Background

We investigated the impact of secondary surgery (2Surg) after a first R1 or R2 resection in the 10931 pts with STS of the limb or trunk wall included in the nationwide NETSARC database from 2010 to 2017.

Methods

NETSARC (netsarc.org) is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDT), funded by the French NCI (INCa). Since 2010, presentation to an MDTB and second pathological review are mandatory for sarcoma pts. Statistics were performed with SPSS23.0. LRFS, metastasis-free survival (MFS), OS compared with the logrank test.

Results

In 5295 (49.4%) patients, sarcoma were located on the lower limb, 3670 (33.6%) on trunk wall, 1966 (18.0%) on upper limb. Local RFS (LRFS) and RFS (p < 0.001), but not OS, were superior for pts operated in a NETSARC center (N = 4417, 41%). LRFS & OS were best for pts presented to a Netsarc MDT (NMDT) AND who were first operated in NETSARC centers; while the worst LRFS & OS were observed in pts presented in a NMDT but first operated outside a NetSARC center (p < 0.001). Among the 2081 pts with a first R1 resection in whom 2Surg was documented, 1047 (50.3%) were reoperated. These R1 reoperated pts had a superior LRFS, metastatic free survival (MFS) and OS (p < 0.001): LRFS (p < 0.001), MFS (p = 0.05) and OS (p < 0.001) were superior after 2Surg only in pts operated 1^st outside a Netsarc center. There were 823 pts with a first surgery with R2 resection in whom 2Surg was documented: 619 (75.2%) were reoperated. R2 reoperated patients had a superior LRFS and OS (p = 0.01). MFS was not different. Again, LRFS (p < 0.001) & OS (p < 0.001) were superior after 2Surg only in pts operated 1^st outside a Netsarc center. Among reoperated pts, those for whom 2Surg was in a NetSARC center had a superior LRFS & RFS (p < 0.001) and OS (p = 0.05).

Conclusions

In this nationwide series of limb or trunk wall STS, 2Surg after a R1 or R2 primary excision was associated with an improved OS only when pts had been operated first outside a reference center. 2Surg in a NETSARC center was associated with a better OS.

Legal entity responsible for the study

Jean-Yves Blay.

Funding

INCA (NetSarc, RREPS, RESOS, LYRICAN (INCA-DGOS-INSERM 12563), ARC fundation, Ligue de L’Ain contre le Cancer, INCA (NetSARC, RREPS, RESOS and LYRICAN (INCA-DGOS-INSERM 12563), InterSARC), La Ligue contre le Cancer, Ligue de L’Ain contre le Cancer, la Fondation ARC, EURACAN (EC 739521).

Disclosure

All authors have declared no conflicts of interest.

Background

Clinical practice guidelines indicate that tumors < =3cm with a suspected sarcoma diagnosis may be proposed for excision first without prior biopsy. We investigated the impact of preoperative biopsy on the outcome of patients with sarcomas < =3 cm (SArcinf3) included in the nationwide NETSARC database from 2010 to 2017.

Methods

NETSARC is a network of 26 reference sarcoma centers with specialized multidisciplinary tumor boards (MDTB), funded by the French NCI (INCa). 1720 of 27894 (6.2%) incident patients had a sarcoma with a documented size < =3 cm at diagnosis in the database. Statistics were performed with SPSS23.0. Local relapse-free survival (LRFS), metastasis-free survival (MFS), overall survival (OS) were compared with the logrank test.

Results

As compared to larger sarcoma, Sarcinf3 were less frequently deep seated, from internal trunk, from visceral or bone sites, metastatic at diagnosis and grade 3 (p < 0.0001 all). The distribution of gender and age were similar. Different NETSARC centers distributions were observed as compared to larger tumors. The most frequent histotypes were LMS, dermatofibrosarcoma, GIST, UPS, angiosarcoma. Preoperative biopsy was reported in 893 of 1720 (51.9%) of Sarcinf3 vs 68.5% for larger tumors (p < 0.0001). Within the entire series of 1720 pts, lack of preoperative biopsy was not found correlated to an increased risk of LRFS, MFS, or death in univariate and multivariate analysis (including gender, age, tumor grade, size, site, depth, histotypes, surgery in NetSARC). Similar results were observed excluding DFSP and within the soft tissue tumor subgroup. Surgery in NETSARC was associated with a lower risk of LRFS in multivariate analysis. However, significantly more patients were re-operated when preoperative biopsy were omitted (21.9% vs 10.0%, p < 0.0001). There were significantly more R1 & R2 resections in the non-biopsy group, both after the first (p < 0.0001) and after the final surgery (p < 0.01).

