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Report from the 4th European Bone Sarcoma Networking meeting: focus on osteosarcoma

Report from the 4th European Bone Sarcoma Networking meeting: focus on osteosarcoma This report summarizes the proceedings of the 4th European Bone Sarcoma Networking Meeting, held in London, England, on 21 June 2017. The meeting brought together scientific and clinical researchers and representatives from sarcoma charities from 19 countries representing five networks across Europe, to present and discuss new develop ‑ ments on bone sarcoma. In view of the challenges is poses, the meeting focussed primarily on osteosarcoma with presentations on developments in our understanding of osteosarcoma genetics and immunology as well as results from preclinical investigations and discussion of recent and ongoing clinical trials. These include studies examining the efficacy of multi ‑ targeted tyrosine kinase inhibitors and checkpoint inhibitors, as well as those with molecular profiling to stratify patients for specific therapies. Discussion was centred on generation of new hypotheses for col‑ laborative biological and clinical investigations, the ultimate goal being to improve therapy and outcome in patients with bone sarcomas. Keywords: Osteosarcoma, Bone sarcoma, Immunotherapy, Genomics, Translational research Introduction as well as those in development, including a number of The 4th European Bone Sarcoma Networking meeting immunotherapy-based trials. Potential therapies based brought together scientific and clinical researchers and on recent osteosarcoma genetic studies and subsequently representatives from sarcoma charities, from 19 coun- immunology and immunotherapy were discussed as well tries representing five networks across Europe to discuss as the role for biomarkers both to identify patients for the latest developments in bone sarcoma research. This these studies and for monitoring of disease. builds on the successful previous meetings [1]. Since the closure of the EURAMOS-1 trial in 2011 there have Current national study programmes been no international phase III studies open for Euro- The first session was an opportunity for national study pean patients with osteosarcoma. In view of this ongoing groups to present recent clinical trials that have recruited unmet need, the meeting focussed primarily on this chal- patients with osteosarcoma, are currently recruiting lenging disease. The meeting opened with presentations osteosarcoma patients or are under development (sum- from National Study Groups on current clinical trials marised in Table  1). The Spanish Group for Research on Sarcoma (GEIS) represented by Nadia Hindi, presented data from GEIS 29 trial, a phase II trial on the combi- *Correspondence: s.strauss@ucl.ac.uk nation of gemcitabine and sirolimus [2]. In this study, Department of Oncology, UCL Cancer Institute, 72 Huntley Street, London WC1A 6DD, UK patients with advanced pretreated osteosarcoma received Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Strauss et al. Clin Sarcoma Res (2018) 8:17 Page 2 of 8 Table 1 Recent European clinical trials recruiting patients with osteosarcoma Trial name Title/description Country Study reference GEIS 29 Multicenter and prospective phase II trial Spain NCT02429973 with gemcitabine and rapamycin in sec‑ ond line of metastatic osteosarcoma GEIS 51 (Palbosarc) Phase II multicenter trial of palbociclib in Spain NCT03242382 second line of advanced sarcomas with CDK4 overexpression GEIS 52 (InmunoSARC) Phase I–II trial of sunitinib plus nivolumab Spain, Italy NCT03277924 after standard treatment in advanced soft tissue and bone sarcomas Sarcome13/0S2016 Randomised phase‑2 trial of mifamurtide France NA (MEPACT ) combined with post‑ operative chemotherapy for newly diagnosed patients up to 50 years with high risk osteosarcoma (metastatic or localized disease with poor histologic response to neoadjuvant chemotherapy). Regobone A phase II study evaluating efficacy and France NCT02389244 safety of regorafenib in patients with metastatic bone sarcomas Cabone Cabozantinib‑s‑malate in treating patients France NCT02243605 with relapsed osteosarcoma or Ewing sarcoma HOPE ITCC‑035 Study of lenvatinib in children and ado‑ France, USA, Germany, Italy, Spain, UK NCT02432274 lescents with refractory or relapsed solid malignancies and young adults with osteosarcoma PembroSARC Combination of MK3475 and metronomic France NCT02406781 cyclophosphamide in patients with advanced sarcomas: multicentre phase II trial PROMO A phase II study of pembrolizumab in Norway, Italy NCT03013127 patients with relapsed or metastatic osteo‑ sarcoma not eligible for curative surgery MAPPYACTS Proof‑ of‑ concept study to stratify targeted France, Ireland, Israel, Italy, Spain NCT02613962 therapies adapted to molecular profiling ESMART European proof‑ of‑ concept therapeutic France, Germany, Italy, Netherlands, Spain, NCT02813135 stratification trial of molecular anomalies UK in relapsed or refractory tumors Can cancer cells be found in blood Enumeration of circulating tumour cells in UK ISRCTN29619083 samples from patients with bone patients with bone sarcomas: an observa‑ sarcoma? tional study NA not available up to six cycles of gemcitabine 800  mg/m days 1 and 8 GEIS 52 (InmunoSARC), which is examining the toler- and Sirolimus (5  mg per day) in a continuous regimen ance and efficacy of the combination of sunitinib and (except the day before and the day of infusion of gem- nivolumab in patients with bone and soft tissue sarcomas citabine). The trial was positive for its primary endpoint, [3, 4]. with a 4-month PFS rate of 44%. Median PFS and OS Nathalie Gaspar, on behalf of The French bone were 2.3 and 7.1 months respectively. Expression of Ribo- sarcoma group presented the upcoming French nucleotide Reductase catalytic subunit 1 (RRM1) was Sarcome13/0S2016 trial. This is a first-line randomised related with a worse outcome, both in terms of PFS and Phase-2 trial of mifamurtide (MEPACT ) combined OS [2]. The GEIS group has another two phase II trials with post-operative chemotherapy for newly diagnosed actively recruiting patients with advanced osteosarcoma: patients up to the age of 50  years with high risk osteo- GEIS 51 (Palbosarc), which is examining the role of the sarcoma (metastatic or localized disease with poor CDK4 inhibitor palbociclib in patients with osteosar- histologic response to neoadjuvant chemotherapy). Sar- coma or soft tissue sarcoma overexpressing CDK4 and come13/OS2016 backbone chemotherapy is based on Strauss et al. Clin Sarcoma Res (2018) 8:17 Page 3 of 8 the previous, Unicancer sponsored, French OS2006/ patients could benefit from precision medicine and it will Sarcome9 trial (M-EI in children, adolescent and young be an opportunity to widen preclinical research studies adults and API-AI in adults) [5, 6]. Post-operative mifa- about sarcomas. murtide administration for 36  weeks, is randomised in The UK National Cancer Research Institute (NCRI) addition to post-operative chemotherapy. This rand - Bone Sarcoma Clinical Studies Group aims to develop omized trial, the first since the controversial INT-033 UK National Institute Health Research (NIHR) portfolio trial, is using a Bayesian design to determine whether studies in primary bone tumours. Sandra Strauss, Lon- the macrophage modulator, mifamurtide, provides ben- don, presented two studies in osteosarcoma, the first, is efit to this group of patients [7]. Several phase-2 tri - a prospective cohort study of patients with newly diag- als for relapsed osteosarcoma patients are on-going in nosed osteosarcoma that aims to (i) describe the expe- France testing different multi-tyrosine kinase inhibitors rience, treatment and outcomes of patients of all ages alone, either randomized versus placebo (Regobone from in the UK; (ii) to investigate the impact of tumour het- 10 years old), or in single arm phase-2 trial (Cabone from erogeneity and tumour evolution on patient outcome 12  years old), as well as associated with chemotherapy through the collection of biological samples; (iii) to vali- (HOPE, ITCC-035, lenvatinib ± etoposide/ifosfamide date biomarkers to accelerate selection of patients with up to 25  years old) [8–10]. Recent international stud- high risk disease into Phase Ib/II clinical trials; (iv) to ies investigating