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  • Extrachromosomal DNA Heterogeneity in Dedifferentiated Liposarcoma: Linking Therapeutic Adaptation and Tumor Immune Evasion: A Narrative Review

  • Seyedeh Paria Bahrani,1,*
    1. Faculty of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran


  • Introduction: Dedifferentiated liposarcoma (DDLPS) is an aggressive soft-tissue sarcoma defined by near-universal amplification of 12q13–15, including CDK4 and MDM2. In 2026, the phase 3 SARC041 trial reported the first positive phase 3 result in DDLPS, with abemaciclib prolonging progression-free survival (PFS) versus placebo. Nevertheless, responses remain incomplete or transient in a subset of patients. Extrachromosomal DNA (ecDNA), which consists of acentric circular DNA segregating unequally at cell division, generates copy-number heterogeneity and is increasingly linked to treatment resistance and immune modulation. Liposarcoma shows one of the highest ecDNA prevalences across cancers, and CDK4 amplification defines DDLPS; yet, to our knowledge, no study has directly linked ecDNA heterogeneity to CDK4/6 inhibitor resistance or to immune phenotype in this disease. Here, we address this gap by integrating evidence from ecDNA biology, CDK4/6 inhibitor trials, and tumor immunology, and propose a testable framework.
  • Methods: We conducted a narrative review of literature published up to September 2026, covering (1) ecDNA biology and prevalence, (2) CDK4/6 inhibition in DDLPS, (3) nongenetic resistance to CDK4/6 inhibitors, (4) ecDNA and tumor immunity, and (5) CDK4/6 inhibitor–immunotherapy combinations. Peer-reviewed articles, conference abstracts, preprints, and clinical trial records were identified through PubMed, journal and preprint-server websites, and ClinicalTrials.gov. Evidence was grouped thematically. Preprints and conference abstracts were explicitly labeled as non-peer-reviewed and were not treated as established evidence.
  • Results: Prevalence. In a pan-cancer whole-genome analysis of 14,778 patients across 39 tumor types, 17.1% of tumors contained ecDNA. Liposarcoma ranked among the highest (54.9%), comparable to glioblastoma (49.1%). ecDNA detection was more frequent after targeted therapy and associated with metastasis and shorter overall survival. Clinical context. In SARC041 (n=108), abemaciclib improved median PFS to 9.7 versus 1.5 months with placebo (HR 0.38; P<0.001), establishing CDK4 inhibition as an effective strategy in DDLPS. Resistance. A 2026 preprint described abemaciclib-tolerant DDLPS subpopulations characterized by increased CDK2, cyclin B1, and pS6, attributed to nongenetic cell-cycle plasticity. Separately, a 2026 preprint in non-DDLPS models suggested that dynamic ecDNA copy-number fluctuation can give rise to drug-tolerant subpopulations. No study has yet resolved ecDNA status in resistant versus sensitive DDLPS cells. Immune context. In other cancers, ecDNA has been associated with reduced immune infiltration, altered antigen-presentation gene expression, and increased regulatory T cells, and pan-cancer data indicate that ecDNA frequently amplifies immunomodulatory genes. Direct evidence linking ecDNA to immune phenotype in adult DDLPS remains lacking, despite reported immune heterogeneity in this tumor. In a phase 2 study of palbociclib plus retifanlimab, the objective response rate was 20% (6/30) with a median PFS of 4.8 months; JUN amplification was enriched among patients with progressive disease, suggesting a potential resistance biomarker. Proposed model. ecDNA heterogeneity and copy-number plasticity may jointly influence (a) adaptation to CDK4/6 inhibition and (b) immune phenotype in DDLPS. This is a hypothesis, not an established causal pathway.
  • Conclusion: Evidence from independent research lines suggests, but does not prove, that ecDNA heterogeneity may contribute to both CDK4/6 inhibitor adaptation and immune evasion in DDLPS. We propose studies integrating single-cell ecDNA profiling with immune markers in matched tumor samples, ideally embedded in ongoing CDK4/6 inhibitor–immunotherapy trials, to test this framework and inform biomarker-guided treatment selection.
  • Keywords: ecDNA; Liposarcoma; CDK4/6 inhibitors; Immune evasion; Tumor heterogeneity

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