Real-world evidence on perioperative chemotherapy in localized soft tissue sarcoma of the extremities and trunk wall; a population-based study.

BACKGROUND: Data from the real-world setting on perioperative chemotherapy in high-risk, localized soft tissue sarcoma (STS) is limited. Real-world data (RWD) includes data derived from patients treated outside clinical trials and often captures long-term follow-up not recorded in clinical trials. The aim of this study was to provide population-based, real-world evidence on perioperative chemotherapy in localized STS. MATERIAL AND METHODS: Adult patients with localized STS in the extremities or trunk wall treated at Oslo University Hospital, Oslo, Norway from 1998 to 2017 were included in the study. Data were extracted from a prospectively maintained database, supplemented by retrospective review of medical records. RESULTS: The total study cohort included 806 patients, of whom 154 (19%) received perioperative chemotherapy. A regimen with anthracycline and ifosfamide was given in 141 of 154 cases (92%). During long-term follow-up two patients developed secondary malignancies, cardiac toxicity was registered in 11 patients (7%) and renal toxicity in 12 patients (8%). Seventy-one of 154 patients (46%) were treated outside of clinical trials and constituted the RWD cohort. The median age at surgery was slightly lower and there were more synovial sarcomas and fewer myxofibrosarcomas in the RWD cohort. No difference in chemotherapy dose intensity was observed. The estimated 5-year metastasis-free survival (MFS) in all patients receiving perioperative chemotherapy was 58%. In the RWD cohort 5-year MFS was 53% and in the clinical study cohort 61% (HR 1.24; 95% CI 0.77-2.00). CONCLUSION: Long-term outcome after perioperative chemotherapy was comparable for patients treated in routine clinical practice to those in clinical trials. Secondary malignancy and cardiac toxicity were observed. The risk of serious late side effects should be included in the decision process on perioperative chemotherapy.

A woman in her fifties with a lump in the palm of her hand. / En kvinne i 50-årene med kul i håndflaten.

A previously healthy woman in her fifties contacted her general practitioner due to a troublesome lump on her hand that had progressed over the course of a year. The final diagnosis surprised those involved and serves as a reminder to both general practitioners and specialists.

Chondrosarcoma local recurrence in the Cancer Registry of Norway cohort (1990-2013): Patterns and impact.

BACKGROUND: There appears to be an association between local recurrence (LR) and risk of metastasis and death in central conventional chondrosarcoma (CCCS) of bone, but this has not been quantified in modern cohorts at a subtype level. METHODS: We identified nonmetastatic cases of CCCS (N = 180) from the Cancer Registry of Norway. We present prognostic analysis of LR accounting for immortal time bias by descriptive statistics and multivariable Cox models. RESULTS: Of 40 LR, one case demonstrated upgrading while two dedifferentiation. LR was associated with increased risk of metastasis (hazard ratio [HR] = 4.1 [confidence interval, 1.5-10.7]) and death (HR = 9.3 [5.0-17.5]) overall. LR was associated with significant increased risk of metastasis for those with a soft tissue component, axial location, malignancy grade 2, but not atypical cartilaginous tumor's, appropriately treated curettage patients, intramedullary tumors, grade 1 histology, extremity location or "Oslo low risk" group status. We found an increased risk of death for all groups except for those treated by appropriate curettage or belonging to the "Oslo low risk" group. About 50% of LR CCCS were asymptomatic and revealed by routine follow-up. CONCLUSIONS: Upgrading of LR for CCCS was a seldom event. LR was associated with significant increased risk of metastasis and death overall, but not for appropriately treated curettage patients or "Oslo low risk" status.

Risk stratification for central conventional chondrosarcoma of bone: A novel system predicting risk of metastasis and death in the Cancer Registry of Norway cohort.