Conclusions

In this nationwide series of 1720 pts with sarcomas<3cm, those operated without a biopsy and those operated after a diagnostic biopsy had a similar LRFS, MFS and OS. However, both the initial and final quality of surgery was worse, and the rate of reoperation was superior in patients operated first without a biopsy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The EUROpean Bone over 40 Sarcoma Study included patients with 41 to 65 years of age with primary malignant bone sarcoma treated with intensive multiagent chemotherapy. Outcome in the subgroup of high-grade osteosarcoma has been published (Ferrari et al. 2017). This report focuses on other bone sarcomas representing the largest prospectively collected dataset based on an international consortium.

Methods

Chemotherapy was based on doxorubicin, cisplatin, ifosfamide, and methotrexate. Tumors registered as MFH, sarcoma NOS, spindle cell sarcoma or undifferentiated sarcoma were grouped as „undifferentiated pleomorphic sarcoma“. Further histologies included leiomyosarcoma, fibrosarcoma and angiosarcoma.

Results

122 patients with other bone sarcoma were registered into EURO-B.O.S.S. and 113 considered evaluable for analysis. Their median age was 52 years (range: 40-66). Eighty-eight bone sarcomas were grouped as UPS, 20 were leiomyosarcomas, and 5 had other histologies (3 fibrosarcoma, 2 angiosarcoma). Chemotherapy according to the EURO-B.O.S.S. recommendations was initiated in all patients. Surgery was performed for 109/113 tumors, prior to chemotherapy in 13, delayed in 96. A macroscopically complete surgical remission of the primary tumor site was obtained in 106/113. At last follow-up, 70 patients were alive, 62 of these in complete remission and 8 with bone sarcoma. Of 43 patients who had died after a median of 2.1 years (0.15-8.8), 37 were reported to have died of progressive bone sarcoma, 2 of other causes (1 neutropenic sepsis, 1 secondary malignancy (myeloma)) and 4 of unknown causes.Table:

1675PD

Conclusions

Multiagent chemotherapy was feasible in this patient population. Outcome seems comparable to high-grade osteosarcoma with a non-significant trend for UPS over leiomyosarcoma. Favorable outcome was associated with extremity site, secondary surgery after neoadjuvant chemotherapy, and good response to primary chemotherapy.

Legal entity responsible for the study

The authors.

Funding

COSS, SSG, ISG.

Disclosure

P. Reichardt: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (institution), Advisory / Consultancy: Pfizer; Honoraria (institution), Advisory / Consultancy: Bayer; Honoraria (institution), Advisory / Consultancy: PharmaMar; Honoraria (institution), Advisory / Consultancy: Lilly; Advisory / Consultancy: Clinigen; Advisory / Consultancy: Deciphera; Advisory / Consultancy: Roche; Honoraria (institution): Amgen. R. Bertulli: Honoraria (self), Speaker Bureau / Expert testimony: Lilly; Honoraria (self), Speaker Bureau / Expert testimony: Italfarmaco; Honoraria (self), Speaker Bureau / Expert testimony: PharmaMar. All other authors have declared no conflicts of interest.

Background

The capacity of inducing tumor shrinkage in advanced soft tissue sarcomas (STS) is an unmet need beyond the first-line of systemic therapy. Pivotal studies of approved drugs reported RECIST response rates below 10%. Thus, it is challenging to relieve symptoms related to tumor volume in patients progressing to anthracycline-based schemes. Besides that, the overall response rate (ORR) is an appropriate surrogate for overall survival. This phase II trial explores the combination of trabectedin (T) and concurrent radiotherapy (RT) in the metastatic setting and is supported by preclinical experiments and previous phase I trial.

