MDM2 amplification + CDK4 amplification

We reviewed demographic data, treatment histories, and overall response rates (ORR). We identified five patients with DDLPS who were treated with CDK4/6i, palbociclib and abemaciclib. In untreated WD/DD LPS, baseline alterations in cyclin D are rare. Our analysis revealed that three patients with DDLPS acquired either cyclin D1 or cyclin D2 amplification in progressing samples following treatment with CDK4/6i. Unlike breast cancer, where cyclin E1 amplification is a well-established driver of resistance to CDK4/6i, these findings suggest a potential role for cyclin D amplification in acquired resistance in LPS.

Additionally, we observed recurring promoter swapping events involving the regulatory regions of the FRS2, PLEKHA5, and TP53 genes. These events resulted in ectopic expression of partner genes, with the ELF1 gene being upregulated by the FRS2 and TP53 promoter regions in two distinct cases.

In our practice, a significant proportion of patients were prescreened with a smaller NGS panel. Despite this fact, we still found actionable alterations in 23,8% of the patients, which is in line with those reported in the literature (22-61%). Our results demonstrate that CGP can provide useful additional information and can be beneficial in the clinical management of patients with mesenchymal tumours.

Several regimens have been tested with modest results regarding their efficacy. Herein we discuss the systemic treatment options for WDLPS and DDLPS and review their reported clinical efficacy results.

Overall, in our uLMS analysis, CDK4 and/or MDM2 amplification was identified in a small subset (2%) of uLMS, the majority of which are TP53/RB1-wildtype. This may suggest that CDK4/MDM2 amplification can be an alternative tumorigenic mechanism in this distinct class of uLMS, which may have therapeutic clinical implications, including possible use of specific cyclin-dependent kinase inhibitors.

Overall, in our uLMS analysis, CDK4 and/or MDM2 amplification was identified in a small subset (2%) of uLMS, the majority of which are TP53/RB1-wildtype. This may suggest that CDK4/MDM2 amplification can be an alternative tumorigenic mechanism in this distinct class of uLMS, which may have therapeutic clinical implications, including possible use of specific cyclin-dependent kinase inhibitors.

This suggests the potential use of MDM2 or CDK4 inhibitors in neoplasms where alterations in these genes do not aid the pathological diagnosis but may help identify potential therapeutic targets. In this review, we delve into the diagnosis and therapeutic implications of tumors with genetic alterations involving the chromosomal region 12q13-15, mainly MDM2, CDK4, and GLI1.

Lipomatous and dedifferentiated components can be sampled and cytomorphologically identified on effusion fluids of liposarcomas, with sufficient cellularity for immunocytochemistry and molecular testing. Although generally associated with poor prognosis, long disease-free survival with sarcomatous effusion is possible with radical surgery and adjuvant treatment.

We also detected a subset of cases with MDM2 and CDK4 amplification, along with CDKN2A and/or RB1 deletion. This emphasizes the clinical relevance of detailed molecular characterization of BCOR-associated ESS to identify potential candidates to CDK4/6 inhibitors.

Molecular-guided precision medicine holds a bright future in bringing more active treatments for advanced sarcoma patients.

This necessitates molecular confirmation even when the histology is convincingly benign, for a confident diagnosis. Our cohort shows that conservative excision without removal of abutted organs is sufficient in most cases.

AC/DLs in RB survivors are characterized by multiplicity, unifying histology, and benign course. Their biology appears distinct from ordinary lipomas, spindle cell lipomas, and atypical lipomatous tumors.