7-H4 + solid tumorsPre- and on-treatment biopsies (Bx)3mg/kg; 10mg/kgSafety, tolerability, PK & PDOngoing1a Combo Safety Lead-InB7-H4+ ovarian cancer3+3 De-escalationFPA150 at RD & 200mg pembrolizumab (pembro)Safety, tolerability, PK & RD FPA150Ongoing1b3 Mono cohortsB7-H4+ breast, ovarian & endometrialDose Expansion (Bx)20mg/kgSafety, tolerability, PD & efficacyOngoing1C1 ComboB7-H4+ ovarian cancerDose Expansion (Bx)200mg pembro & RD FPA150Safety, tolerability, PD & efficacyNot yet started Results At 3/15/2019 data snapshot, 29 pts with solid tumors (12 ovarian, 7 GI, 3 GYN, 3 head/neck, 2 GU, and 2 other) received FPA150 in dose escalation (n=21) and dose exploration (n=8). FPA150 demonstrated ∼ dose-proportional exposure at doses ≥0.3mg/kg and half-life of 1-2 weeks. To date, no dose-limiting toxicities, treatment-related serious adverse events or treatment-related adverse events (TRAEs) leading to drug discontinuation have been identified (1 Grade 3 TRAE of decreased lymphocyte count); others were Grade 1-2, with most common being diarrhea (16.7%), and fatigue (13.8%). Enrollment to phase Ib mono and phase Ia combo is ongoing. Expanded safety, PD and activity from phase Ib mono and phase Ia combo will be presented. Conclusions FPA150 RD for phase Ib mono identified as 20mg/kg (Sachdev, ASCO 2019). Mono appears well tolerated during dose escalation/exploration allowing evaluation in combination therapy. Sachdev, J et al. Phase Ia/1b study of first-in-class B7-H4 antibody, FPA150, as monotherapy in patients with advanced solid tumors. Proc Am. Soc. Clin. Oncol 2019. Clinical trial identification NCT03514121. Legal entity responsible for the study Five Prime Therapeutics, Inc. Funding Five Prime Therapeutics, Inc. Disclosure Z.A. Wainberg: Advisory / Consultancy: Bristol Meier Squibb; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Merck; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Novartis; Advisory / Consultancy: Bayer. J.C. Sachdev: Honoraria (self): Celgene; Honoraria (self): Novartis; Honoraria (self): Puma Technology; Honoraria (self): Tempus; Honoraria (self): Ipsen; Advisory / Consultancy: Celgene; Research grant / Funding (institution): Celgene; Travel / Accommodation / Expenses: Celgene; Advisory / Consultancy: Five Prime Therapeutics. T. Bauer: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses, institution: Ignyta; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Guardant Health; Advisory / Consultancy, Research grant / Funding (institution): Loxo; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution), Self and institution: Pfizer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Moderna Therapeutics; Speaker Bureau / Expert testimony, Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Medpacto; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Mirati Therapeutics; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): AbbVie; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): MabVax; Research grant / Funding (institution): Stemline Therapeutics; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Glaxo Smith Kline; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Genentech; Research grant / Funding (institution): Immunogen; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): Merimack; Research grant / Funding (institution): Immunogen. S. Pant: Advisory / Consultancy: Mirati Therapeutics; Advisory / Consultancy: Eli Lilly; Advisory / Consultancy: Red hill Biopharma Ltd; Advisory / Consultancy: Xencor; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: Novartis; Advisory / Consultancy: Rgenix; Advisory / Consultancy: Sanofi-Aventis; Advisory / Consultancy: Arqule; Advisory / Consultancy: Bristol-Myers Squibb; Advisory / Consultancy: Onco Response; Advisory / Consultancy: Sanofi US Services Inc; Advisory / Consultancy: GlaxoSmith Kline; Speaker Bureau / Expert testimony: Tyme, Inc; Speaker Bureau / Expert testimony: 4-D Pharma. S. Chawla: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Roche; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Threshold Pharmaceuticals; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: CytRx; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Ignyta; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Immune Design; Honoraria (self), Speaker Bureau / Expert testimony: TRACON Pharma; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Karyopharm Therapeutics; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Sarcoma Alliance for REsearch Through Collaboration; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen. N. Marina: Full / Part-time employment: Five Prime Therapeutics. H. Xiang: Full / Part-time employment: Five Prime Therapeutics. W. Deng: Full / Part-time employment: Five Prime Therapeutics. M. Schmidt: Full / Part-time employment: Five Prime Therapeutics. A. Patnaik: Advisory / Consultancy: Bayer; Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech; Advisory / Consultancy, Research grant / Funding (institution): Merck; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Bristo-Myers Squibb; Research grant / Funding (institution): Pfizer; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Plexxikon; Research grant / Funding (institution): Corvus Pharmaceuticals; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Forty-seven; Research grant / Funding (institution): Five Prime Therapeutics; Research grant / Funding (institution): Infinity Pharmaceuticals; Research grant / Funding (institution): Proximagen; Research grant / Funding (institution): Pieris; Research grant / Funding (institution): Surface Oncology; Research grant / Funding (institution): Livson; Research grant / Funding (institution): Vigeo Therapeutics; Research grant / Funding (institution): Astella Pharma. P. LoRusso: Advisory / Consultancy: AbbVie; Advisory / Consultancy: Agios; Advisory / Consultancy: Alexion; Advisory / Consultancy: Ariad; Advisory / Consultancy: Five Prime Therapeutics; Advisory / Consultancy: GenMab; Advisory / Consultancy: Glenmark; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Menarini; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche-Genentech; Advisory / Consultancy: Genentech; Advisory / Consultancy: CytomX; Advisory / Consultancy: Omniox; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Takeda; Advisory / Consultancy: SOTIO; Advisory / Consultancy: Cybrexa; Advisory / Consultancy: Agenus; Advisory / Consultancy: Tyme.