BACKGROUND AND OBJECTIVES: Interobserver variability in histological grading of central conventional chondrosarcoma (CCCS) limits the quality of patient information and research progression. We aim to quantify known and new prognostic variables and propose a risk stratification model. METHOD: We selected 149 cases from the Cancer Registry of Norway. Cox proportional hazard models were estimated. Based on these results a dichotomous risk classification was proposed and presented by Kaplan-Meier estimates for rates of local recurrence, metastasis, and disease-specific survival. RESULTS: The influence of axial skeletal location (Hazard ratio [HR] = 19.06), a soft tissue component ≥1 cm (HR = 13.45), and histological grade 3 (HR = 16.46) are all significant in predicting the rate of metastasis. The creation of a variable combining axial skeletal location and a soft tissue component ≥1 cm strongly predicts the risk of metastasis (HR = 14.02; P < .001) and death (HR = 2.74; P = .030) at multivariate analysis, making the histological grade insignificant. Together with metastasis at diagnosis (HR = 285.65; P < .001), this forms the basis of our proposed risk stratification, producing a small high-risk group (39 cases with 33% risk of metastasis) and a large low-risk group (103 cases with 2% risk of metastasis) without a histological grade. CONCLUSION: Axial skeletal location and a soft tissue component ≥1 cm combined divides a CCCS cohort into low- and high-risk groups without a histological grade.

Soft-tissue sarcoma in adolescents and young adults compared with older adults: A report among 5000 patients from the Scandinavian Sarcoma Group Central Register.

BACKGROUND: In recent years, there has been growing awareness of the distinct characteristics of adolescents and young adults (AYA) diagnosed with cancer. Soft-tissue sarcoma (STS) accounts for approximately 1% of all cancers diagnosed in adults and 8% of cancers diagnosed in AYA. To the best of our knowledge, only a few sarcoma registers include data regarding histological subtype, age at diagnosis, and detailed clinical information. Therefore, little is known regarding clinical presentation and outcomes in AYA diagnosed with STS. METHODS: Using the Scandinavian Sarcoma Group Central Register, data were obtained regarding 4977 patients who were diagnosed with STS for the period between 1986 and 2011. AYA (those aged 18-39 years) were compared with older adults (OA; those aged 40-80 years) with respect to clinical presentation, treatment, and outcome. RESULTS: There were 868 AYA and 4109 OA. Overall and by STS subtype, there were significant differences noted between AYA and OA with regard to presentation, treatment, and survival. The distribution of STS subtypes was different between OA and AYA (eg, OA were more likely to be diagnosed with malignant fibrous histiocytoma compared with AYA [34% vs 16%; P < .001]). OA also were more likely to have tumors measuring ≥5 cm (68% vs 56%; P < .001) and a higher malignancy grade (75% vs 67%; P < .001). In the majority of STS subtypes AYA had significantly better overall survival and less disease recurrence compared with OA, but this finding was not true for those with malignant peripheral nerve sheath tumors. CONCLUSIONS: There are several differences between AYA and OA with STS with regard to presentation, treatment, and survival, and such differences must be taken into consideration when designing clinical trials. Additional work also is needed to characterize the potential biological mechanisms underlying these differences.

Chondrosarcoma in Norway 1990-2013; an epidemiological and prognostic observational study of a complete national cohort.

BACKGROUND: Knowledge of chondrosarcoma (CS) of bone to date is based on institutional reports and registry publications with limits in reporting, detail and quality of data. METHOD: We have performed a retrospective search of CS of bone in the National Cancer Registry in Norway from 1990-2013, cross checked against local tumor databases with further quality control and supplementation of all data from clinical files. The time period is defined by the routine use of axial imaging in clinical practice. A total of 311 cases are included. We performed 108 pathological reviews and 223 radiological reviews. The manuscript was prepared according to the STROBE checklist for strengthening of observational studies. We performed uni-/multivariate cox analyses to define independent prognostic variables from the main cohort of central CS of bone. RESULTS: The incidence of CS of bone in Norway is 2.85/million/yr. for both sexes overall, rising to 3.45/million/yr. in the last 5-year period. There is an increase in the most common central CS subtype, stronger for women than for men. Central CS had, in general 10-15% local recurrence rates, all evident by 5 years while metastasis rate increases with location and grade. Exceptions are extremity grade 1 CS which displayed no metastatic events and axial grade-3 disease with high rates (50%) of both local and metastatic relapse. Peripheral CS had limited metastatic potential (2%), but rates of local relapse (13%) continue to appear towards 10 years of follow up. Malignancy grade 3 independently predicts rate of metastasis and presence of soft tissue component predicts local recurrence, metastasis and survival. CONCLUSION: Rates of local recurrence, metastasis and disease specific survival follow clear patterns depending on subtype, location and grade allowing better tailoring of follow-up regimes. Malignancy grade 3 and the presence of a soft tissue component independently predict behavior for central CS of bone.

Use of liquid biopsies to monitor disease progression in a sarcoma patient: a case report.