Methods

Patients received T 1.5 mg/m² in 24-h infusion and started RT (30 Gy, 3 Gy/day) from the end of the first T perfusion. Most relevant inclusion criteria were metastatic progressing STS, a maximum of two previous systemic lines for advanced disease with at least one previous anthracycline-based line. Neither all the lesions nor all the sites were required to be irradiated. The main endpoint was ORR by RECIST 1.1. A Simon 2-stage was used to estimate 35% ORR of interest for further investigation (α = 0.1, power 90%; P0 = 0.10). Central pathology and radiological review were mandatory.

Results

From 10/2017 to 11/2018, 27 patients were enrolled. Histologies were: leiomyosarcoma 7 (26%), synovial sarcoma 6 (22%), liposarcoma 4 (15%) and other 10 (37%). The median of previous lines was 2, and ECOG distribution was 0: 19 (70%) and 1: 8 (30%). With a median follow-up of 6 months (1-12), there were 9 events of progression and 3 events of death. The 6-month PFSR was 75% and the 6-month OSR was 86%. From 26 evaluable patients by RECIST, there were 15 PR (57.7%), 7 SD (26.9%) and 4 PD (15.4%). One G3 and 3 G1 pneumonitis were observed. One toxic death occurred (sepsis) being G3-4 neutropenia observed of 7 (26%) while febrile neutropenia was reported in 2 (7.4%) cases.

Conclusions

T concurrent with RT showed a relevant activity in progressing metastatic setting in a wide range of STS types, giving options for tumor shrinkage beyond the first-line of advanced STS. The RECIST ORR of 57.7% and 6-m PFSR of 75% confirm the synergy of T+RT.

Clinical trial identification

NCT02275286.

Legal entity responsible for the study

GEIS (Spanish Group for Research on Sarcoma).

Funding

GEIS, ISG (Italian Sarcoma Group), FSG (French Sarcoma Group); PharmaMar.

Disclosure

J. Martin Broto: Research grant / Funding (institution): EISAI; Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Lilly. A. Italiano: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Inmune Design; Honoraria (self), Advisory / Consultancy: Epizyme; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Bayer; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self): Novartis; Research grant / Funding (self): Merck Serono; Research grant / Funding (self): AstraZeneca/MedImmune; Research grant / Funding (self): MSD Oncology. R.M. Alvarez Alvarez: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Boehringer Ingelheim; Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Honoraria (self): Pierre Fabre; Honoraria (self): Pfizer; Honoraria (self), Research grant / Funding (institution): Novartis; Honoraria (self): Bayer; Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (self): Roche; Research grant / Funding (self): AstraZeneca; Research grant / Funding (self): Peregrine Pharmaceuticals; Research grant / Funding (self): AbbVie; Research grant / Funding (self): Merrimack; Research grant / Funding (institution): Janssen. A. Lopez Pousa: Travel / Accommodation / Expenses: PharmaMar. A. Redondo: Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Roche; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Advisory / Consultancy: Clovis Oncology; Research grant / Funding (institution): Eisai. J. Blay: Honoraria (self), Research grant / Funding (self): PharmaMar. A. Gronchi: Honoraria (self), Advisory / Consultancy: Novartis; Advisory / Consultancy: Bayer; Honoraria (self), Advisory / Consultancy: Lilly; Advisory / Consultancy, Travel / Accommodation / Expenses: Nanobiotix; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Honoraria (self): Pfizer. N. Hindi: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: PharmaMar; Research grant / Funding (institution): Eisai; Research grant / Funding (institution): Novartis. All other authors have declared no conflicts of interest.

Background

Lenvatinib (LEN) is a multikinase inhibitor of VEGFR1–3 and other targets. We report data from phase Ib dose-finding and phase II expansion cohorts of LEN + etoposide + ifosfamide in pts with r/r osteosarcoma.

Methods

Pts were aged 2 to ≤ 25 years with r/r osteosarcoma and <2 prior VEGF-targeted therapies. The phase Ib starting dose was LEN 11 mg/m²/day + ifosfamide 3000 mg/m² + etoposide 100 mg/m² daily/3 days. On determination of the recommended phase II dose (RPh2D) of LEN + chemo, pts were enrolled into the phase II expansion cohort. Primary end points: phase Ib, RPh2D; phase II, 4 months’ progression-free survival (PFS-4).