2529 Background: B7-H4, a transmembrane protein of the B7 family, is a negative regulator of T cell function, expressed at high levels on several cancers, including approximately 50% of breast, ovarian and endometrial cancers. FPA150 is a fully human antibody against B7-H4 that blocks inhibition of T cell activity and has enhanced antibody-dependent cell-mediated cytotoxicity. It is the first therapeutic molecule targeting B7-H4 to enter the clinic. We report preliminary results from an ongoing phase 1a/1b study of FPA150 in advanced solid tumors. Methods: Phase 1a included dose escalation in which B7-H4-unselected patients with advanced solid tumors were treated with FPA150 at doses between 0.01 to 20 mg/kg every three weeks (Q3W) in an accelerated titration followed by 3+3 design and a separate dose exploration cohort in which B7-H4+ (H-score≥100) patients were treated at doses of 3 or 10 mg/kg Q3W with mandatory pre- and on-treatment biopsies. Results: As of 12/31/2018, 24 patients with a median of 3 prior therapies were treated with FPA150, 6 of whom were in the B7-H4+ dose exploration cohort. Seven patients from dose escalation were also retrospectively identified as B7-H4+. Most patients received FPA150 at 3 mg/kg (n=8) or 10 mg/kg (n=6). Median number of doses was 3 (range 1-11). No dose-limiting toxicities or treatment-related serious adverse events were reported, and there were no treatment-related AEs (TRAEs) leading to discontinuation of FPA150. Most TRAEs were Grade 1-2, with diarrhea and fatigue most common (16.7%). Grade 3 TRAE hypertension occurred in 1 patient. FPA150 displayed approximately dose-proportional exposure at doses ≥0.3 mg/kg with half-life of 1-2 weeks. Conclusions: FPA150 monotherapy demonstrated a favorable safety profile and evaluation of anti-tumor activity is ongoing. 20 mg/kg Q3W was selected as the recommended dose. Phase 1b enrollment of FPA150 monotherapy in patients with B7-H4+ breast, ovarian and endometrial cancer began in February 2019. We will present updated safety, PK, and preliminary biomarker and efficacy data. Clinical trial information: NCT03514121.

91 Background: GC with FGFR2b overexpression or FGFR2 amplification is associated with a poor prognosis. Bemarituzumab (bema, FPA144) is a first-in-class humanized monoclonal IgG1 antibody that selectively blocks FGFR2b and triggers antibody-dependent cell-mediated cytotoxicity. With favorable safety and activity as a single agent in 2L+ patients with FGFR2b+ GC, the global, randomized, double-blind, placebo-controlled FIGHT study (NCT03343301) is evaluating the front-line combination of bema with mFOLFOX6. We report here the results from the phase I evaluation of the combination. Methods: Patients (pts) with unresectable, locally advanced or metastatic gastrointestinal malignancy (irrespective of FGFR2b status) for whom mFOLFOX6 would be appropriate were eligible for enrollment in the phase I. Her2+ disease or prior treatment with FGF-FGFR inhibitors was not allowed. All pts in the Phase 1 received mFOLFOX6 combined with bema in Q2W cycles. Cohort 1 (3+3) began with bema 6 mg/kg and cohort 2 (Rolling-6) bema 15 mg/kg with one dose of 7.5 mg/kg on C1D8. A dose-limiting toxicity (DLT) evaluation window of 28 days was used for both cohorts. Results: Cohorts 1 and 2 treated 3 pts and 9 pts respectively with a median of 4 and 2 prior lines of therapy. As of the iDMC data-cut on July 24, 2018, the median duration of treatment was 15 wks for cohort 1 and 4 wks for cohort 2; 6/9 pts in cohort 2 continue on treatment. No DLTs were identified. No adverse events (AEs) led to treatment discontinuation. There were no newly identified bema-related toxicities and the only ≥ Gr 2 AE attributable to bema in cohort 2 was fatigue (1 pt/Gr 2). The most common AEs overall were fatigue (6 pts/50%), nausea, vomiting and diarrhea (5 pts/42% each) and were generally attributed to FOLFOX or underlying disease. The ≥ Gr 3 AEs present in ≥ 1 pt were fatigue and neutropenia (2 pts/Gr 3 each). mFOLFOX6 did not affect bema exposure and all evaluable pts in cohort 2 achieved the target ≥ 60 µg/mL trough concentration by day 15. 2/7 pts at the data-cut had FGFR2b+ GC. Conclusions: Bema in combination with mFOLFOX6 has acceptable safety to proceed with the cohort 2 dose to the phase III portion of the FIGHT trial in previously untreated patients with FGFR2b+ GC. Clinical trial information: NCT03343301.