immune check point inhibitors (anti- identify factors influencing decisions about local therapy PD1 and anti-PDL1), alone have not been as promising and outcomes. She also outlined a multicenter observa- as hoped and further work is required to understand tional study lead by Kenny Rankin, Newcastle evaluating mechanisms of resistance and which patients are likely to the potential of using MT1-MMP1 to isolate circulating respond to these agents [11, 12]. Results of a combination tumour cells (CTCs) in patients with osteosarcoma at French study with metronomic cyclophosphamide are diagnosis and subsequent treatment stages. To date the awaited (PembroSARC) [13]. The next trial for paediatric study has recruited 30 patients across four sites [15]. and adult patients with osteosarcoma relapse is being dis- The session concluded with a presentation by Jakob cussed within the ITCC Consortium (Innovative Thera - Anninga, Nijmegen, of a study investigating the effect pies for Children with Cancer) and consideration is being of dose-intensity on event-free survival (EFS) in groups given to combination of two promising approaches, a of patients with localized osteosarcoma. Clinical data multi-tyrosine kinase inhibitor and an immune modula- from MRC BO06 was used to perform a landmark analy- tor. Inclusion of osteosarcoma with molecular profiling in sis, which aimed to cluster patients on the similarity of the multiarm phase-1/2 trial AcSé-eSMART ITCC-057 the individual received dose-intensity (iRDI). The group provides an opportunity to investigate the activity of a demonstrated a more accurate relationship between PARP inhibitor in combination with irinotecan or WEE1 iRDI and EFS when investigated by the whole individual inhibitor with carboplatin [14]. treatment-history, i.e. using longitudinal treatment-data, Elisa Tirtei, Turin, on behalf of The Italian Sarcoma compared to using either intention-to-treat analysis or Group presented a study that opened in November 2016 just the final value of iRDI. Their results suggest that indi - and is a collaboration with the Italian Onco-Haematology vidual tolerability is an important issue in EFS and that Paediatric Association (AIEOP) and Italian Institute for maintenance of treatment intensification towards an Genomic Medicine of Turin. It is a prospective, multicen- individual’s biological tolerance is beneficial. tre study to analyse the tumour genomic profile of paedi - atric and adult patients with new diagnoses of sarcoma Genetic targets in osteosarcoma or relapsed/refractory sarcoma. By comparing tumour A number of presentations focused on recent data gen- samples with the corresponding non-tumour tissue (e.g. erated from sequence analyses performed in osteosar- peripheral blood), the aim of the study is to define the coma, with identification of potential genetic targets and genomic profile of each sample taking advantage of a a discussion of the clinical implications of these find - next generation sequencing (NGS) platform. A panel of ings. Sam Behjati, Cambridge, presented findings of the 410 genes to analyse using the Illumina technique have osteosarcoma study of the International Cancer Genome been chosen. Furthermore, starting from fresh sarcoma Consortium. In that analysis, 112 childhood and adult samples obtained from surgical biopsies, the group aim tumours, encompassing all major histological subtypes, to establish in  vitro cultures and in  vivo patient-derived were studied by whole exome (n = 75) or whole genome xenografts (PDX) to generate working models. To date, sequencing (n = 37). In 32/112 cases an actionable muta- the study has recruited nine patients and has demon- tion was identified, including 20 cases with amplifica - strated the feasibility of this approach. It will now expand tions of receptor tyrosine kinases. Amongst these were to all paediatric Italian oncology departments, so all amplifications of IGF1R that occurred in ~ 10% of cases, a Strauss et al. Clin Sarcoma Res (2018) 8:17 Page 4 of 8 finding that was validated by FISH in an extension cohort appropriate treatment. At the same time, other types of of 87 cases. Overall the findings of this study provide a HR deficiency may be present in osteosarcoma, that do rationale for a basket trial in osteosarcoma that focuses not resemble BRCA1/BRCA2 deficiency in breast cancer. on actionable mutations, including amplifications of the These results indicate that distinguishing patients with IGF1R gene [16]. the various forms of genomic instability is not only pos- Daniel Baumhoer, Basel, presented the findings of a sible, it is critical. whole exome sequence analysis of 31 osteosarcomas, Ola Myklebost, Oslo, presented studies of the sensitiv- which demonstrated that these tumours show highly ity of the EuroBoNet osteosarcoma cell line panel to the complex karyotypes with abundant structural and PARP inhibitor, Talazoparib [23]. The cell lines had vari - numerical aberrations and a multitude of different driver able responses, from similar to that of the highly sensi- genes. However, despite the great amount of inter- and tive BRCA-mutated breast cancer cell line SUM149 to intratumoural heterogeneity, in their analysis, the major- that of the insensitive control HeLa, and responses of the ity of tumours (> 85%) appear to acquire a deficiency osteosarcoma lines were long-lasting when the drug was in homologous recombination (HR) repair that could removed. Various biomarkers were investigated, includ- potentially be therapeutically exploited by using PARP- ing mutations in HRR genes, presence of SNV mutation inhibitors [17]. It is well recognized that PARP-inhibitors profile 3, and the sensitivity to platinum drugs. None of are effective in tumours harbouring deleterious germline these were strongly predictive, but the response to oxali- or somatic mutation in BRCA1/2, i.e. breast and ovar- platin performed best, with the response being confirmed ian cancer, as shown by many studies [18]. Patients with in  vivo in a mouse PDX model. A trial was proposed to wild-type BRCA who have a homologous recombination investigate predictive markers, including the potential of deficiency (“BRCAness”) have also been shown to be sen - the highly variable whole genome profiles. sitive to PARP inhibition [19] as well as platinum-based Michaela Nathrath, Munich, representative of the chemotherapy [20]. He presented pre-clinical data on the Cooperative Osteosarcoma Study Group’s biology panel, efficacy of PARP-inhibitors in reducing cell viability oste - also summarised the case for studying PARP inhibi- osarcoma cell lines, which has been demonstrated by a tors in osteosarcoma based on the above evidence of number of groups [21]. He concluded on the basis of this Kovac et al. [17] and data from cell lines suggesting that evidence, that although there is no universally accepted BRCA-like phenotype is a unifying trait in osteosar- test to assess the sensitivity of tumours to this treatment coma. She suggested that the synthetic lethality concept (so-called “BRCAness”) in patients upfront, there is a using this BRCAness might be a new effective therapeu - molecular rationale to try this approach also in patients tic approach in osteosarcoma but also discussed that ideally within the framework of a clinical study. optimal techniques to select the patients who are likely Accurate methods to detect HR-deficiency in clini - to respond to PARP inhibitors have still to be defined cal samples to identify the patients that can benefit from and also that understanding drug resistance to PARP these treatments are highly sought and a number are inhibitors is important. Despite these challenges, a under development. Andrea Degasperi, Cambridge, pre- multi-center Phase-II study with a PARP inhibitor com- sented a novel method to predict BRCA1 and BRCA2 bined with chemotherapy including biomarker positive deficiency based on mutational signatures, called HRDe - relapsed osteosarcoma patients is planned in Heidelberg/ tect, which is a classifier that identifies tumours with Germany. a specific type of HR defect—BRCA1 or BRCA2 defi - The session concluded with a discussion on the evi - ciency in particular [22]. HRDetect was trained on whole dence presented for the potential role for PARP inhibi- genome sequenced (WGS) breast cancers and validated tors in osteosarcoma. It