New Strategies in Sarcoma: Linking Genomic and Immunotherapy Approaches to Molecular Subtype

Lim, Jamie; Poulin, Neal; Nielsen, Torsten O.

doi:10.1158/1078-0432.ccr-15-0831

Cited by 37 publications

(40 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This finding suggests that overexpression of H19 and HOTAIR, together with let-7 downregulation, all concur to induce EZH2 and, in turn, chromatin remodeling and mesenchymal transdifferentiation in FS-DFSP (19,(39)(40)(41). A role for epigenetic reprogramming in fibrosarcomatous transformation was also supported by the finding that 66 genes enriched in FS-DFSP versus DFSP are reported to undergo epigenetic regulation (11), and recent evidence is consistent with the involvement of chromatin remodeling in translocation-associated sarcomas (42). Overall, our analyses point at EZH2 as a promising target in DFSP.…”

Section: Discussionmentioning

confidence: 57%

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

Stacchiotti

Astolfi

Gronchi

et al. 2016

Molecular Cancer Research

View full text Add to dashboard Cite

Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma. At times, a fibrosarcomatous transformation marked by a more aggressive clinical behavior may be present. We investigated the natural history and the molecular bases of progression from classic DFSP to the fibrosarcomatous form (FS-DFSP), looking, retrospectively, at the outcome of all patients affected by primary DFSP treated at our institution from 1993 to 2012 and analyzing the molecular profile of 5 DFSPs and 5 FS-DFSPs by an integrated genomics approach (whole transcriptome sequencing, copy number analysis, FISH, qRT-PCR, IHC). The presence of fibrosarcomatous features was identified in 20 (7.6%) patients out of 263 DFSP. All cases were treated with macroscopic complete surgery. A local relapse occurred in 4 of 23 patients who received a microscopic marginal surgery (2 classic DFSP, 2 FS-DFSP), while metastasis affected 2 patients, both FS-DFSP (10% of FS-DFSP), being the first event. DFSP evolution to FS-DFSP was paralleled by a transcriptional reprogramming. The recurrent loss of chromosome 22q appeared to contribute to this phenomenon by promoting the expression of epigenetic regulators, such as EZH2. Loss of the p16/CDKN2A/INK4A locus at 9p was also observed in two FS-DFSP metastatic cases.Implications: FS-DFSP is a rare subgroup among DFSP, with a 10% metastatic risk, that was independent from local recurrence and that was not observed in DFSP, that were all cured by wide surgery. Chromosome 22q deletion might play a role in FS-DFSP, and p16 loss may convey a poor outcome. EZH2 dysregulation was also found and represents a druggable target.

show abstract

Section: Discussionmentioning

confidence: 57%

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

Stacchiotti

Astolfi

Gronchi

et al. 2016

Molecular Cancer Research

View full text Add to dashboard Cite

show abstract

“…Multiple recent genomic studies have provided better insight into sarcoma biology through a more accurate classification by molecular subtype, identification of recurrent mutations in oncogenic pathways and evidence of epigenetic dysregulation [9]. Barretina et al [10] for example, recently provided a comprehensive database of sarcoma genome alterations in 207 samples of STS; despite their elucidation of genes and signaling pathways not previously associated with STS, we still lack appropriate pharmacologic tools for targeting specific genomic alterations.…”

Section: Discussionmentioning

confidence: 99%

Response to anti-PD1 therapy with nivolumab in metastatic sarcomas

et al. 2016

View full text Add to dashboard Cite

BackgroundManipulation of immune checkpoints such as CTLA4 or PD-1 with targeted antibodies has recently emerged as an effective anticancer strategy in multiple malignancies. Sarcomas are a heterogeneous group of diseases in need of more effective treatments. Different subtypes of soft tissue and bone sarcomas have been shown to express PD-1 ligand.MethodsWe retrospectively analyzed a cohort of patients (pts) with relapsed metastatic/unresectable sarcomas, who were treated with nivolumab provided under a patient assistance program from the manufacturer. Pts underwent CT or PET/CT imaging at baseline and after at least four doses of nivolumab; RECIST 1.1 criteria were used for response assessment.ResultsTwenty-eight pts with soft tissue (STS, N = 24) or bone sarcoma (N = 4), received IV nivolumab 3 mg/kg every 2 weeks from July 2015. Median age was 57 (24–78), male:female ratio was 14:14; the median number of nivolumab cycles was eight. Eighteen pts concomitantly received pazopanib at 400–800 mg daily. The most common side effect was grade 1–2 LFT elevations; grade 3–4 toxicity occurred in five patients (colitis, LFT elevations, pneumonitis). Twenty-four pts received at least four cycles. We observed three partial responses: one dedifferentiated chondrosarcoma, one epithelioid sarcoma and one maxillary osteosarcoma (last two patients on pazopanib); nine patients had stable disease including three leiomyosarcomas; 12 patients had progression of disease including 4 leiomyosarcoma. Clinical benefit (response + stability) was observed in 50% of the evaluable patients.ConclusionsThese data provide a rationale for further exploring the efficacy of nivolumab and other checkpoint inhibitors in soft tissue and bone sarcoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s13569-016-0064-0) contains supplementary material, which is available to authorized users.