BACKGROUND: Many patients experience local recurrence or metastases after receiving potentially curative treatment, and early detection of these events is important for disease control. Recent technological advances make it possible to use blood plasma containing circulating cell-free tumour DNA (ctDNA) as a liquid biopsy. In this case report we show how serial liquid biopsies can be used to monitor the disease course and detect disease recurrence in a sarcoma patient. CASE PRESENTATION: A 55-year-old male presented with a rapidly growing, painful palpable mass in the left groin region, and a biopsy revealed a high-grade malignant spindle cell sarcoma. No metastases were detected on radiologic imaging scans. Using targeted resequencing with a custom 900 cancer gene panel, eight somatic mutations among them KRAS and NF1, were identified in the primary tumour. Targeted resequencing of plasma cell-free DNA (ctDNA) collected before and after surgery and at disease progression confirmed the presence of six of eight mutations at all three time points. The ctDNA level, estimated from the somatic allele frequencies of these six mutations, was high in plasma taken at the time of surgery, at levels similar to the primary tumour. Detection of low levels of ctDNA three days after surgery indicated persistent microscopic disease. Repeated radiologic imaging six weeks postoperatively showed widespread metastatic disease in the lungs, skeleton and the pelvic region. At this time point there was a dramatic increase in the ctDNA level, reflecting the disease progression of the patient. The patient had an unusually aggressive cancer, and succumbed to the disease 13 weeks after surgery. CONCLUSIONS: This case report demonstrated that targeted resequencing of ctDNA from longitudinal collected plasma can be used to monitor disease progression in a soft tissue sarcoma patient, including manifestation of metastatic disease. The ctDNA represented the genomic profile of the tumour, supporting clinical use of liquid biopsies to identify tumour-specific mutations as well as recurrent disease.

Denosumab in patients with giant-cell tumor of bone in Norway: results from a nationwide cohort.

BACKGROUND: Denosumab is a relatively new treatment option for patients with giant-cell tumor of bone (GCTB). The purpose of this study was to report the results for patients treated in Norway. MATERIALS AND METHODS: Patients treated with denosumab for GCTB were identified from the clinical databases at the Norwegian sarcoma reference centers. Data were retrieved from the clinical databases and supplemented by retrospective review of patient records. Denosumab was given as a subcutaneous injection every 4 weeks with loading doses on day 8 and 15 in cycle 1. RESULTS: Eighteen patients treated with denosumab for GCTB were identified. Denosumab was given for recurrent disease in seven cases and as first-line treatment in 11 patients, of which 6 received therapy as part of a neoadjuvant/adjuvant strategy and 5 for surgically unsalvageable primary tumor. Ten of 12 patients with unresectable disease are still on denosumab without progression with median treatment duration of 41 months (range 18-60). Two patients discontinued treatment due to osteonecrosis of the jaw and reduced compliance, respectively. In the adjuvant group, four patients experienced disease recurrence after stopping denosumab. In three of six patients, the extent of surgery was reduced due to neoadjuvant therapy. Seventeen of 18 patients underwent response evaluation with 18F-FDG PET/CT at median 4.7 weeks from starting denosumab. Median baseline SUVmax was 11.0 and median SUVmax at evaluation was 4.9 (p < 0.001). CONCLUSIONS: In a nationwide GCTB patient cohort, denosumab was an effective agent and durable responses were observed. Our results do not support the use of adjuvant therapy in routine clinical practice. 18F-FDG PET/CT could be a valuable tool for early response evaluation.

The Scandinavian Sarcoma Group Central Register: 6,000 patients after 25 years of monitoring of referral and treatment of extremity and trunk wall soft-tissue sarcoma.

Purpose - We wanted to examine the potential of the Scandinavian Sarcoma Group (SSG) Central Register, and evaluate referral and treatment practice for soft-tissue sarcomas in the extremities and trunk wall (STS) in the Nordic countries. Background - Based on incidence rates from the literature, 8,150 (7,000-9,300) cases of STS of the extremity and trunk wall should have been diagnosed in Norway, Finland, Iceland, and Sweden from 1987 through 2011. The SSG Register has 6,027 cases registered from this period, with 5,837 having complete registration of key variables. 10 centers have been reporting to the Register. The 5 centers that consistently report treat approximately 90% of the cases in their respective regions. The remaining centers have reported all the patients who were treated during certain time periods, but not for the entire 25-year period. Results - 59% of patients were referred to a sarcoma center untouched, i.e. before any attempt at open biopsy. There was an improvement from 52% during the first 5 years to 70% during the last 5 years. 50% had wide or better margins at surgery. Wide margins are now achieved less often than 20 years ago, in parallel with an increase in the use of radiotherapy. For the centers that consistently report, 97% of surviving patients are followed for more than 4 years. Metastasis-free survival (MFS) increased from 67% to 73% during the 25-year period. Interpretation - The Register is considered to be representative of extremity and trunk wall sarcoma disease in the population of Scandinavia, treated at the reporting centers. There were no clinically significant differences in treatment results at these centers.