was agreed that a number of on independent cohorts of breast, ovarian and pancre- questions remain outstanding, including the challenges atic cancers. This classifier is currently the most accurate of conducting a clinical trial without an optimal bio- method for predicting BRCA1 or BRCA2 deficiency in marker; that PARP inhibitors are most likely to be of such tumours (AUC ~ 0.98) [22]. However, when applied benefit in combination with cytotoxic agents but that the to osteosarcomas in the ICGC data set, HRDetect pre- optimal combination is presently unknown. It was also dicted that only one sample of the 37 WGS samples felt the osteosarcoma community may not have exploited tested was similar to BRCA1/BRCA2-deficient breast the value of tyrosine kinase inhibitors (TKIs) in osteo- cancers. Although HRDetect has not yet been validated sarcoma yet and that benefit in selected patients may in osteosarcoma, due to the rarity of BRCA1/BRCA2 have been hidden in previous studies. Discussions cov- deficient bone tumours, this result indicates that BRCA1/ ered whether the recent data from Sam Behjati was suf- BRCA2 deficient-like tumours may not be very common ficient to consider further biomarker-driven studies using in osteosarcoma and need to be carefully stratified for appropriate TKIs. Strauss et al. Clin Sarcoma Res (2018) 8:17 Page 5 of 8 Immunotherapy rationale, targets and other killer (CIK) cells in patients with advanced and/or refrac- studies tory sarcoma. These cells were ex  vivo expanded, HLA- S. Rubina Baglio, Amsterdam, discussed the results unrestricted T-/NK-cells, with NKG2D and MIC A/B as of her investigation on the local inflammation of the anti-tumour targets [26, 27]. In vitro studies in mice have tumour microenvironment induced by osteosarcoma shown significant tumour cell killing using this method. tumour cells. In a xenograft mouse model of osteosar- The results of a French study to characterize the micro- coma, the research group demonstrated that the tumour environment in the biopsies of 126 patients was pre- cells release extracellular vesicles (EVs), carrying a mem- sented by Francoise Rédini, Nantes. The French phase brane-bound form of TGFβ, that “educate” mesenchymal 3 trial (OS 2006) testing the combination of Zometa stem cells to support tumour growth and lung metasta- with chemotherapy and surgery did not improve the sis formation. This effect was caused by a switch in the outcome of patients with osteosarcoma. The authors mesenchymal stem cell cytokine expression profile, and studied the presence of infiltrating immune cells (CD68/ could be fully revoked by the administration of the IL-6 CD163 tumour-infiltrating macrophages, CD8 lym - receptor antibody tocilizumab [24]. These findings pro - phocytes, osteoclasts, and the PD1/PDL-1 checkpoint) vide a rationale for novel therapeutic strategies based on in the biopsies of patients who participated in the OS immunomodulatory drugs for osteosarcoma patients. In 2006 trial. It was shown that high CD163 levels signifi - addition, the research group found evidence of increased cantly correlated with greater overall survival and with levels of EV-bound TGFβ in the circulation of osteosar- longer metastasis PFS independently of diagnosis sta- coma patients, which might provide an option for min- tus. CD8 staining was positive in > 50% of cases with a imally-invasive therapy response monitoring with liquid median staining of 1%. Lower CD8 levels were associated biopsies. She concluded that the tumour ‘educated’ mes- with metastatic disease at diagnosis and only the pres- enchymal stem cells might modulate a local immunosup- ence of CD8-positive cells significantly correlated with pressive niche, which could be targeted to stop tumour improved overall survival in patients who were treated progression. with the bisphosphonate Zometa . It was concluded that Kjetil Boye, Oslo, presented the PROMO-study, which immunohistochemical analysis of the microenvironment commenced in May 2017, and will be carried out in col- in osteosarcoma patient biopsies could represent a novel laboration with Bologna, Italy. This is a non-randomized, tool for therapeutic stratification. investigator-initiated phase-II study with pembrolizumab Katia Scotlandi, Italy, presented the results of a study monotherapy for patients with metastatic, unresectable of the effect of Trabectedin on the differentiation and osteosarcoma. The study has a 2-stage design, and the immune environment in a murine osteosarcoma model. primary endpoint is clinical benefit rate (SD+PR+CR) Of the two models, mOS13 formed smaller tumours, had at 18  weeks using RECIST v1.1. Secondary endpoints an increased bone matrix deposition and a lower meta- include progression-free survival (PFS), overall response static deposition than mOS69 [28]. In the more differen - rate and duration of response evaluated by RECIST tiated tumours a higher monocyte/macrophage (CD68 ), 18 + + + and immune-related response criteria, response by F-leucocyte (CD45 ) and lymphocyte (CD4 /CD8 ) infil - FDG PET/CT, overall survival, safety and health-related tration was demonstrated. Results in patient samples quality of life. A total of 25 patients are expected to be showed a better survival in subjects that had high levels + + included in the study. of cytotoxic T-cells (CD8 /Tia1 : long term cumulative Anne-Marie Cleton-Jansen, Leiden, presented a study survival 81%, versus 45% in patients who were CD8 / of the expression of HLA and PD-L1 as well as the pres- Tia ) [29]. PD-L1 was positive in 14% of the patients, and ence of infiltrating lymphocytes in a series of 87 primary had a worse survival in a subset with a C D8 infiltrate. osteosarcomas and metastases from 26 patients, to estab- In murine osteosarcoma, Trabectedin inhibited tumour lish whether immunotherapy could be beneficial to meta - growth and metastasis formation, affected gene-tran - static and chemotherapy refractory osteosarcoma. T cell scription via RUNX2 activation to a more differentiated infiltrate and PD-L1 expression increased during disease phenotype, and also induced the recruitment/expansion progression, suggesting that T-cell based immunotherapy of adaptive T cells. However, analysis of tumour-infiltrat - with adoptive cell transfer, peptide vaccines or check- ing T cell phenotype and activation state from trabect- point blockade could be a suitable approach for meta- edin-treated mice showed increased PD-1 checkpoint static osteosarcoma patients. Down regulation of HLA-A inhibitor expression on CD8 T cells, compatible with molecules may be a limiting factor, but only in a small their impaired function. It was concluded from this study fraction of the patients [25]. that Trabectedin reprogrammed the tumour associated Elisa Tirtei, Turin, presented the outline of a phase- micro-environment, providing the foundation for combi- I trial for the infusion of autologous, cytokine induced nation therapies with immune checkpoint inhibitors. Strauss et al. Clin Sarcoma Res (2018) 8:17 Page 6 of 8 Bone sarcomas and especially osteosarcomas are newly-developed European Reference Networks (EURA- highly heterogeneous. This heterogeneity both between CAN/PaedCan), which aim to increase access of patients tumours (inter-tumour heterogeneity) and within to specialist care and are currently focusing on develop- tumours (intra-tumour heterogeneity) can be related to ing clinical practice guidelines, training dissemination genetic and non-genetic factors and introduces signifi - and determining how shared data collection could ben- cant challenges for classifying patients that might benefit efit improvements in care for rare diseases [35]. It was from targeted therapies. It has been suggested that CTCs also noted that SIOP Europe was in advanced planning may reflect the biological evolution (e.g. new mutation of a clinical forum bringing together specialists from events) of primary tumours and associated metastases. all tumour types affecting children and young people Unfortunately, in contrast to carcinomas, in which CTCs to allow cross cutting interdisciplinary work. This first have been isolated from epithelial markers (e.g. EpCAM), Annual Meeting of the European Society for Paediatric there are no specific markers expressed by sarcoma cells. Oncology, to be held May 20–25, 2019 in Prague, Czech