- Email: [email protected]
Immune classification of soft tissue sarcoma predicts clinical outcome
abstracts
Annals of Oncology
1678PD
Immune classification of soft tissue sarcoma predicts clinical outcome
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 Sante´ et de la Recherche Me´dicale, the University of Paris, Sorbonne University, the Programme Cartes d’Identite´ 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.
Volume 30 | Supplement 5 | October 2019
Unravelling omics landscape and targeting oncogenic pathways in undifferentiated pleomorphic sarcomas (UPS)
M. Toulmonde1, C. Lucchesi2, S. Verbeke3, A. Crombe4, V. Chaire3, A. Laroche3, F. Le Loarer5, F. Bertucci6, J. Adam7, F. Bertolo2, D. Geneste2, L. Bianchini8, B. DadoneMontaudie8, T. Hembrough9, F. Cecchi10, F. Giles11, A. Italiano1 1 Medical Oncology, Institut Bergonie´, Bordeaux, France, 2Bioinformatics, Institut Bergonie´, Bordeaux, France, 3INSERM U1218, Institut Bergonie´, Bordeaux, France, 4 Radiology, Institut Bergonie´, Bordeaux, France, 5Pathology, Institut Bergonie´, Bordeaux, France, 6CRCM, Institut Paoli Calmettes, Marseille, France, 7Pathology, Gustave Roussy, Villejuif, France, 8IRCAN, University of Nice-Sophia Antipolis, Nice, France, 9Oncology, NantOmics, LLC, Rockville, MD, USA, 10Translational Medicine, NantOmics, LLC, Rockville, MD, USA, 11Developmental Therapeutics, Epigene Therapeutics, Chicago, IL, USA 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 RNAsequencing, 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 antitumor 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.
1680P
A global patient-driven Facebook study in a very rare sarcoma: Health-related quality of life in epithelioid hemangioendothelioma (EHE) patients
M.E. Weidema1, O. Husson2, W.T. van der Graaf3, H. Leonard4, B.H. de Rooij5, L. Hartle De Young6, I.M.E. Desar1, L.V. van de Poll-Franse7 1 Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands, 2 Psychosocial Research and Epidemiology, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), Amsterdam, Netherlands, 3Medical Oncology, Netherlands Cancer Institue - Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands, 4EHE Rare Cancer Charity, Surrey, UK, 5Research & Development, The Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands, 6Patient Liaison Services, EHE Foundation, Anchorage, AK, USA, 7Department of Psychosocial Studies and Epidemiology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands Background: EHE is a vascular sarcoma with an incidence of 1 per 1 million/year, and an unpredictable clinical course with significant symptom burden. Recruiting EHE patients for studies is difficult and health-related quality of life (HRQoL) in these patients is unknown. We aimed to study the impact of EHE symptom burden on HRQoL. Methods: The study was initiated after EHE patients’ foundations approached our research group to study HRQoL. After ethical approval, patients were recruited from the global EHE Facebook group from May-October 2018. Data were collected using the unique, well-established online PROFILES (Patient Reported Outcomes Following Initial treatment and Long-term Evaluation of Survivorship) registry. Latent class cluster analysis was performed to identify groups based on 10 frequently reported symptoms. Differences in HRQoL (EORTC-QLQ-C30) between clusters were examined. Results: Of 138 patients who registered in PROFILES, 115 (83%) completed the survey. Three clusters of EHE patients were identified with low (A) intermediate (B) and high (C) symptom burden. Highly symptomatic patients had clinically relevant lower scores on HRQoL compared to the other two groups (p < 0.001) (Table). These patients suffered mostly from pain, insomnia and fatigue and more often had bone/pleural lesions.
doi:10.1093/annonc/mdz283 | v689
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz283.011/5577012 by guest on 24 October 2019
F. Petitprez1, A. de Reynie`s1, E.Z. Keung2, T.W-W. Chen3, C-M. Sun4, Y-M. Jeng3, L-P. Hsiao3, L. Lacroix4, C. Lucchesi5, M. Toulmonde6, M.A. Burgess7, V. Bolejack8, D. Reinke9, A.J. Lazar10, C.L. Roland2, J. Wargo1, A. Italiano11, C. Saute`s-Fridman4, H.A. Tawbi12, W.H. Fridman13 1 CIT Research Program, Ligue Contre le Cancer, Paris, France, 2Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 3 Department of Oncology, NTU - National Taiwan University - College of Medicine, Taipei City, Taiwan, 4INSERM U1138, Cordeliers Research Center, Paris, France, 5 Bioinformatics, Institut Bergonie´, Bordeaux, France, 6Medical Oncology, Institute Bergonie´, Bordeaux, France, 7Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA, 8Cancer Research and Biostatistics, Seattle, WA, USA, 9Sarcoma Alliance for Research Through Collaboration, Ann Arbor, MI, USA, 10Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA, 11 Early Phase Trials Unit, Institute Bergonie´, Bordeaux, France, 12Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 13Team Inflammation, Complement and Cancer, INSERM U1138, Centre de Recherche des Cordeliers, Sorbonne Universite´, Universite´ de Paris, Paris, France
1679PD
Annals of Oncology
1678PD
Immune classification of soft tissue sarcoma predicts clinical outcome
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 Sante´ et de la Recherche Me´dicale, the University of Paris, Sorbonne University, the Programme Cartes d’Identite´ 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.