Prognostic factors and follow-up strategy for superficial soft-tissue sarcomas: Analysis of 622 surgically treated patients from the scandinavian sarcoma group register.

BACKGROUND AND OBJECTIVES: Our study aimed to describe the clinical outcome of patients with superficial soft-tissue sarcomas (SSTS), define prognostic factors and provide evidence for a rational surveillance scheme. METHODS: Data for 622 consecutive, surgically treated SSTS patients were retrieved from the Scandinavian Sarcoma Group Register. We assessed the rates of local recurrence (LR) and metastasis (M), as well as overall survival (OS), local recurrence free-survival (LRFS) and metastasis-free survival (MFS) of the cohort. RESULTS: The incidence of LR and M was 9% and 12%, respectively. OS at 5 years was 79%, LRFS was 74% and MFS 76%. Factors that affected OS, LRFS, and MFS were tumor size and patient age. Additionally, tumor grade was an independent prognostic factor for LRFS. The majority of LR and M events were observed the first 2 years of follow-up. Clear surgical margins were correlated to lower risk for LR. Selected patients benefited from adjuvant radiotherapy. CONCLUSIONS: SSTS have a favourable prognosis, which is mainly determined by tumour-associated factors. Adequate surgical margins are important for local control, whereas radiotherapy has a secondary role. The data support current surveillance schemes, with a closer follow-up the first 2 years after surgery.

Referral patterns, treatment and outcome of high-grade malignant bone sarcoma in Scandinavia--SSG Central Register 25 years' experience.

AIMS: The objectives of this study were to present changes in referral patterns, treatment and survival in patients with high-grade malignant bone sarcoma in Sweden and Norway based on data in the Scandinavian Sarcoma Group (SSG) Central Register. METHOD: Data on 1,437 patients with diagnosis 1986-2010 was analyzed. RESULTS: Osteosarcoma was the most frequentl diagnosis (45%), followed by Ewing sarcoma (21%) and chondrosarcoma (17%). Thirty-one percent of Swedish and 41% of Norwegian patients had tumors in the axial skeleton. Eighty-six percent of extremity tumors and 66% of axial tumors were referred to a sarcoma center prior to unplanned surgery or biopsy. During the past decade, limb salvage surgery has risen from under 50% to over 80%. Five-year overall survival in non-metastatic osteosarcoma was 70% for extremity tumors, and 35% for axial tumors. No improvement in osteosarcoma survival was observed during the last decade. Five-year survival in Ewing sarcoma improved from 50% to 69%. CONCLUSION: Referral patterns in bone sarcomas have improved. However, greater efforts should be dedicated to improving referral of patients with possible tumors in the axial skeleton to multidisciplinary teams (MDTs). Overall survival of patients with high-grade malignant bone sarcomas in Sweden and Norway is in line with other reports.

Prognostic role of en-bloc resection and late onset of bone metastasis in patients with bone-seeking carcinomas of the kidney, breast, lung, and prostate: SSG study on 672 operated skeletal metastases.

BACKGROUND AND OBJECTIVES: In metastatic disease, decisions regarding potential surgery require reliable data about the patient's survival. In this study, we evaluated different prognostic factors and their impact in four common primary tumors causing bone metastases. METHODS: Data were acquired from the Scandinavian Sarcoma Group (SSG) metastasis registry. The patients underwent surgery between July 1999 and July 2009. This study included breast, prostate, lung, and kidney cancer cases, with a total of 672 operated non-spinal metastases. Differences in prognostic factors were evaluated using the Kaplan-Meier method with long-rank test. Cox regression multivariate analysis was performed to identify statistically independent prognostic factors. RESULTS: Significant factors affecting survival were the presence of organ metastases, overall heath status, and disease load. In kidney cancer, en bloc resection of solitary metastases was associated with a significant fourfold longer survival compared to intralesional surgery. Preoperative radiotherapy was associated with higher complication and reoperation rates. CONCLUSIONS: This data summary is important tool for clinicians to evaluate survival and choose treatment options for patients suffering from metastatic bone disease.

