To Quiesce or Senesce, That Is the Question for Dedifferentiated Liposarcoma.

Dedifferentiated liposarcoma (DDLPS) has an appealing therapeutic target due to its CDK4 amplification on chromosome 12q. The understanding of geroconversion from quiescent cells to senescent cells defines a patient's response to CDK4 inhibitors. This new observation will inform not only the ongoing phase III clinical trial of abemaciclib, but all future clinical trials in DDLPS. See related article by Gleason et al., p. 703.

Racial and ethnic variation in presentation and outcomes of high-grade soft tissue sarcoma at a Southeastern United States comprehensive cancer center.

BACKGROUND: High-grade soft tissue sarcoma is rare and associated with poor prognosis. This study examines racial and ethnic variation in presentation and outcomes at a Southeastern US cancer center. METHODS: Among an institutional cohort of patients seen between January 2016-December 2021, racial and ethnic differences were evaluated using chi-squared tests, Kaplan Meier curves, and Cox proportional hazards models. RESULTS: There were 295 patients (71 â€‹% Non-Hispanic White, 24 â€‹% Black, 3 â€‹% Hispanic White, 2 â€‹% Other). Black representation was greater than national cohorts (24 â€‹% vs. 12 â€‹%). Histological subtype varied by race/ethnicity (p â€‹= â€‹0.007). Adjusting for histology and stage, survival was worse for Black vs. White patients (HR 1.71, 95 â€‹% CI 1.07-2.76) and those with metastatic disease (5.47, 3.54-8.44). In non-metastatic patients, survival differences for Black vs. White patients were attenuated by receipt of multi-modal treatment (1.53, 0.82-2.88). CONCLUSION: Observed racial disparities in survival of high-grade sarcoma may be addressed by early, multidisciplinary management.

Genomic Patterns of Malignant Peripheral Nerve Sheath Tumor (MPNST) Evolution Correlate with Clinical Outcome and Are Detectable in Cell-Free DNA.

Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis. SIGNIFICANCE: MPNST is the most common cause of death and morbidity for individuals with NF1, a relatively common tumor predisposition syndrome. Our results suggest that somatic copy-number and methylation profiling of tumor or cfDNA could serve as a biomarker for early diagnosis and to stratify patients into prognostic and treatment-related subgroups. This article is highlighted in the In This Issue feature, p. 517.

Immune checkpoint inhibitor resistance in soft tissue sarcoma.

The emergence of immunotherapy as a cancer therapy has dramatically changed the treatment paradigm of systemic cancer therapy. There have been several trials evaluating immune checkpoint blockade (ICI) in soft tissue sarcoma. While there is generally a limited response in sarcoma, a subset of patients has durable responses to immunotherapy. This is attributable to a variety of factors including histologic subtype, tumor-infiltrating lymphocytes, and the tumor microenvironment among others. There is ongoing translational and clinical research evaluating ICI resistance in sarcoma and identifying therapeutic strategies to overcome this resistance. Herein, we provide a review of the current data, proposed mechanisms of resistance, and potential approaches to overcome this resistance.

Truly Man's Best Friend: Canine Cancers Drive Drug Repurposing in Osteosarcoma.

While metastatic osteosarcoma is rare in humans, it is the most common bone tumor found in any breed of dog. Given the genetic similarities between canine and human osteosarcomas, canine clinical trials allow for rapid testing and drug repurposing at a speed that cannot be achieved using patients with osteosarcoma. See related article by Regan et al., p. 662.

Correction: Aberrant ATRX protein expression is associated with poor overall survival in NF1-MPNST.

[This corrects the article DOI: 10.18632/oncotarget.25195.].

A phase II study of pazopanib as front-line therapy in patients with non-resectable or metastatic soft-tissue sarcomas who are not candidates for chemotherapy.