However, sarcoma cells like other cancer cells frequently Republic, is likely to represent a good opportunity to sus- show a differential size compared to normal cells and a tain collaborative working between bone tumour experts. lower deformability. Size and deformability criteria have been used in pre-clinical models for isolating CTCs and Conclusion could serve as proof-of-concept for pilot clinical trials in Osteosarcoma is a challenging disease with little bone sarcoma [30]. Dominique Heymann, Sheffield, pre - improvement in survival for three decades. To further sented a pilot study that is using the Parsortix System improve outcomes, international collaboration propelled to enrich for CTCs, which are then isolated and captured by initiatives like the European Bone Sarcoma Network using the DEPArray System. is essential. Novel insights from studies on genomics, Finally, Michel Vanden Eynden, Belgium, presented a altered signalling pathways and sarcoma immunology as project investigating telomere maintenance in paediatric well as biomarkers to identify patients for clinical trials tumours, with a focus on osteosarcoma. Most cancers and to monitor disease were discussed. These built on (85–90%) are known to reactivate telomerase to achieve presentations from previous meetings and included dis- cellular immortalisation [31]. However, another mecha- cussion about potential clinical trials, which now need to nism, based on homologous recombination between be taken forward to develop proposals for national and telomeric sequences, called alternative lengthening of for collaborative research and trials. Telomeres (ALT), is also able to provide cells with indefi - nite replication potential. It has been shown that ALT Abbreviations cells are characterized by the presence of a more relaxed AcSé‑ eSMART : Secured access to innovative therapies—European proof‑ of‑ telomeric chromatin that may account for the elevated concept therapeutic stratification trial of molecular anomalies in relapsed of refractory tumours in children; anti‑PD1: anti‑Programmed Death 1; anti‑PDL1: rates of telomeric sister chromatid recombinations typi- anti‑Programmed Death Ligand 1; API‑AI: adriamycin, cisplatin, ifosfamide– cally found in these cells [32, 33]. ALT is known to be adriamycin, ifosfamide; AUC : area under curve; BRCA1/2: BReast CAncer gene found mainly in paediatric tumours, with about 50% of 1/2; CDK4: cyclin‑ dependent kinase 4; CTC: cir culating tumour cells; EEC: EURO EWING Consortium; EOI: European Osteosarcoma Intergroup; EURAMOS: osteosarcoma showing ALT features [34]. At present, EURopean and American Osteosarcoma Study Group; EuroBoNeT: European understanding ALT mechanism is a major challenge; as network to promote research into uncommon cancers in adults and children: it is absent from normal somatic cells, it represents an pathology, biology and genetics of bone tumours; euroSARC : clinical trials in rare SARComas initiative; FISH: fluorescence in situ hybridization; GEIS: Grupo attractive target for cancer therapy, but specific inhibitors Espanol de Investigacion en Sarcomas Asociacion; HR: homologous recom‑ have not been identified yet. To better understand this bination; IGF1R: insulin like growth factor 1 receptor; iRDI: individual received mechanism and assess its relevance as a new prognostic dose intensity; ITCC : innovative therapies for children with cancer; M‑EI: methotrexate–etoposide, ifosfamide; MT1‑MP1: membrane ‑type matrix metal‑ biomarker or a new target for therapy, a collaboration loproteinase‑1; NCRI: National Cancer Research Institute; NGS: next generation with all paediatric oncology departments of university sequencing; NIHR: National Institute for Health Research; OS: overall survival; hospitals across Belgium has been created, which will PARP: poly ADP ribose polymerase; PDX: patient‑ derived xenograft; PFS: progression‑free survival; RRM1: Ribonucleotide Reductase catalytic subunit 1; allow tumour collection all across Belgium and further SFCE: Société Française des Cancers de l’Enfant; SNV: single‑nucleotide variant; investigation on ALT in paediatric cancers. TKI: tyrosine kinase inhibitor; WEE1: WEE1 G2 Checkpoint Kinase; WGS: whole genome sequencing. Future networking Authors’ contributions The meeting concluded with a discussion on role of SJS, JA, JW and AE participated in the conception and design of the future networks for osteosarcoma and commitment manuscript, collected the data from all co‑authors, led the drafting of the manuscript, and revised the article critically. SJS, JA, SRB, DB, SB, SRB, KB, JMB, to support networking opportunities as being integral A‑M C‑ J, AD, MF, FF, NG, DH, NH, CL, OM, MN, FR, KS, ET and MVE provided to facilitate collaboration and thereby improve out- information regarding their group’s research for inclusion into the manuscript comes for patients. Opportunities for this lie within Strauss et al. Clin Sarcoma Res (2018) 8:17 Page 7 of 8 and revised the article critically. All authors read and approved the final References manuscript. 1. 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Not applicable. Eur J Cancer. 2018;88:57–66. Organisation The 4th European Bone Sarcoma Networking meeting was 7. Meyers PA, Schwartz CL, Krailo M, Kleinerman ES, Betcher D, Bernstein held in London, England on 21 June 2017 with funding support from the ML, et al. Osteosarcoma: a randomized, prospective trial of the addition EURO EWING Consortium and Create for Chloë. of ifosfamide and/or muramyl tripeptide to cisplatin, doxorubicin, and high‑ dose methotrexate. J Clin Oncol. 2005;23(9):2004–11. 8. A phase II study evaluating efficacy and safety of regorafenib in patients Competing interests with metastatic bone sarcomas. https ://Clini calTr ials.gov/show/NCT02 SB reports grants from Deutsche Krebshilfe, Deutsche Forschungsgemein‑38924 4. Accessed 16 Jul 2018. schaft, European Science foundation, personal fees from Lilly, Bayer, Pfizer, 9. Cabozantinib‑s‑malate in treating patients with relapsed osteosar ‑ Novartis, Isofol, and Clinigen, outside submitted works. All other authors coma or Ewing sarcoma. https ://Clini calTr ials.gov/show/NCT02 24360 5. declare that they have no competing interests. Accessed 16 Jul 2018. 10. Study of lenvatinib in children and adolescents with refractory or Availability of data and materials relapsed solid malignancies and young adults with osteosarcoma. https Not applicable.://Clini calTr ials.gov/show/NCT02 43227 4. Accessed 16 Jul 2018. 11. Tawbi HA, Burgess M, Bolejack V, Van Tine BA, Schuetze SM, Hu J, D’Angelo Consent for publication S, Attia S, Riedel RF, Priebat DA, Movva S, Davis LE, Okuno SH, Reed DR, Not applicable. Crowley J, Butterfield LH, Salazar R, Rodriguez‑ Canales J, Lazar AJ, Wistuba II, Baker LH, Maki RG, Reinke D, Patel S. Pembrolizumab in advanced soft‑ Ethics approval and consent to participate tissue sarcoma and bone sarcoma (SARC028): a multicentre, two‑ cohort, Not applicable. single‑arm, open‑label, phase 2 trial. Lancet Oncol. 2017;18(11):1493–501. https ://doi.org/10.1016/S1470 ‑2045(17)30624 ‑1 Funding 12. Geoerger B, Karski EE, Zwaan M, Casanova M, Marshall LV, DuBois SG, et al. The workshop was supported in part by Create for Chloë. The research leading A phase I/II study of atezolizumab in pediatric and young adult patients to these results and the information described in this article have received with refractory/relapsed solid tumors(iMATRIXAtezolizumab). J Clin funding from The Norwegian Cancer Society and The Liddy Shriver Sarcoma Oncol. 2017;35(15_suppl):10524. Initiative. EURO EWING Consortium (EEC) project has received funding 13. Combination of MK3475 and metronomic cyclophosphamide in patients from the European Union’s Seventh Framework Programme for research, with advanced sarcomas: multicentre phase II trial. https ://Clini calTr ials. technological development and demonstration under grant agreement no. gov/show/NCT02 40678 1. Accessed 16 Jul 2018. 