Tumor mutation burden and checkpoint immunotherapy markers in primary and metastatic synovial sarcoma

He, Mai; Abro, Brooj; Kaushal, Madhurima; Chen, Ling; Chen, Tiffany; Gondim, Mercia; Yan, Weisi; Neidich, Julie; Dehner, Louis P.; Pfeifer, John D.

doi:10.1016/j.humpath.2020.04.007

Cited by 29 publications

(26 citation statements)

References 42 publications

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“…Additionally, no significant difference in TMB was observed between primary and metastatic pairs in triple-negative breast cancer [30]. In synovial sarcoma, median TMB was lower in matched metastatic lesions (median 3.2 / Mb) than in primary tumours (median 3.3 / Mb) [77].…”

Section: Tmb Status Variation Between Primary Tumour and Paired Metastasesmentioning

confidence: 82%

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Discordance of immunotherapy response predictive biomarkers between primary lesions and paired metastases in tumours: A systematic review and meta-analysis

et al. 2021

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Background: Several biomarkers predict the efficacy of immunotherapy, which is essential for selecting patients who would potentially benefit. Discordant status of these biomarkers between primary tumours and paired metastases has been increasingly revealed. We aimed to comprehensively summarize the incidence of this phenomenon. Methods: Databases were searched to identify studies reporting primary-to-metastatic conversion of biomarkers, including programmed death ligand-1 (PD-L1), programmed cell death protein-1 (PD-1), PD-L2, tumour-infiltrating lymphocyte (TIL), tumour mutational burden (TMB), and microsatellite instability (MSI). Findings: 56 studies with 2739 patients were included. The pooled discordance rate of PD-L1 was 22%. The percentage of PD-L1 changed from positive to negative was 41%, whereas that from negative to positive was 16%. The discordance rate for PD-1 and PD-L2 was 26% and 22%, respectively. TIL level was found with a discordance rate of 39%, and changes from high to low (50%) occurred more than that from low to high (16%). No significant difference in TMB was observed between two sites in most studies. MSI status discordance was found in 6% patients, with a percentage of 9% from MSI-high to microsatellite instable (MSS) and 0% from MSS to MSI-high. Interpretation: Our study demonstrates that PD-L1, PD-1, PD-L2, and TIL level had high frequency of discordance, while TMB and MSI status were less likely to change between primary tumours and paired metastases. Therefore, evaluating those frequently altered biomarkers of both primary and metastatic tumours is strongly recommended for precise clinical decision of immune checkpoint treatment. Fund: The National Natural Science Foundation of China (81872152).

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Section: Tmb Status Variation Between Primary Tumour and Paired Metastasesmentioning

confidence: 82%

“…[22,27,28,39,40,44,52,53], four studies reported PD-L2[22,29,44,62], twelve studies reported TIL[20,29,30,43,46,[69][70][71][72][73][74][75], five studies reported TMB[23,30,[76][77][78], and six studies reported MSI status…”

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confidence: 99%

Discordance of immunotherapy response predictive biomarkers between primary lesions and paired metastases in tumours: A systematic review and meta-analysis

et al. 2021

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“…Sarcoma studies consistently show TMB is low [13,71,72] and microsatellites are stable [73,74] across subtypes. Low TMB has been observed in subtype-specific cohorts of alveolar soft-part [75], Ewing [76,77], synovial [78], and osteosarcoma [76]. Tumor mutational burden was not associated with immune biomarkers in pleomorphic dermal sarcoma [78,79] or survival in synovial sarcoma [78], but negatively correlated with survival in pediatric Ewing sarcoma [80].…”

Section: Tumor Mutation Burden and Microsatellite Instabilitymentioning

confidence: 94%

“…Low TMB has been observed in subtype-specific cohorts of alveolar soft-part [75], Ewing [76,77], synovial [78], and osteosarcoma [76]. Tumor mutational burden was not associated with immune biomarkers in pleomorphic dermal sarcoma [78,79] or survival in synovial sarcoma [78], but negatively correlated with survival in pediatric Ewing sarcoma [80]. Currently there are no prognostic data on microsatellite instability.…”