Volume 30 | Supplement 5 | October 2019
Unravelling omics landscape and targeting oncogenic pathways in undifferentiated pleomorphic sarcomas (UPS)
M. Toulmonde1, C. Lucchesi2, S. Verbeke3, A. Crombe4, V. Chaire3, A. Laroche3, F. Le Loarer5, F. Bertucci6, J. Adam7, F. Bertolo2, D. Geneste2, L. Bianchini8, B. DadoneMontaudie8, T. Hembrough9, F. Cecchi10, F. Giles11, A. Italiano1 1 Medical Oncology, Institut Bergonie´, Bordeaux, France, 2Bioinformatics, Institut Bergonie´, Bordeaux, France, 3INSERM U1218, Institut Bergonie´, Bordeaux, France, 4 Radiology, Institut Bergonie´, Bordeaux, France, 5Pathology, Institut Bergonie´, Bordeaux, France, 6CRCM, Institut Paoli Calmettes, Marseille, France, 7Pathology, Gustave Roussy, Villejuif, France, 8IRCAN, University of Nice-Sophia Antipolis, Nice, France, 9Oncology, NantOmics, LLC, Rockville, MD, USA, 10Translational Medicine, NantOmics, LLC, Rockville, MD, USA, 11Developmental Therapeutics, Epigene Therapeutics, Chicago, IL, USA 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 RNAsequencing, 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 antitumor 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.
1680P
A global patient-driven Facebook study in a very rare sarcoma: Health-related quality of life in epithelioid hemangioendothelioma (EHE) patients
M.E. Weidema1, O. Husson2, W.T. van der Graaf3, H. Leonard4, B.H. de Rooij5, L. Hartle De Young6, I.M.E. Desar1, L.V. van de Poll-Franse7 1 Medical Oncology, Radboud University Medical Center, Nijmegen, Netherlands, 2 Psychosocial Research and Epidemiology, Netherlands Cancer Institute/Antoni van Leeuwenhoek hospital (NKI-AVL), Amsterdam, Netherlands, 3Medical Oncology, Netherlands Cancer Institue - Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands, 4EHE Rare Cancer Charity, Surrey, UK, 5Research & Development, The Netherlands Comprehensive Cancer Organization, Utrecht, Netherlands, 6Patient Liaison Services, EHE Foundation, Anchorage, AK, USA, 7Department of Psychosocial Studies and Epidemiology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands Background: EHE is a vascular sarcoma with an incidence of 1 per 1 million/year, and an unpredictable clinical course with significant symptom burden. Recruiting EHE patients for studies is difficult and health-related quality of life (HRQoL) in these patients is unknown. We aimed to study the impact of EHE symptom burden on HRQoL. Methods: The study was initiated after EHE patients’ foundations approached our research group to study HRQoL. After ethical approval, patients were recruited from the global EHE Facebook group from May-October 2018. Data were collected using the unique, well-established online PROFILES (Patient Reported Outcomes Following Initial treatment and Long-term Evaluation of Survivorship) registry. Latent class cluster analysis was performed to identify groups based on 10 frequently reported symptoms. Differences in HRQoL (EORTC-QLQ-C30) between clusters were examined. Results: Of 138 patients who registered in PROFILES, 115 (83%) completed the survey. Three clusters of EHE patients were identified with low (A) intermediate (B) and high (C) symptom burden. Highly symptomatic patients had clinically relevant lower scores on HRQoL compared to the other two groups (p < 0.001) (Table). These patients suffered mostly from pain, insomnia and fatigue and more often had bone/pleural lesions.
doi:10.1093/annonc/mdz283 | v689
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz283.011/5577012 by guest on 24 October 2019
F. Petitprez1, A. de Reynie`s1, E.Z. Keung2, T.W-W. Chen3, C-M. Sun4, Y-M. Jeng3, L-P. Hsiao3, L. Lacroix4, C. Lucchesi5, M. Toulmonde6, M.A. Burgess7, V. Bolejack8, D. Reinke9, A.J. Lazar10, C.L. Roland2, J. Wargo1, A. Italiano11, C. Saute`s-Fridman4, H.A. Tawbi12, W.H. Fridman13 1 CIT Research Program, Ligue Contre le Cancer, Paris, France, 2Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 3 Department of Oncology, NTU - National Taiwan University - College of Medicine, Taipei City, Taiwan, 4INSERM U1138, Cordeliers Research Center, Paris, France, 5 Bioinformatics, Institut Bergonie´, Bordeaux, France, 6Medical Oncology, Institute Bergonie´, Bordeaux, France, 7Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA, 8Cancer Research and Biostatistics, Seattle, WA, USA, 9Sarcoma Alliance for Research Through Collaboration, Ann Arbor, MI, USA, 10Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA, 11 Early Phase Trials Unit, Institute Bergonie´, Bordeaux, France, 12Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA, 13Team Inflammation, Complement and Cancer, INSERM U1138, Centre de Recherche des Cordeliers, Sorbonne Universite´, Universite´ de Paris, Paris, France
1679PD