(P 121) ACQUIRED CYCLIN D AMPLIFICATION IS A MECHANISM FOR RESISTANCE TO CDK4/6 INHIBITORS IN DEDIFFERENTIATED LIPOSARCOMA

Objective: Cell cycle dysregulation leading to aberrant cell proliferation is a hallmark of cancer. The cyclin D1-cyclin-dependent kinase 4/6 (CDK4/6) axis plays a crucial role in the oncogenesis of several malignancies, including breast cancer and liposarcoma (LPS). In well-differentiated and dedifferentiated (WD/DD) LPS, amplification of CDK4 and MDM2 occurs in over 90% of cases. Consequently, targeting the cell cycle has become an appealing therapeutic strategy. CDK4/6 inhibitors (CDK4/6i) have revolutionized the treatment of hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+ HER2-) metastatic breast cancer, leading to significant improvements in progression-free survival (PFS). Similarly, CDK4/6i have improved PFS in patients with LPS. However, resistance mechanisms to CDK4/6i in LPS remain unclear. As observed in breast cancer, many patients with LPS exhibit intrinsic resistance to CDK4/6i, and those who initially respond often develop resistance and disease progression. Several resistance mechanisms to CDK4/6 inhibition have been identified in breast cancer, including inactivation of RB1, amplification of AURKA, and Cyclin E1 (CCNE1) overexpression. Notably, cyclin D amplification has not been as strongly associated with acquired resistance in breast cancer. The primary focus of this study was to evaluate acquired cyclin D and cyclin E amplifications as potential mechanisms of resistance to CDK4/6i in LPS.

Methods: We retrospectively identified patients with liposarcoma who were treated with CDK4/6i therapy, either alone or in combination with a second agent, and underwent MSK-IMPACT (Memorial Sloan Kettering Cancer Center - Integrated Mutation Profiling of Actionable Cancer Targets) next-generation sequencing (NGS) panel testing through February 9, 2024. We included only patients who had NGS performed before the initiation of CDK4/6i treatment and again after discontinuing CDK4/6i therapy for disease progression. We evaluated patients who had alterations in cyclin D or E in their NGS reports. We reviewed demographic data, treatment histories, and overall response rates (ORR).

Results: We identified five patients with DDLPS who were treated with CDK4/6i, palbociclib and abemaciclib. One patient was excluded from analysis due to inadequate tumor content. Of the remaining four patients, two received palbociclib with an anti-PD-1 inhibitor, one palbociclib alone, and one abemaciclib alone. The average duration of treatment was 121 weeks (range: 64-193). NGS was performed on surgically resected tissue for recurrent disease in all 4 patients.Three of the four patients acquired cyclin D1 (1 patient) or cyclin D2 (2 patients) amplifications.
The other patient had cyclin D1 gain at baseline but fold change in amplification could not be determined by NGS. No patients acquired inactivation mutations of RB1.

Conclusion: 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. Further research is needed to explore the molecular mechanisms underlying CDK4/6i resistance in LPS and to develop targeted strategies to overcome this resistance and improve patient outcomes.