602856. French bone sarcoma group GROUPOS sarcoma13 trial INCa, PHRC 14. Proof‑ of‑ concept study to stratify targeted therapies adapted to molecu‑ 2016, Unicancer for financial support and Takeda for drug supply of the lar profiling. https ://Clini calTr ials.gov/show/NCT02 61396 2. Accessed 16 sarcome13/0S2016 trial. King’s Baudouin Foundation and Salus Sanguinis pro‑ Jul 2018. vided financial support to the project presented by MVE. CTC investigations 15. Can cancer cells be found counted in blood samples from patients with (Sheffield) were supported by the Bone Cancer Research Trust (research pro ‑ bone sarcoma? https ://www.isrct n.com/ISRCT N2961 9083?q=29619 ject number 144681). Funding was provided to SJS and JSW by the National 083&filte rs=&sort=&offse t=1&total Resul ts=1&page=1&pageS Institute for Health Research, UCLH Biomedical Research Centre. ize=10&searc hType =basic ‑searc h. Accessed 16 Jul 2018. 16. Behjati S, Tarpey PS, Haase K, Ye H, Young MD, Alexandrov LB, et al. Recur‑ rent mutation of IGF signalling genes and distinct patterns of genomic Publisher’s Note rearrangement in osteosarcoma. Nat Commun. 2017;8:15936. Springer Nature remains neutral with regard to jurisdictional claims in pub‑ 17. Kovac M, Blattmann C, Ribi S, Smida J, Mueller NS, Engert F, et al. Exome lished maps and institutional affiliations. sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nat Commun. 2015;6:8940. Received: 8 May 2018 Accepted: 11 July 2018 18. Robson M, Im SA, Senkus E, Xu B, Domchek SM, Masuda N, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377(6):523–33. Strauss et al. Clin Sarcoma Res (2018) 8:17 Page 8 of 8 19. Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez‑Lopez R, et al. 28. Ratti C, Botti L, Cancila V, Galvan S, Torselli I, Garofalo C, et al. Trabectedin DNA‑repair defects and olaparib in metastatic prostate cancer. 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Gobin M, et al. Alternative lengthening of telomeres is characterized Blocking tumor‑ educated MSC paracrine activity halts osteosarcoma by reduced compaction of telomeric chromatin. Nucleic Acids Res. progression. Clin Cancer Res. 2017;23(14):3721–33. 2014;42(7):4391–405. 25. Sundara Y T, Kostine M, Cleven AH, Bovee JV, Schilham MW, Cleton‑ 34. Heaphy CM, Subhawong AP, Hong SM, Goggins MG, Montgomery EA, Jansen AM. Increased PD‑L1 and T ‑ cell infiltration in the presence Gabrielson E, et al. Prevalence of the alternative lengthening of telomeres of HLA class I expression in metastatic high‑ grade osteosarcoma: a telomere maintenance mechanism in human cancer subtypes. Am J rationale for T‑ cell‑based immunotherapy. Cancer Immunol Immunother. Pathol. 2011;179(4):1608–15. 2017;66(1):119–28. 35. Commission E. European reference networks. https ://ec.europ a.eu/healt 26. Rustichelli D, Castiglia S, Gunetti M, Mareschi K, Signorino E, Muraro M, h/ern/netwo rks_en. Accessed 16 Jul 2018. et al. Validation of analytical methods in compliance with good manufac‑ turing practice: a practical approach. J Transl Med. 2013;11:197. 27. Sangiolo D, Mesiano G, Gammaitoni L, Aglietta M, Grignani G. Activity of cytokine‑induced killer cells against bone and soft tissue sarcoma. Oncoimmunology. 2014;3:e28269. Ready to submit your research ? Choose BMC and benefit from: fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Sarcoma Research Springer Journals

Report from the 4th European Bone Sarcoma Networking meeting: focus on osteosarcoma

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Biomedicine; Cancer Research; Oncology; Surgical Oncology
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Abstract

This report summarizes the proceedings of the 4th European Bone Sarcoma Networking Meeting, held in London, England, on 21 June 2017. The meeting brought together scientific and clinical researchers and representatives from sarcoma charities from 19 countries representing five networks across Europe, to present and discuss new develop ‑ ments on bone sarcoma. In view of the challenges is poses, the meeting focussed primarily on osteosarcoma with presentations on developments in our understanding of osteosarcoma genetics and immunology as well as results from preclinical investigations and discussion of recent and ongoing clinical trials. These include studies examining the efficacy of multi ‑ targeted tyrosine kinase inhibitors and checkpoint inhibitors, as well as those with molecular profiling to stratify patients for specific therapies. Discussion was centred on generation of new hypotheses for col‑ laborative biological and clinical investigations, the ultimate goal being to improve therapy and outcome in patients with bone sarcomas. Keywords: Osteosarcoma, Bone sarcoma, Immunotherapy, Genomics, Translational research Introduction as well as those in development, including a number of The 4th European Bone Sarcoma Networking meeting immunotherapy-based trials. Potential therapies based brought together scientific and clinical researchers and on recent osteosarcoma genetic studies and subsequently representatives from sarcoma charities, from 19 coun- immunology and immunotherapy were discussed as well tries representing five networks across Europe to discuss as the role for biomarkers both to identify patients for the latest developments in bone sarcoma research. This these studies and for monitoring of disease. builds on the successful previous meetings [1]. Since the closure of the EURAMOS-1 trial in 2011 there have Current national study programmes been no international phase III studies open for Euro- The first session was an opportunity for national study pean patients with osteosarcoma. In view of this ongoing groups to present recent clinical trials that have recruited unmet need, the meeting focussed primarily on this chal- patients with osteosarcoma, are currently recruiting lenging disease. The meeting opened with presentations osteosarcoma patients or are under development (sum- from National Study Groups on current clinical trials marised in Table  1). The Spanish Group for Research on Sarcoma (GEIS) represented by Nadia Hindi, presented data from GEIS 29 trial, a phase II trial on the combi- *Correspondence: s.strauss@ucl.ac.uk nation of gemcitabine and sirolimus [2]. In this study, Department of Oncology, UCL Cancer Institute, 72 Huntley Street, London WC1A 6DD, UK patients with advanced pretreated osteosarcoma received Full list of author information is available at the end of the article © The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Strauss et al. Clin Sarcoma Res (2018) 8:17 Page 2 of 8 Table 1 Recent European clinical trials recruiting patients with osteosarcoma Trial name Title/description Country Study reference GEIS 29 Multicenter and prospective phase II trial Spain NCT02429973 with gemcitabine and rapamycin in sec‑ ond line of metastatic osteosarcoma GEIS 51 (Palbosarc) Phase II multicenter trial of palbociclib in Spain NCT03242382 second line of advanced sarcomas with CDK4 overexpression GEIS 52 (InmunoSARC) Phase I–II trial of sunitinib plus nivolumab Spain, Italy NCT03277924 after standard treatment in advanced soft tissue and bone sarcomas Sarcome13/0S2016 Randomised phase‑2 trial of mifamurtide France NA (MEPACT ) combined with post‑ operative chemotherapy for newly diagnosed patients up to 50 years with high risk osteosarcoma (metastatic or localized disease with poor histologic response to neoadjuvant chemotherapy). Regobone A phase II study evaluating efficacy and France NCT02389244 safety of regorafenib in patients with metastatic bone sarcomas Cabone Cabozantinib‑s‑malate in treating patients France NCT02243605 with relapsed osteosarcoma or Ewing sarcoma HOPE ITCC‑035 Study of lenvatinib in children and ado‑ France, USA, Germany, Italy, Spain, UK NCT02432274 lescents with refractory or relapsed solid malignancies and young adults with osteosarcoma PembroSARC Combination of MK3475 and metronomic France NCT02406781 cyclophosphamide in patients with advanced sarcomas: multicentre phase II trial PROMO A phase II study of pembrolizumab in Norway, Italy NCT03013127 patients with relapsed or metastatic osteo‑ sarcoma not eligible for curative surgery MAPPYACTS Proof‑ of‑ concept study to stratify targeted France, Ireland, Israel, Italy, Spain NCT02613962 therapies adapted to molecular profiling ESMART European proof‑ of‑ concept therapeutic France, Germany, Italy, Netherlands, Spain, NCT02813135 stratification trial of molecular anomalies UK in relapsed or refractory tumors Can cancer cells be found in blood Enumeration of circulating tumour cells in UK ISRCTN29619083 samples from patients with bone patients with bone sarcomas: an observa‑ sarcoma? tional study NA not available up to six cycles