Results

In the phase Ib dose-finding cohort (n = 22), pts received LEN 11 mg/m² (n = 7) and 14 mg/m² (n = 15) + chemo. Dose-limiting toxicities were: Grade (G) 4 thrombocytopenia (n = 1; LEN 11 mg/m²), G4 thrombocytopenia and G3 epistaxis (n = 1; LEN 14 mg/m²), G2 oral dysesthesia, G3 muscle spasm, and G2 back pain (n = 1; LEN 14 mg/m²). RPh2D was LEN 14 mg/m² + chemo. In the expansion cohort (n = 20), the median number of LEN cycles received was 4 (range: 1–7). As reported in the database, the most frequent treatment-emergent adverse events (TEAEs) were platelet count decreased/thrombocytopenia (50%/30%), neutropenia/neutrophil count decreased (45%/25%), anemia (45%), nausea (40%), ALT increased, diarrhea, and white blood cell count decreased (30% each). Most frequent G ≥ 3 TEAEs were neutropenia/neutrophil count decreased (45%/25%), platelet count decreased/thrombocytopenia (40%/20%), white blood cell count decreased (30%), and anemia (25%). Pneumothorax was observed in the dose-finding cohort (n = 6) and expansion cohort (n = 1); 2 (dose-finding cohort) were ≥G3; and 1 was post-thoracotomy. 4 Pts (dose-finding cohort) discontinued treatment due to TEAEs. There were no treatment-related fatal serious AEs. In the dose-finding combination cohort, 12/18 evaluable pts (66.7%) achieved PFS-4. In the phase II expansion cohort, 5/8 evaluable pts (62.5%) achieved PFS-4.

Conclusions

The combination of RPh2D LEN (14 mg/m²) + chemo had a manageable safety profile with promising preliminary evidence of efficacy.

Clinical trial identification

NCT02432274.

Legal entity responsible for the study

Eisai Inc.

Funding

Eisai Inc.

Disclosure

A. Longhi: Non-remunerated activity/ies, non-financial support: PharmaMar, Takeda; Research grant / Funding (institution): Takeda. M. Casanova: Advisory / Consultancy, advisory role: Bayer; Advisory / Consultancy, advisory role: Lilly; Advisory / Consultancy, advisory role: Roche; Advisory / Consultancy, advisory role: Tesaro. S.S. Bielack: Travel / Accommodation / Expenses, site fees for study preparation: Eisai; Travel / Accommodation / Expenses, personal fees from Clinigen: Clinigen; Travel / Accommodation / Expenses, personal fees from Lilly: Lilly; Travel / Accommodation / Expenses, personal fees from Novartis: Novartis; Travel / Accommodation / Expenses, personal fees from Bayer: Bayer; Travel / Accommodation / Expenses, personal fees from Pfizer: Pfizer; Travel / Accommodation / Expenses, personal fees from Isofol: Isofol; Travel / Accommodation / Expenses, personal fees from Sensorion: Sensorion; Travel / Accommodation / Expenses, personal fees from Ipsen: Ipsen; Advisory / Consultancy, Institution negotiating consultancy agreement with Eisai: Eisai. S. Gallego Melcon: Travel / Accommodation / Expenses: Loxo Oncology; Advisory / Consultancy: Bayer, Eusa. All other authors have declared no conflicts of interest.

Background

Anthracycline based chemotherapy remains the standard of care for first-line treatment for advanced and metastatic soft tissue sarcoma. In some instances, patients may not be a candidate for chemotherapy based on age or other comorbidities leaving no viable treatment option. Pazopanib is a multi-targeted tyrosine kinase inhibitor that is FDA approved as a second-line and beyond treatment for metastatic soft tissue sarcoma. We proposed a phase II study to evaluate pazopanib as a first-line agent in patients with non-resectable or metastatic disease who are not candidates for cytotoxic chemotherapy.

Methods

Eligible patients were at least 18 years old, not a candidate for chemotherapy, and had not received prior systemic therapy for sarcoma. Initial starting dose of pazopanib was 200mg BID titrated to 800mg daily. The primary endpoint was clinical benefit rate (CBR) (CR + PR + SD per RECIST 1.1) at 16 weeks. The sample size of 56 evaluable patients was calculated to provide 80% power to test a hypothesized CBR of ≥ 35% against an unfavorable CBR of ≤ 20%. If ≥ 17 patients achieved benefit, the null CBR of 20% would be rejected would be rejected at a nominal 5% alpha level (actual alpha=0.043). Secondary endpoints included PFS rate, OS, quality of life, and serum biomarkers.