Pathological subtrochanteric fractures in 194 patients: a comparison of outcome after surgical treatment of pathological and non-pathological fractures.

BACKGROUND: The surgical treatment of pathological subtrochanteric fractures has been associated with technical difficulties and frequent failures. We analyzed survival, risk factors for death, and outcome after surgical treatment. METHODS: The study group consisted of 194 patients with pathological subtrochanteric femur fractures operated during 1999-2009. Cox multiple-regression analysis was performed to study risk factors and results were expressed as hazard ratios (HR). We included a control group with non-pathological subtrochanteric fractures (n = 87) for comparison. RESULTS: The median age at surgery was 68 (29-96) years in the study group and 82 (66-101) in the controls. The 1-year survival rate after surgery was 33% (95% CI: 26-40) in the study group and 85% (79-93) in the controls. In the study group, the risk of death after surgery was increased for patients ≥65 years of age (HR 1.5, 95% CI: 1.1-2.1), with a moderate (HR 2.2, 1.5-3.4) and poor (HR 2.9, 1.6-5.2) Karnofsky score, with visceral metastases (HR 1.6, 1.1-2.3), and perioperative hemoglobin levels <100 g/L (HR 2.2, 1.3-3.7). In patients with pathological fractures, there was no statistically significant difference concerning reoperation rates comparing intramedullary nails (9%) with endoprostheses (6%; P = 0.3). CONCLUSIONS: Surgery for pathological subtrochanteric femur fractures is a relatively safe and effective procedure.

Complications and survival after surgical treatment of 214 metastatic lesions of the humerus.

BACKGROUND: The humerus is the second most common long-bone site of metastatic bone disease. We report complications, risk factors for failure, and survival of a large series of patients operated on for skeletal metastases of the humerus. MATERIALS AND METHODS: This study was based on 208 patients treated surgically for 214 metastatic lesions of the humerus. Reconstructions were achieved by intramedullary nails in 148, endoprostheses in 35, plate fixation in 21, and by other methods in 10. RESULTS: The median age at surgery was 67 years (range, 29-87 years). Breast cancer was the primary tumor in 31%. The overall failure rate of the surgical reconstructions was 9%. The reoperation rate was 7% in the proximal humerus, 8% in the diaphysis, and 33% in the distal part of the bone. Among 36 operations involving an endoprosthesis, 2 were failures (6%) compared with 18 of 178 osteosynthetic devices (10%). In the osteosynthesis group, intramedullary nails failed in 7% and plate fixation failed in 22%. Multivariate Cox regression analysis showed that prostate cancer was associated with an increased risk of failure after surgery (hazard ratio, 7; P < 0.033). The cumulative survival after surgery was 40% (95% confidence interval [CI] 34-47) at 1 year, 21% (95% CI, 15-26) at 2 years, and 16% (95% CI, 12-19) at 3 years. CONCLUSIONS: Our method of choice is the cemented hemiprosthesis for pathologic proximal humeral fractures and interlocked intramedullary nail for lesions in the diaphysis. Pathologic fractures in the distal humerus are uncommon and associated with a very high reoperation rate.

Radiotherapy or surgery for spine metastases?

BACKGROUND AND PURPOSE: Radiotherapy (RT) remains the cornerstone of management of spine metastases (SM), even though surgery is a well-established treatment for selected patients. We compared the use of RT and surgery in a population-based cohort of patients with SM, investigated pre-treatment factors that were associated with use of these treatment modalities, and examined survival. PATIENTS AND METHODS: 903 patients in the south-eastern Norway who were admitted for RT or surgery for SM for the first time during an 18-month period in 2007-2008 were identified and their medical records were reviewed. RESULTS: The primary treatment was surgery in 58 patients and RT in 845 patients, including 704 multiple-fraction (MF) and 141 single-fraction (SF) RT schedules. 11 of 607 patients without motor impairment (2%) and 47 of 274 patients with motor impairment (17%) underwent primary operations. 11 of 58 operated patients and 244 of 845 irradiated patients died within 2 months after the start of treatment. 26% of those who received multiple-fraction RT or surgery died within 2 months. INTERPRETATION: Motor impairment was the main indication for surgery. Better identification of patients with short survival is needed to avoid time-consuming treatment (major surgery and long-term RT).