of gemcitabine 800  mg/m days 1 and 8 GEIS 52 (InmunoSARC), which is examining the toler- and Sirolimus (5  mg per day) in a continuous regimen ance and efficacy of the combination of sunitinib and (except the day before and the day of infusion of gem- nivolumab in patients with bone and soft tissue sarcomas citabine). The trial was positive for its primary endpoint, [3, 4]. with a 4-month PFS rate of 44%. Median PFS and OS Nathalie Gaspar, on behalf of The French bone were 2.3 and 7.1 months respectively. Expression of Ribo- sarcoma group presented the upcoming French nucleotide Reductase catalytic subunit 1 (RRM1) was Sarcome13/0S2016 trial. This is a first-line randomised related with a worse outcome, both in terms of PFS and Phase-2 trial of mifamurtide (MEPACT ) combined OS [2]. The GEIS group has another two phase II trials with post-operative chemotherapy for newly diagnosed actively recruiting patients with advanced osteosarcoma: patients up to the age of 50  years with high risk osteo- GEIS 51 (Palbosarc), which is examining the role of the sarcoma (metastatic or localized disease with poor CDK4 inhibitor palbociclib in patients with osteosar- histologic response to neoadjuvant chemotherapy). Sar- coma or soft tissue sarcoma overexpressing CDK4 and come13/OS2016 backbone chemotherapy is based on Strauss et al. Clin Sarcoma Res (2018) 8:17 Page 3 of 8 the previous, Unicancer sponsored, French OS2006/ patients could benefit from precision medicine and it will Sarcome9 trial (M-EI in children, adolescent and young be an opportunity to widen preclinical research studies adults and API-AI in adults) [5, 6]. Post-operative mifa- about sarcomas. murtide administration for 36  weeks, is randomised in The UK National Cancer Research Institute (NCRI) addition to post-operative chemotherapy. This rand - Bone Sarcoma Clinical Studies Group aims to develop omized trial, the first since the controversial INT-033 UK National Institute Health Research (NIHR) portfolio trial, is using a Bayesian design to determine whether studies in primary bone tumours. Sandra Strauss, Lon- the macrophage modulator, mifamurtide, provides ben- don, presented two studies in osteosarcoma, the first, is efit to this group of patients [7]. Several phase-2 tri - a prospective cohort study of patients with newly diag- als for relapsed osteosarcoma patients are on-going in nosed osteosarcoma that aims to (i) describe the expe- France testing different multi-tyrosine kinase inhibitors rience, treatment and outcomes of patients of all ages alone, either randomized versus placebo (Regobone from in the UK; (ii) to investigate the impact of tumour het- 10 years old), or in single arm phase-2 trial (Cabone from erogeneity and tumour evolution on patient outcome 12  years old), as well as associated with chemotherapy through the collection of biological samples; (iii) to vali- (HOPE, ITCC-035, lenvatinib ± etoposide/ifosfamide date biomarkers to accelerate selection of patients with up to 25  years old) [8–10]. Recent international stud- high risk disease into Phase Ib/II clinical trials; (iv) to ies investigating immune check point inhibitors (anti- identify factors influencing decisions about local therapy PD1 and anti-PDL1), alone have not been as promising and outcomes. She also outlined a multicenter observa- as hoped and further work is required to understand tional study lead by Kenny Rankin, Newcastle evaluating mechanisms of resistance and which patients are likely to the potential of using MT1-MMP1 to isolate circulating respond to these agents [11, 12]. Results of a combination tumour cells (CTCs) in patients with osteosarcoma at French study with metronomic cyclophosphamide are diagnosis and subsequent treatment stages. To date the awaited (PembroSARC) [13]. The next trial for paediatric study has recruited 30 patients across four sites [15]. and adult patients with osteosarcoma relapse is being dis- The session concluded with a presentation by Jakob cussed within the ITCC Consortium (Innovative Thera - Anninga, Nijmegen, of a study investigating the effect pies for Children with Cancer) and consideration is being of dose-intensity on event-free survival (EFS) in groups given to combination of two promising approaches, a of patients with localized osteosarcoma. Clinical data multi-tyrosine kinase inhibitor and an immune modula- from MRC BO06 was used to perform a landmark analy- tor. Inclusion of osteosarcoma with molecular profiling in sis, which aimed to cluster patients on the similarity of the multiarm phase-1/2 trial AcSé-eSMART ITCC-057 the individual received dose-intensity (iRDI). The group provides an opportunity to investigate the activity of a demonstrated a more accurate relationship between PARP inhibitor in combination with irinotecan or WEE1 iRDI and EFS when investigated by the whole individual inhibitor with carboplatin [14]. treatment-history, i.e. using longitudinal treatment-data, Elisa Tirtei, Turin, on behalf of The Italian Sarcoma compared to using either intention-to-treat analysis or Group presented a study that opened in November 2016 just the final value of iRDI. Their results suggest that indi - and is a collaboration with the Italian Onco-Haematology vidual tolerability is an important issue in EFS and that Paediatric Association (AIEOP) and Italian Institute for maintenance of treatment intensification towards an Genomic Medicine of Turin. It is a prospective, multicen- individual’s biological tolerance is beneficial. tre study to analyse the tumour genomic profile of paedi - atric and adult patients with new diagnoses of sarcoma Genetic targets in osteosarcoma or relapsed/refractory sarcoma. By comparing tumour A number of presentations focused on recent data gen- samples with the corresponding non-tumour tissue (e.g. erated from sequence analyses performed in osteosar- peripheral blood), the aim of the study is to define the coma, with identification of potential genetic targets and genomic profile of each sample taking advantage of a a discussion of the clinical implications of these find - next generation sequencing (NGS) platform. A panel of ings. Sam Behjati, Cambridge, presented findings of the 410 genes to analyse using the Illumina technique have osteosarcoma study of the International Cancer Genome been chosen. Furthermore, starting from fresh sarcoma Consortium. In that analysis, 112 childhood and adult samples obtained from surgical biopsies, the group aim tumours, encompassing all major histological subtypes, to establish in  vitro cultures and in  vivo patient-derived were studied by whole exome (n = 75) or whole genome xenografts (PDX) to generate working models. To date, sequencing (n = 37). In 32/112 cases an actionable muta- the study has recruited nine patients and has demon- tion was identified, including 20 cases with amplifica - strated the feasibility of this approach. It will now expand tions of receptor tyrosine kinases. Amongst these were to all paediatric Italian oncology departments, so all amplifications of IGF1R that occurred in ~ 10% of cases, a Strauss et al. Clin Sarcoma Res (2018) 8:17 Page 4 of 8 finding that was validated by FISH in an extension cohort appropriate treatment. At the same time, other types of of 87 cases. Overall the findings of this study provide a HR deficiency may be present in osteosarcoma, that do rationale for a basket trial in osteosarcoma that focuses not resemble BRCA1/BRCA2 deficiency in breast cancer. on actionable mutations, including amplifications of the These results indicate that distinguishing patients with IGF1R gene [16]. the various forms of genomic instability is not only pos- Daniel Baumhoer, Basel, presented the findings of a sible, it is critical. whole exome sequence analysis of 31 osteosarcomas, Ola Myklebost, Oslo, presented studies of the sensitiv- which demonstrated that these tumours show highly ity of the EuroBoNet osteosarcoma cell line panel to the complex karyotypes with abundant structural and PARP inhibitor, Talazoparib [23]. The cell lines had vari - numerical aberrations and a multitude of different driver able responses, from similar to that of the highly sensi- genes. However, despite the great amount of inter- and tive BRCA-mutated breast cancer cell line SUM149 to intratumoural heterogeneity, in their analysis, the major- that of the insensitive