Results

56 patients are included in the intention-to-treat analysis. Currently 52 patients are evaluable for CBR. Data from the final 4 patients will be added at the time of presentation. Median PFS was 12 (8.29∼24.14) weeks and PFS rate at 16 weeks was 40% (CI 0.2893-0.5617). Median OS was 8.6 months, CBR=36.5% (19/52), 95% CI = 0.2362∼0.5104, 2-sided exact binomial test p = 0.00507. No new or unexpected adverse events were seen. The most common Grade I-II adverse events were diarrhea, nausea, and anemia. The most common grade III-IV adverse events were hypertension and liver function test (LFT) abnormalities. Longitudinal quality of life analysis will be added at the time of presentation as well.

Conclusions

Given that the primary endpoint was met, these data suggest that there is a benefit to front-line pazopanib in patients who are not candidates for cytotoxic chemotherapy.

Clinical trial identification

NCT02300545.

Legal entity responsible for the study

Washington University in St Louis.

Funding

Novartis/GSK.

Disclosure

M. Agulnik: Advisory / Consultancy: Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Bayer; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Bayer. M. Varun: Travel / Accommodation / Expenses: Deciphera; Research grant / Funding (institution): Immunocellular; Research grant / Funding (institution): Orbus Therapeutics. M. Milhem: Advisory / Consultancy: Amgen; Advisory / Consultancy: Trieza; Advisory / Consultancy: Biontech; Advisory / Consultancy: Blueprint medicine cooperation; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Array BioPharma, Inc. S. Robinson: Research grant / Funding (institution): TRACON; Honoraria (institution), Advisory / Consultancy: BTG International; Honoraria (institution), Advisory / Consultancy: Society of Interventional Radiology Foundation. S. Attia: Research grant / Funding (institution): AB Science; Research grant / Funding (institution): TRACON Pharma; Research grant / Funding (institution): CytRX Corporation; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Immune Design; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Epizyme; Research grant / Funding (institution): BluePrint Medicine; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): CBA Pharma; Research grant / Funding (institution): Desmoid Tumor Research Foundation; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Philogen; Research grant / Funding (institution): Laboratories; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): BTG; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): FORMA Therapeutics. B.A. Van Tine: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Tracon; Advisory / Consultancy: CytRX; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Plexxicon; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Adaptimmune; Speaker Bureau / Expert testimony: Caris; Advisory / Consultancy: Bayer. All other authors have declared no conflicts of interest.

Background

Soft tissue sarcomas (STS) form a group of rare cancers which accounts for around 1% of tumours. Although up to 15% of patients respond in immunotherapy trials, there are no biomarkers predicting response of STS to checkpoint blockade therapies yet.

Methods

We analysed transcriptomic data of 4 publicly available cohorts, accounting for more than 600 STS. We used MCP-counter, a deconvolution method to estimate the tumour microenvironment (TME) composition Based on MCP-counter estimates, we established a robust immune classificationof STS tumors into 5 Sarcoma Immune Classes, labelled A, B, C, D and E. These classes exhibited different type and extents of TME. We validated the profiles of these 5 groups on a 72-patients cohort using immunohistochemichal (IHC) stainings for CD3, CD8, CD20 and CD34.

Results

One group (A: 23.3% of tumours) exhibits a very low to low immune infiltrate for all TME cell types. Another class (C: 14.5% of all tumours) displays moderate immune infiltrate and a strong presence of endothelial cells. Finally, another group (E: 15.6%) is highly infiltrated by all immune cell types. The two remaining groups (B: 27.4% and D: 19.4%) are heterogeneous, respectively rather highly and lowly infiltrated. The immune high group E is associated with an overexpression of several immune checkpoint genes: PDCD1 (PD-1), CD274 (PD-L1), PDCD1LG2 (PD-L2), LAG3, HAVCR2 (TIM-3), CTLA4. On 72 patients, we showed that the immune-high group could be identified by the IHC-visible presence of tertiary lymphoid structures (TLS), defined as T cell aggregates juxtaposing B cell aggregates. The immune-high group also exhibited prolonged overall survival as compared with other groups. Using data from a phase II clinical trial with pembrolizumab, we show that responders can be identified as class E tumours, therefore allowing patient selection.