Pediatric osteosarcoma is most commonly diagnosed during adolescence and young adulthood and requires treatment with surgical intervention and intensive chemotherapy. While the exact molecular mechanism leading to osteosarcoma has yet to be elucidated, some syndromes and genetic conditions have been associated with development of the disease. Treatment of osteosarcoma has always included surgical intervention with amputation being most common prior to the introduction of multi-agent chemotherapy. The introduction of multi-agent chemotherapy along with improved surgical techniques have allowed increasing use of limb-salvage surgery. Current investigations including the use of modern chemotherapy show no detectable survival difference between amputation and limb salvage surgery. Standard neo-adjuvant and adjuvant regimens using a combination of doxorubicin, cisplatin and methotrexate, with or without ifosfamide have become the standard in the medical management of osteosarcoma. Other newer agents, such as HER2 receptor monoclonal antibody and muramyl tripeptide phosphatidylethanolamine have also been investigated and are included in this review.

Background Ewing sarcoma (ES) is a malignancy of bone and soft tissue in children and adults. Previous registry-based studies indicate that Latino patients with ES have inferior outcomes compared to non-Latino patients, though an etiology for this difference could not be identified. To explore possible differences that might underlie this disparity, we conducted a retrospective study to compare clinical characteristics, tumor features, healthcare access, and treatment outcomes between Latino and non-Latino patients with ES. Methods Primary data for 218 ES patients treated at two academic medical centers between 1980 and 2010 were collected. Categorical data were compared using Fisher exact tests; Wilcoxon rank-sum tests were used for continuous variables. Survival was estimated using Kaplan–Meier analysis and compared using log-rank testing. Results Latino patients were diagnosed at a younger age (P = 0.014). All other clinical and histological data were similar between groups, including radiologic and histologic response to neoadjuvant chemotherapy. Latino patients had lower socioeconomic status (P = 0.001), were less likely to have insurance (P = 0.001), and were more likely to present to the emergency room at onset of symptoms (P = 0.031) rather than to primary care physicians. Five-year event free survival (EFS) and overall survival (OS) were similar between Latino and non-Latino patients (EFS: 60.5% vs. 50.9% P = 0.37; OS: 77.6% vs. 68.6% P = 0.54). Conclusion Latino patients with ES present at a younger age, and have evidence of impaired access to healthcare. Response to initial therapy appears similar between Latino and non-Latino patients. Pediatr Blood Cancer 2014;61:233–237. © 2013 Wiley Periodicals, Inc.

To evaluate health status and participation restrictions in survivors of childhood extremity sarcomas.Members of the Childhood Cancer Survivor Study cohort with extremity sarcomas who completed questionnaires in 1995, 2003, or 2007 were included.Cohort study of survivors of extremity sarcomas.Childhood extremity sarcoma survivors (N=1094; median age at diagnosis, 13y (range, 0-20y); current age, 33y (range, 10-53y); 49% male; 87.5% white; 75% had lower extremity tumors) who received their diagnosis and treatment between 1970 and 1986.Not applicable.Prevalence rates for poor health status in 6 domains and 5 suboptimal social participation categories were compared by tumor location and treatment exposure with generalized estimating equations adjusted for demographic/personal factors and time/age.In adjusted models, when compared with upper extremity survivors, lower extremity survivors had an increased risk of activity limitations but a lower risk of not completing college. Compared with those who did not have surgery, those with limb-sparing (LS) and upper extremity amputations (UEAs) were 1.6 times more likely to report functional impairment, while those with an above-the-knee amputation (AKA) were 1.9 times more likely to report functional impairment. Survivors treated with LS were 1.5 times more likely to report activity limitations. Survivors undergoing LS were more likely to report inactivity, incomes$20,000, unemployment, and no college degree. Those with UEAs more likely reported inactivity, unmarried status, and no college degree. Those with AKA more likely reported no college degree. Treatment with abdominal irradiation was associated with an increased risk of poor mental health, functional impairment, and activity limitation.Treatment of lower extremity sarcomas is associated with a 50% increased risk for activity limitations; upper extremity survivors are at a 10% higher risk for not completing college. The type of local control influences health status and participation restrictions. Both of these outcomes decline with age.