control HeLa, and responses of the ity of tumours (> 85%) appear to acquire a deficiency osteosarcoma lines were long-lasting when the drug was in homologous recombination (HR) repair that could removed. Various biomarkers were investigated, includ- potentially be therapeutically exploited by using PARP- ing mutations in HRR genes, presence of SNV mutation inhibitors [17]. It is well recognized that PARP-inhibitors profile 3, and the sensitivity to platinum drugs. None of are effective in tumours harbouring deleterious germline these were strongly predictive, but the response to oxali- or somatic mutation in BRCA1/2, i.e. breast and ovar- platin performed best, with the response being confirmed ian cancer, as shown by many studies [18]. Patients with in  vivo in a mouse PDX model. A trial was proposed to wild-type BRCA who have a homologous recombination investigate predictive markers, including the potential of deficiency (“BRCAness”) have also been shown to be sen - the highly variable whole genome profiles. sitive to PARP inhibition [19] as well as platinum-based Michaela Nathrath, Munich, representative of the chemotherapy [20]. He presented pre-clinical data on the Cooperative Osteosarcoma Study Group’s biology panel, efficacy of PARP-inhibitors in reducing cell viability oste - also summarised the case for studying PARP inhibi- osarcoma cell lines, which has been demonstrated by a tors in osteosarcoma based on the above evidence of number of groups [21]. He concluded on the basis of this Kovac et al. [17] and data from cell lines suggesting that evidence, that although there is no universally accepted BRCA-like phenotype is a unifying trait in osteosar- test to assess the sensitivity of tumours to this treatment coma. She suggested that the synthetic lethality concept (so-called “BRCAness”) in patients upfront, there is a using this BRCAness might be a new effective therapeu - molecular rationale to try this approach also in patients tic approach in osteosarcoma but also discussed that ideally within the framework of a clinical study. optimal techniques to select the patients who are likely Accurate methods to detect HR-deficiency in clini - to respond to PARP inhibitors have still to be defined cal samples to identify the patients that can benefit from and also that understanding drug resistance to PARP these treatments are highly sought and a number are inhibitors is important. Despite these challenges, a under development. Andrea Degasperi, Cambridge, pre- multi-center Phase-II study with a PARP inhibitor com- sented a novel method to predict BRCA1 and BRCA2 bined with chemotherapy including biomarker positive deficiency based on mutational signatures, called HRDe - relapsed osteosarcoma patients is planned in Heidelberg/ tect, which is a classifier that identifies tumours with Germany. a specific type of HR defect—BRCA1 or BRCA2 defi - The session concluded with a discussion on the evi - ciency in particular [22]. HRDetect was trained on whole dence presented for the potential role for PARP inhibi- genome sequenced (WGS) breast cancers and validated tors in osteosarcoma. It was agreed that a number of on independent cohorts of breast, ovarian and pancre- questions remain outstanding, including the challenges atic cancers. This classifier is currently the most accurate of conducting a clinical trial without an optimal bio- method for predicting BRCA1 or BRCA2 deficiency in marker; that PARP inhibitors are most likely to be of such tumours (AUC ~ 0.98) [22]. However, when applied benefit in combination with cytotoxic agents but that the to osteosarcomas in the ICGC data set, HRDetect pre- optimal combination is presently unknown. It was also dicted that only one sample of the 37 WGS samples felt the osteosarcoma community may not have exploited tested was similar to BRCA1/BRCA2-deficient breast the value of tyrosine kinase inhibitors (TKIs) in osteo- cancers. Although HRDetect has not yet been validated sarcoma yet and that benefit in selected patients may in osteosarcoma, due to the rarity of BRCA1/BRCA2 have been hidden in previous studies. Discussions cov- deficient bone tumours, this result indicates that BRCA1/ ered whether the recent data from Sam Behjati was suf- BRCA2 deficient-like tumours may not be very common ficient to consider further biomarker-driven studies using in osteosarcoma and need to be carefully stratified for appropriate TKIs. Strauss et al. Clin Sarcoma Res (2018) 8:17 Page 5 of 8 Immunotherapy rationale, targets and other killer (CIK) cells in patients with advanced and/or refrac- studies tory sarcoma. These cells were ex  vivo expanded, HLA- S. Rubina Baglio, Amsterdam, discussed the results unrestricted T-/NK-cells, with NKG2D and MIC A/B as of her investigation on the local inflammation of the anti-tumour targets [26, 27]. In vitro studies in mice have tumour microenvironment induced by osteosarcoma shown significant tumour cell killing using this method. tumour cells. In a xenograft mouse model of osteosar- The results of a French study to characterize the micro- coma, the research group demonstrated that the tumour environment in the biopsies of 126 patients was pre- cells release extracellular vesicles (EVs), carrying a mem- sented by Francoise Rédini, Nantes. The French phase brane-bound form of TGFβ, that “educate” mesenchymal 3 trial (OS 2006) testing the combination of Zometa stem cells to support tumour growth and lung metasta- with chemotherapy and surgery did not improve the sis formation. This effect was caused by a switch in the outcome of patients with osteosarcoma. The authors mesenchymal stem cell cytokine expression profile, and studied the presence of infiltrating immune cells (CD68/ could be fully revoked by the administration of the IL-6 CD163 tumour-infiltrating macrophages, CD8 lym - receptor antibody tocilizumab [24]. These findings pro - phocytes, osteoclasts, and the PD1/PDL-1 checkpoint) vide a rationale for novel therapeutic strategies based on in the biopsies of patients who participated in the OS immunomodulatory drugs for osteosarcoma patients. In 2006 trial. It was shown that high CD163 levels signifi - addition, the research group found evidence of increased cantly correlated with greater overall survival and with levels of EV-bound TGFβ in the circulation of osteosar- longer metastasis PFS independently of diagnosis sta- coma patients, which might provide an option for min- tus. CD8 staining was positive in > 50% of cases with a imally-invasive therapy response monitoring with liquid median staining of 1%. Lower CD8 levels were associated biopsies. She concluded that the tumour ‘educated’ mes- with metastatic disease at diagnosis and only the pres- enchymal stem cells might modulate a local immunosup- ence of CD8-positive cells significantly correlated with pressive niche, which could be targeted to stop tumour improved overall survival in patients who were treated progression. with the bisphosphonate Zometa . It was concluded that Kjetil Boye, Oslo, presented the PROMO-study, which immunohistochemical analysis of the microenvironment commenced in May 2017, and will be carried out in col- in osteosarcoma patient biopsies could represent a novel laboration with Bologna, Italy. This is a non-randomized, tool for therapeutic stratification. investigator-initiated phase-II study with pembrolizumab Katia Scotlandi, Italy, presented the results of a study monotherapy for patients with metastatic, unresectable of the effect of Trabectedin on the differentiation and osteosarcoma. The study has a 2-stage design, and the immune environment in a murine osteosarcoma model. primary endpoint is clinical benefit rate (SD+PR+CR) Of the two models, mOS13 formed smaller tumours, had at 18  weeks using RECIST v1.1. Secondary endpoints an increased bone matrix deposition and a lower meta- include progression-free survival (PFS), overall response static deposition than mOS69 [28]. In the more differen - rate and duration of response evaluated by RECIST tiated tumours a higher monocyte/macrophage (CD68 ), 18 + + + and immune-related response criteria, response by F-leucocyte (CD45 ) and lymphocyte (CD4 /CD8 ) infil - FDG PET/CT, overall survival, safety and health-related tration was demonstrated. Results in patient samples quality of life. A total of 25 patients are expected to be showed a better