Conclusions

We have defined a novel immune-based classification of STS into 5 classes, among which an immune-high group characterized by a strong infiltration by all immune cell and expression of immune checkpoints, presence of TLS and longer overall survival. This class groups responders to PD-1 blockade in a phase II clinical trial.

Legal entity responsible for the study

INSERM.

Funding

Institut National de la Santé et de la Recherche Médicale, the University of Paris, Sorbonne University, the Programme Cartes d’Identité des Tumeurs (CIT) from the Ligue Nationale Contre le Cancer, Institut National du Cancer (HTE-INSERM plan cancer, C16082DS), Association pour la Recherche sur le Cancer (ARC), Cancer Research for Personalized Medecine programme, “FONCER contre le cancer” programme, Labex Immuno-Oncology, the National Institute of Health, Moon Shot program at MD Anderson Cancer Center, Ministry of Education and Ministry of Science and Technology of Taiwan, National Taiwan University, Merck, Inc, SARC, Sarcoma Foundation of America, and the QuadW Foundation.

Disclosure

T.W. Chen: Advisory / Consultancy, Research grant / Funding (self): Eisai; Advisory / Consultancy: Lilly. M.A. Burgess: Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Eisai. J. Wargo: Advisory / Consultancy: Merck; Advisory / Consultancy: BMS; Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Roche; Advisory / Consultancy: Genentech; Advisory / Consultancy: Illumina. H.A. Tawbi: Advisory / Consultancy, Research grant / Funding (self): BMS; Advisory / Consultancy, Research grant / Funding (self): Merck; Advisory / Consultancy, Research grant / Funding (self): Genentech; Research grant / Funding (self): Celgene; Research grant / Funding (self): GSK. W.H. Fridman: Advisory / Consultancy: MedImmune; Advisory / Consultancy: Novartis; Advisory / Consultancy: Servier; Advisory / Consultancy: Pierre Fabre. All other authors have declared no conflicts of interest.

Background

UPS are a heterogenous group of poorly differentiated tumors. We hypothesized that there is a link between dedifferentiation state of UPS and immune infiltrate and that this relationship relies on specific pathways activation and related genomics alterations with potential therapeutic impact. Main objectives were to generate a comprehensive Omics landscape of true UPS and test potential targets for therapeutics approach on cell lines and patient tumour derived mouse xenografts (PDX).

Methods

We analysed 135 UPS cases, 25 of which were selected for full exome and RNA sequencing, proteomics profiling conducted by data-independent acquisition mass spectrometry, as well as immune profiling by immunohistochemistry (IHC).

Results

Using unsupervised consensus clustering and hierarchical clustering of RNA-sequencing, we identified two main groups of patients: group A and B, with associated gene clusters. Group A was mainly enriched in genes that play a crucial role in both normal development and stemcellness, notably FGFR2. Group B was strongly enriched in genes involved in immunity. Using proteomics analysis we found two main proteomic groups - PA and PB – that highly correlated with the two main genetic groups - A and B. The proteome group PB, associated with the immune-high group B, was significantly enriched in immune response pathways, whereas the proteome group PA, associated with the immune-low group A, was mainly enriched in MYC targets and epithelial mesenchymal transition pathways. We then further assessed the therapeutic potential of this classification by using in vitro and in vivo PDX models directly derived from patient tumor samples from the molecular profiling study. We showed robust anti-tumor activity of FGFR2 inhibitor JNJ-42756493 and of NEO2734, a first-in-class epigenetic modifier that notably inhibits Bromodomain and Extra-Terminal domain (BET) family and Cyclic AMP response element binding protein (CREB)-binding (CBP) proteins, in models from group A, selectively.

Conclusions

This integrated analysis of UPS allowed the identification of two main entities with distinct molecular features, immune phenotypes, as well as differential sensitivity to specific anti-cancer agents.

Legal entity responsible for the study

The authors.

Funding

La Ligue.

Disclosure

All authors have declared no conflicts of interest.