Outcome of First-Line Systemic Treatment for Unresectable Conventional, Dedifferentiated, Mesenchymal, and Clear Cell Chondrosarcoma

Chondrosarcomas, malignant cartilaginous neoplasms, are capable of transitioning to highly aggressive, metastatic, and treatment-refractory states, resulting in significant patient mortality. Here, we aim to uncover the transcriptional program directing such tumor progression in chondrosarcomas. We conduct weighted correlation network analysis to extract a characteristic gene module underlying chondrosarcoma malignancy. Hypoxia-inducible factor-2α (HIF-2α, encoded by EPAS1) is identified as an upstream regulator that governs the malignancy gene module. HIF-2α is upregulated in high-grade chondrosarcoma biopsies and EPAS1 gene amplification is associated with poor prognosis in chondrosarcoma patients. Using tumor xenograft mouse models, we demonstrate that HIF-2α confers chondrosarcomas the capacities required for tumor growth, local invasion, and metastasis. Meanwhile, pharmacological inhibition of HIF-2α, in conjunction with the chemotherapy agents, synergistically enhances chondrosarcoma cell apoptosis and abolishes malignant signatures of chondrosarcoma in mice. We expect that our insights into the pathogenesis of chondrosarcoma will provide guidelines for the development of molecular targeted therapeutics for chondrosarcoma.

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“…Aside from cisplatin, doxorubicin is one of the most commonly used anti-tumor agents in chondrosarcoma chemotherapy 48,49 .…”

Section: Resultsmentioning

confidence: 99%

A system-level approach identifies HIF-2α as a critical regulator of chondrosarcoma progression

et al. 2020

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“…On the other hand, however, the limited data on the response to neoadjuvant chemotherapy in our series only indicated a relative resistance of DDCS to most classical anti-bone sarcoma drugs. Several studies have indicated that ifosfamide-based adjuvant chemotherapy [8] or doxorubicin monotherapy [22] may offer survival benefit for patients with DDCS. In our series, the combination of doxorubicin and cisplatin was found significantly associated with delayed disease progression.…”

Section: Sarcomamentioning

confidence: 99%

Prognostic Factors in Dedifferentiated Chondrosarcoma: A Retrospective Analysis of a Large Series Treated at a Single Institution

Miao

Choy

Raskin

et al. 2019

Sarcoma

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Background. Dedifferentiated chondrosarcomas (DDCSs) are highly malignant tumors with a dismal prognosis and present a significant challenge in clinical management. Methods. In an IRB approved retrospective protocol, we identified 72 patients with DDCS treated at our institution between 1993 and 2017 and reviewed clinicopathological characteristics, treatment modalities, and outcomes to analyze prognostic factors. Results. Femur (44.4%), pelvis (22.2%), and humerus (12.5%) were most commonly involved sites. Twenty-three patients (31.9%) presented with distant metastasis, and 3 (4.2%) of them also had regional lymph node involvement. The median overall survival (OS) was 13.9 months. On multivariate analysis, pathological fracture, larger tumor size, lymph node involvement, metastasis at diagnosis, extraosseous extension, and undifferentiated pleomorphic sarcoma component correlated with worse OS, whereas surgical resection and chemotherapy were associated with improved OS. For progression-free survival (PFS), pathological fracture and metastasis at diagnosis showed increased risk, while chemotherapy was associated with decreased risk. Among patients who received chemotherapy, doxorubicin and cisplatin were significantly associated with improved PFS but not OS. Among patients without metastasis at diagnosis, 17 (34.7%) developed local recurrence. Thirty-one (63.3%) developed distant metastases at a median interval of 18.1 months. On multivariate analysis, R1/R2 resection was related with local recurrence, while macroscopic dedifferentiated component was associated with distant metastasis. Conclusions. The prognosis of DDCS is poor. Complete resection remains a significant prognostic factor for local control. Chemotherapy with doxorubicin and cisplatin seems to have better PFS. More prognostic, multicenter trials are warranted to further explore the effectiveness of chemotherapy in selected DDCS patients.

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“…Complete en bloc surgical resection is the gold standard treatment and should be offered whenever feasible. Generally, chondrosarcoma is chemo-and radiation-resistant, and the treatment of advanced disease poses a huge clinical challenge [25,26].…”

Section: Current Therapeutic Approaches In Chondrosarcomamentioning

confidence: 99%

Is the IDH Mutation a Good Target for Chondrosarcoma Treatment?

et al. 2020

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Chondrosarcomas are rare cancers of bone that arise from the malignant transformation of cells of chondrocytic lineage. They are known to be resistant to systemic cytotoxic chemotherapy and radiotherapy. The mainstay of management of localised disease is en bloc surgical resection with curative intent. Metastatic chondrosarcoma has a dismal prognosis, and to date, there are no proven effective systemic therapies in the advanced setting. Genomic studies have demonstrated that 50 to 80% of chondrosarcomas harbour a mutation in either the IDH1 or IDH2 gene. IDH inhibitors are currently under investigation in clinical trials, after showing promising results in phase 1 studies in IDH mutated cancers. In chondrosarcoma, IDH mutations represent an attractive target, however, early results with IDH inhibitors in IDH mutated chondrosarcoma are modest and the final results of ongoing trials are eagerly awaited.

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Outcome of First-Line Systemic Treatment for Unresectable Conventional, Dedifferentiated, Mesenchymal, and Clear Cell Chondrosarcoma

Cited by 37 publications

References 29 publications

A system-level approach identifies HIF-2α as a critical regulator of chondrosarcoma progression

A system-level approach identifies HIF-2α as a critical regulator of chondrosarcoma progression

Prognostic Factors in Dedifferentiated Chondrosarcoma: A Retrospective Analysis of a Large Series Treated at a Single Institution

Is the IDH Mutation a Good Target for Chondrosarcoma Treatment?

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