Bone mineral density surveillance for childhood, adolescent, and young adult cancer survivors: evidence-based recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Childhood, adolescent, and young adult cancer survivors are at increased risk of reduced bone mineral density. Clinical practice surveillance guidelines are important for timely diagnosis and treatment of these survivors, which could improve bone mineral density parameters and prevent fragility fractures. Discordances across current late effects guidelines necessitated international harmonisation of recommendations for bone mineral density surveillance. The International Late Effects of Childhood Cancer Guideline Harmonization Group therefore established a panel of 36 experts from ten countries, representing a range of relevant medical specialties. The evidence of risk factors for very low and low bone mineral density and fractures, surveillance modality, timing of bone mineral density surveillance, and treatment of very low and low bone mineral density were evaluated and critically appraised, and harmonised recommendations for childhood, adolescent, and young adult cancer survivors were formulated. We graded the recommendations based on the quality of evidence and balance between potential benefits and harms. Bone mineral density surveillance is recommended for survivors treated with cranial or craniospinal radiotherapy and is reasonable for survivors treated with total body irradiation. Due to insufficient evidence, no recommendation can be formulated for or against bone mineral density surveillance for survivors treated with corticosteroids. This surveillance decision should be made by the survivor and health-care provider together, after careful consideration of the potential harms and benefits and additional risk factors. We recommend to carry out bone mineral density surveillance using dual-energy x-ray absorptiometry at entry into long-term follow-up, and if normal (Z-score > -1), repeat when the survivor is aged 25 years. Between these measurements and thereafter, surveillance should be done as clinically indicated. These recommendations facilitate evidence-based care for childhood, adolescent, and young adult cancer survivors internationally.

Adjuvant chemotherapy and postoperative radiotherapy in high-risk soft tissue sarcoma patients defined by biological risk factors-A Scandinavian Sarcoma Group study (SSG XX).

PURPOSE: To investigate the outcome following adjuvant doxorubicin and ifosfamide in a prospective non-randomised study based on a soft tissue sarcoma (STS) patient subgroup defined by specific morphological characteristics previously shown to be at a high-risk of metastatic relapse. The expected 5-year cumulative incidence of metastases in patients with this risk profile has previously been reported to be about 50% without adjuvant chemotherapy. METHODS: High-risk STS was defined as high-grade morphology (according to the Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC] grade II-III) and either vascular invasion or at least two of the following criteria: tumour size ≥8.0 cm, infiltrative growth and necrosis. Six cycles of doxorubicin (60 mg/m2) and ifosfamide (6 g/m2) were given. Postoperative accelerated radiotherapy was applied and scheduled between cycles 3 and 4. RESULTS: For the 150 eligible patients, median follow-up time for metastases-free survival was 3.9 years (range 0.2-8.7). Five-year metastases-free survival (MFS) was 70.4% (95% confidence interval [CI]: 63.1-78.4) with a local recurrence rate of 14.0% (95% CI: 7.8-20.2). For overall survival (OS), the median follow-up time was 4.4 years (range: 0.2-8.7). The five-year OS was 76.1% (95% CI: 68.8-84.2). Tumour size, deep location and reduced dose intensity (<80%) had a negative impact on survival. Toxicity was moderate with no treatment-related death. CONCLUSIONS: A benefit of adjuvant chemotherapy, compared to similar historical control groups, was demonstrated in STS patients with defined poor prognostic factors. Vascular invasion, tumour size, growth pattern and necrosis may identify patients in need of adjuvant chemotherapy.

Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma.

Osteosarcoma is a primary malignancy of bone that affects children and adults. Here, we present the largest sequencing study of osteosarcoma to date, comprising 112 childhood and adult tumours encompassing all major histological subtypes. A key finding of our study is the identification of mutations in insulin-like growth factor (IGF) signalling genes in 8/112 (7%) of cases. We validate this observation using fluorescence in situ hybridization (FISH) in an additional 87 osteosarcomas, with IGF1 receptor (IGF1R) amplification observed in 14% of tumours. These findings may inform patient selection in future trials of IGF1R inhibitors in osteosarcoma. Analysing patterns of mutation, we identify distinct rearrangement profiles including a process characterized by chromothripsis and amplification. This process operates recurrently at discrete genomic regions and generates driver mutations. It may represent an age-independent mutational mechanism that contributes to the development of osteosarcoma in children and adults alike.