Section: Tumor Mutation Burden and Microsatellite Instabilitymentioning

confidence: 99%

Sarcomas: Immune biomarker expression and checkpoint inhibitor trials

Zhu

Shenasa

Nielsen

2020

Cancer Treatment Reviews

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Sarcomas are a heterogenous group of mesenchymal cancers comprising over 100 subtypes. Current chemotherapy for all but a very few subtypes has limited efficacy, resulting in 5-year relative survival rates of 16% for metastatic patients. While sarcomas have often been regarded as an "immune cold" tumor category, recent biomarker studies have confirmed a great deal of immune heterogeneity across sarcoma subtypes. Reports from the first generation of clinical trials treating sarcomas with immunotherapy demonstrate a few positive responses, supporting efforts to stratify patients to optimize response rates. This review summarizes recent advances in knowledge around immune biomarker expression in sarcomas, the potential use of new technologies to complement these study results, and clinical trials particularly of immune checkpoint inhibitor therapy in sarcomas.Each of the immune biomarkers assessed was reviewed for subtype-specific expression patterns and correlation with prognosis. Overall, there is extensive heterogeneity of immune biomarker presence across sarcoma subtypes, and no consensus on the prognostic effect of these biomarkers. New technologies such as multiplex immunohistochemistry and high plex in situ profiling may offer more insights into the sarcoma microenvironment. To date, clinical trials using immune checkpoint inhibitor monotherapy have not shown compelling clinical benefits. Combination therapy with dual checkpoint inhibitors or in combinations with other agents has yielded more promising results in dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma, angiosarcoma and alveolar soft-part sarcoma. Better understanding of the sarcoma immune status through biomarkers may help decipher the reasons behind differential responses to immunotherapy.

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“…Most cases of SS have a low tumor mutational burden (TMB), but occasionally a high TMB may be present, explaining the 10% response rate to checkpoint immunotherapy observed in clinical trials in patients with SS [ 106 ].…”

Section: Tumors Of Uncertain Differentiationmentioning

confidence: 99%

Toward a Personalized Therapy in Soft-Tissue Sarcomas: State of the Art and Future Directions

Montella¹,

Altucci

Sarno

et al. 2021

Cancers

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Soft-tissue sarcomas are rare tumors characterized by pathogenetic, morphological, and clinical intrinsic variability. Median survival of patients with advanced tumors are usually chemo- and radio-resistant, and standard treatments yield low response rates and poor survival results. The identification of defined genomic alterations in sarcoma could represent the premise for targeted treatments. Summarizing, soft-tissue sarcomas can be differentiated into histotypes with reciprocal chromosomal translocations, with defined oncogenic mutations and complex karyotypes. If the latter are improbably approached with targeted treatments, many suggest that innovative therapies interfering with the identified fusion oncoproteins and altered pathways could be potentially resolutive. In most cases, the characteristic genetic signature is discouragingly defined as “undruggable”, which poses a challenge for the development of novel pharmacological approaches. In this review, a summary of genomic alterations recognized in most common soft-tissue sarcoma is reported together with current and future therapeutic opportunities.

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Tumor mutation burden and checkpoint immunotherapy markers in primary and metastatic synovial sarcoma

Cited by 29 publications

References 42 publications

Discordance of immunotherapy response predictive biomarkers between primary lesions and paired metastases in tumours: A systematic review and meta-analysis

Discordance of immunotherapy response predictive biomarkers between primary lesions and paired metastases in tumours: A systematic review and meta-analysis

Sarcomas: Immune biomarker expression and checkpoint inhibitor trials

Toward a Personalized Therapy in Soft-Tissue Sarcomas: State of the Art and Future Directions

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