show abstract

“…Those with high immune infiltrate and high mutational load or complex karyotype appear to be the best candidates. 10 To date, no studies have evaluated the PD-1/PD-L1 axis in chondrosarcoma. The first clinical data on the immune checkpoint blockade strategy in these patients will be shortly provided with the ongoing phase II trial evaluating the anti PD-1 antibody pembrolizumab in advanced bone and soft-tissue sarcomas.…”

Section: Discussionmentioning

confidence: 99%

“…Their expression and role in sarcomas is not yet well characterized but is currently under investigation. 10 However, to date there is scarce data regarding the immune microenvironment and the presence of the immune checkpoint PD-1 with its ligand PD-L1 in chondrosarcoma. Recently, a preclinical study revealed the absence of PD-L1 expression in six mesenchymal chondrosarcomas.…”

mentioning

confidence: 99%

Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype

et al. 2016

View full text Add to dashboard Cite

Therapies targeting the programmed cell death 1 (PD-1) or its ligand (PD-L1) promote antitumor T-cell activity, leading to unprecedented long-lasting tumor responses in some advanced cancers. Because of radiotherapy and chemotherapy resistance, no effective treatments have been defined for advanced chondrosarcomas. We here report an immunohistochemical analysis of PD-L1 expression in a large series of conventional, mesenchymal, clear cell and dedifferentiated chondrosarcomas using tissue microarrays. In the PD-L1-positive tumors, we analyzed the immune microenvironment (T-cell and macrophage infiltration as well as HLA class I expression) using whole sections. PD-L1 expression was absent in conventional (n = 119), mesenchymal (n = 19) and clear cell (n = 20) chondrosarcomas. Forty-one percent (9 of the 22) of dedifferentiated chondrosarcomas displayed PD-L1 positivity. These results were confirmed in an independent cohort using whole tissue sections of dedifferentiated chondrosarcomas in which PD-L1 expression was detected in 52% (11 of the 21) of cases. PD-L1 expression was exclusively found in the dedifferentiated component and expression positively correlated with other immune parameters such as high number of tumor-infiltrating lymphocytes (P = 0.014) and positive HLA class I expression (P = 0.024) but not with patient overall survival (P = 0. Chondrosarcomas constitute a malignant group of cartilaginous matrix-producing neoplasms, with diverse morphological features and clinical behavior. 1 Conventional chondrosarcoma is the second most common primary bone malignancy after osteosarcoma and can be categorized according to their location into central (85%) and peripheral chondrosarcomas (15%). Their histology is similar, with atypical chondrocytes and abundant extracellular matrix, but they differ at the genetic level. Notably, mutations in isocitrate dehydrogenase (IDH) 1 and 2 are found in approximately half of conventional central chondrosarcomas while mutations in genes encoding exostosin (EXT) 1 and 2 characterize peripheral chondrosarcomas. 2,3 Histological grade is strongly correlated with clinical prognosis with a 10-year survival rate of 83% for atypical cartilaginous tumor/grade I but only 29% for grade III. In addition to conventional chondrosarcoma, several rare subtypes of chondrosarcoma are discerned (dedifferentiated, mesenchymal and clear cell), together constituting 10-15% of all chondrosarcomas. Clear cell chondrosarcoma is a low-grade malignant tumor with a 10-year survival rate reported around 90% while dedifferentiated and mesenchymal chondrosarcoma are both highly malignant, with frequent occurrence of distant metastases and o30% survival at 5 and 10 years, respectively. 4

show abstract

New Strategies in Sarcoma: Linking Genomic and Immunotherapy Approaches to Molecular Subtype

Cited by 37 publications

References 72 publications

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

Evolution of Dermatofibrosarcoma Protuberans to DFSP-Derived Fibrosarcoma: An Event Marked by Epithelial–Mesenchymal Transition–like Process and 22q Loss

Response to anti-PD1 therapy with nivolumab in metastatic sarcomas

Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype

Contact Info

Product

Resources

About