BACKGROUND: Cytotoxic chemotherapy remains the standard of care first-line treatment for advanced and metastatic soft-tissue sarcomas (STSs). Certain patients may not be chemotherapy candidates based upon age or co-morbidities, leaving limited treatment options. Pazopanib is a multi-targeted tyrosine kinase inhibitor that is FDA-approved for metastatic STS after the first line. We proposed a phase II study evaluating pazopanib as a first-line agent in patients with advanced disease who are deemed not to be candidates for chemotherapy. METHODS: Eligible patients were at least 18 years old, not candidates for chemotherapyand were treatment naive. Pazopanib was titrated from 200 mg twice daily to a goal of 800 mg daily. The primary end point was the clinical benefit rate (CBR) (CBR = completed response + partial response + stable disease per Response Evaluation Criteria in Solid Tumours [RECIST 1.1]) at 16 weeks. The sample size of 56 evaluable patients was calculated to provide 80% power to test a hypothesised CBR of ≥35% against an unfavourable CBR of ≤20%. If ≥ 17 patients achieved benefit, the null CBR of 20% would be rejected at a nominal 5% alpha level. Secondary end points included progression-free survival (PFS), overall survival (OS), quality of life and serum biomarkers. FINDINGS: Fifty-six patients were enrolled from May 2015 to February 2019 and are included in the intention-to-treat analysis. Median PFS was 3.67 (2.62-7.25) months. Median OS was 14.16 (95% confidence interval [CI]: 8.4-NR) months, CBR = 39.29% (22/56) (CI = 0.265-0.533, p = 0.0007). No new or unexpected adverse events were seen. The most common grade I-II events were diarrhoea, nausea and fatigue. The most common grade III-IV events were hypertension and liver function test abnormalities. INTERPRETATION: These data suggest that there is a benefit to front-line pazopanib in patients with STS who are not candidates for cytotoxic chemotherapy.

Secondary Sarcomas: Biology, Presentation, and Clinical Care.

Secondary sarcomas are a subset of sarcomas that occur in patients with prior cancer diagnoses and are associated with environmental or genetic factors. Although secondary sarcomas are rare in general, there are predisposing factors that can substantially increase this risk in certain populations. Herein, we review the environmental factors with the strongest association of sarcoma risk, including chemical exposure, certain viruses, cytotoxic and immunosuppressive agents, chronic edema, and radiation exposure. Additionally, the most common genetic disorders that carry a predisposition for sarcoma development will be discussed, including hereditary retinoblastoma (RB), Li-Fraumeni syndrome (LFS), neurofibromatosis type 1 (NF1), and DICER1 syndrome. Although treatment does not generally differ for sporadic versus secondary sarcomas, awareness of the risk factors can alter therapeutic strategies to minimize risk, aid prompt diagnosis by increasing clinical suspicion, and allow for appropriate surveillance and genetic counseling for those patients with cancer predisposition syndromes.

Aberrant ATRX protein expression is associated with poor overall survival in NF1-MPNST.

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive soft tissue sarcomas that can occur sporadically or in the setting of the Neurofibromatosis type 1 (NF1) cancer predisposition syndrome. These tumors carry a dismal overall survival. Previous work in our lab had identified ATRX chromatin remodeler (ATRX), previously termed, Alpha Thalassemia/Mental Retardation Syndrome X Linked as a gene mutated in a subset of MPNSTs. Given the great need for novel biomarkers and therapeutic targets for MPNSTs, we sought to determine the expression of ATRX in a larger subset of sporadic and NF1 associated MPNSTs (NF1-MPNSTs). We performed immunohistochemistry (IHC) on 74 MPNSTs (43 NF1-associated and 31 sporadic), 21 plexiform neurofibromas, and 9 atypical neurofibromas. Using this approach, we have demonstrated that 58% (43/74) of MPNSTs have aberrant ATRX expression (<80% nuclear expression) compared to only 7% (2/30) of benign (plexiform and atypical) neurofibromas. Second, we demonstrated that 65% (28/43) of NF1-MPNSTs displayed aberrant ATRX expression as did 48% (15/31) of sporadic MPNSTs. Finally, we show that aberrant ATRX expression was associated with a significantly decreased overall survival for patients with NF1-MPNST (median OS of 17.9 months for aberrant expression and median OS not met (>120 months) for intact expression, p = 0.0276). In summary, we demonstrate that ATRX is aberrantly expressed in the majority of NF1-MPNSTs, but not plexiform or atypical neurofibromas. Additionally, aberrant ATRX expression is associated with decreased overall survival in NF1-MPNST, but not sporadic MPNST and may serve as a prognostic marker for patients with NF1-MPNST.