survival in subjects that had high levels + + included in the study. of cytotoxic T-cells (CD8 /Tia1 : long term cumulative Anne-Marie Cleton-Jansen, Leiden, presented a study survival 81%, versus 45% in patients who were CD8 / of the expression of HLA and PD-L1 as well as the pres- Tia ) [29]. PD-L1 was positive in 14% of the patients, and ence of infiltrating lymphocytes in a series of 87 primary had a worse survival in a subset with a C D8 infiltrate. osteosarcomas and metastases from 26 patients, to estab- In murine osteosarcoma, Trabectedin inhibited tumour lish whether immunotherapy could be beneficial to meta - growth and metastasis formation, affected gene-tran - static and chemotherapy refractory osteosarcoma. T cell scription via RUNX2 activation to a more differentiated infiltrate and PD-L1 expression increased during disease phenotype, and also induced the recruitment/expansion progression, suggesting that T-cell based immunotherapy of adaptive T cells. However, analysis of tumour-infiltrat - with adoptive cell transfer, peptide vaccines or check- ing T cell phenotype and activation state from trabect- point blockade could be a suitable approach for meta- edin-treated mice showed increased PD-1 checkpoint static osteosarcoma patients. Down regulation of HLA-A inhibitor expression on CD8 T cells, compatible with molecules may be a limiting factor, but only in a small their impaired function. It was concluded from this study fraction of the patients [25]. that Trabectedin reprogrammed the tumour associated Elisa Tirtei, Turin, presented the outline of a phase- micro-environment, providing the foundation for combi- I trial for the infusion of autologous, cytokine induced nation therapies with immune checkpoint inhibitors. Strauss et al. Clin Sarcoma Res (2018) 8:17 Page 6 of 8 Bone sarcomas and especially osteosarcomas are newly-developed European Reference Networks (EURA- highly heterogeneous. This heterogeneity both between CAN/PaedCan), which aim to increase access of patients tumours (inter-tumour heterogeneity) and within to specialist care and are currently focusing on develop- tumours (intra-tumour heterogeneity) can be related to ing clinical practice guidelines, training dissemination genetic and non-genetic factors and introduces signifi - and determining how shared data collection could ben- cant challenges for classifying patients that might benefit efit improvements in care for rare diseases [35]. It was from targeted therapies. It has been suggested that CTCs also noted that SIOP Europe was in advanced planning may reflect the biological evolution (e.g. new mutation of a clinical forum bringing together specialists from events) of primary tumours and associated metastases. all tumour types affecting children and young people Unfortunately, in contrast to carcinomas, in which CTCs to allow cross cutting interdisciplinary work. This first have been isolated from epithelial markers (e.g. EpCAM), Annual Meeting of the European Society for Paediatric there are no specific markers expressed by sarcoma cells. Oncology, to be held May 20–25, 2019 in Prague, Czech However, sarcoma cells like other cancer cells frequently Republic, is likely to represent a good opportunity to sus- show a differential size compared to normal cells and a tain collaborative working between bone tumour experts. lower deformability. Size and deformability criteria have been used in pre-clinical models for isolating CTCs and Conclusion could serve as proof-of-concept for pilot clinical trials in Osteosarcoma is a challenging disease with little bone sarcoma [30]. Dominique Heymann, Sheffield, pre - improvement in survival for three decades. To further sented a pilot study that is using the Parsortix System improve outcomes, international collaboration propelled to enrich for CTCs, which are then isolated and captured by initiatives like the European Bone Sarcoma Network using the DEPArray System. is essential. Novel insights from studies on genomics, Finally, Michel Vanden Eynden, Belgium, presented a altered signalling pathways and sarcoma immunology as project investigating telomere maintenance in paediatric well as biomarkers to identify patients for clinical trials tumours, with a focus on osteosarcoma. Most cancers and to monitor disease were discussed. These built on (85–90%) are known to reactivate telomerase to achieve presentations from previous meetings and included dis- cellular immortalisation [31]. However, another mecha- cussion about potential clinical trials, which now need to nism, based on homologous recombination between be taken forward to develop proposals for national and telomeric sequences, called alternative lengthening of for collaborative research and trials. Telomeres (ALT), is also able to provide cells with indefi - nite replication potential. It has been shown that ALT Abbreviations cells are characterized by the presence of a more relaxed AcSé‑ eSMART : Secured access to innovative therapies—European proof‑ of‑ telomeric chromatin that may account for the elevated concept therapeutic stratification trial of molecular anomalies in relapsed of refractory tumours in children; anti‑PD1: anti‑Programmed Death 1; anti‑PDL1: rates of telomeric sister chromatid recombinations typi- anti‑Programmed Death Ligand 1; API‑AI: adriamycin, cisplatin, ifosfamide– cally found in these cells [32, 33]. ALT is known to be adriamycin, ifosfamide; AUC : area under curve; BRCA1/2: BReast CAncer gene found mainly in paediatric tumours, with about 50% of 1/2; CDK4: cyclin‑ dependent kinase 4; CTC: cir culating tumour cells; EEC: EURO EWING Consortium; EOI: European Osteosarcoma Intergroup; EURAMOS: osteosarcoma showing ALT features [34]. At present, EURopean and American Osteosarcoma Study Group; EuroBoNeT: European understanding ALT mechanism is a major challenge; as network to promote research into uncommon cancers in adults and children: it is absent from normal somatic cells, it represents an pathology, biology and genetics of bone tumours; euroSARC : clinical trials in rare SARComas initiative; FISH: fluorescence in situ hybridization; GEIS: Grupo attractive target for cancer therapy, but specific inhibitors Espanol de Investigacion en Sarcomas Asociacion; HR: homologous recom‑ have not been identified yet. To better understand this bination; IGF1R: insulin like growth factor 1 receptor; iRDI: individual received mechanism and assess its relevance as a new prognostic dose intensity; ITCC : innovative therapies for children with cancer; M‑EI: methotrexate–etoposide, ifosfamide; MT1‑MP1: membrane ‑type matrix metal‑ biomarker or a new target for therapy, a collaboration loproteinase‑1; NCRI: National Cancer Research Institute; NGS: next generation with all paediatric oncology departments of university sequencing; NIHR: National Institute for Health Research; OS: overall survival; hospitals across Belgium has been created, which will PARP: poly ADP ribose polymerase; PDX: patient‑ derived xenograft; PFS: progression‑free survival; RRM1: Ribonucleotide Reductase catalytic subunit 1; allow tumour collection all across Belgium and further SFCE: Société Française des Cancers de l’Enfant; SNV: single‑nucleotide variant; investigation on ALT in paediatric cancers. TKI: tyrosine kinase inhibitor; WEE1: WEE1 G2 Checkpoint Kinase; WGS: whole genome sequencing. Future networking Authors’ contributions The meeting concluded with a discussion on role of SJS, JA, JW and AE participated in the conception and design of the future networks for osteosarcoma and commitment manuscript, collected the data from all co‑authors, led the drafting of the manuscript, and revised the article critically. SJS, JA, SRB, DB, SB, SRB, KB, JMB, to support networking opportunities as being integral A‑M C‑ J, AD, MF, FF, NG, DH, NH, CL, OM, MN, FR, KS, ET and MVE provided to facilitate collaboration and thereby improve out- information regarding their group’s research for inclusion into the manuscript comes for patients. Opportunities for this lie within Strauss et al. Clin Sarcoma Res (2018) 8:17 Page 7 of 8 and revised the article critically. All authors read and approved the final References manuscript. 1. 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Clinical Sarcoma Research – Springer Journals

Published: Aug 10, 2018

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