Not Every De-Differentiated Liposarcoma is The Same

The more oncologists come to understand liposarcoma, the clearer it becomes that it is a difficult disease.

There are approximately 13,000 soft tissue sarcomas(STS) comprising of 50+ different subtypes that are newly diagnosed annually. Liposarcoma is one of the top 2 subsets of soft tissue sarcomas, representing a rare connective tissue malignancy.¹

Advances in medicine have offered an improved classification system for liposarcoma, and the treatment landscape is ever evolving as new targets are being identified.

Why Does Histopathology Matter?

While the classification system makes it seem as though standard definitions exist for the different types of liposarcoma, the histopathological findings and differences in gene amplification are of great importance. When the tumor was first defined in the mid-to-late 1970s, it was defined as a spectrum where on the left side or one end existed low-grade well-differentiated liposarcoma (WDL) and on the right side or other end existed dedifferentiated liposarcoma (DDL), where the de-differentiated or transformed component was a high-grade spindle cell sarcoma that was otherwise non-descript.

However, a clear continuum exists as the WDL transitions into a DDL with increased cellularity, atypia, and additional characteristics that are variably described as “incipient differentiation” versus actually labeling it as a DDL. It is important to remember that there are various degrees/grades of “de-differentiation” that can take place, which may impact the natural history of the disease, the rate of progression and therefore the progression-free survival (PFS) for patients. Ultimately, one pathologist’s de-differentiated liposarcoma may not be the same as another pathologist’s de-differentiated liposarcoma. While 2 patients may have the same exact diagnosis as a line item on the pathology report, the behavior of each of their tumors may be significantly different depending on the degree/grade of de-differentiation.

These subtle histopathological differences may mean that clinical outcomes for patients and treatment responses can drastically differ. In addition to paying close attention to the immunohistochemical characteristics, the molecular characteristics of the tumor are gaining attention when formulating tailored, targeted treatment plans for patients. The overwhelming majority of WDL/DDL are going to show CDK4/6 amplification and MDM2 amplification, serving as the basis for an increasing number of therapeutic studies targeting these molecular aberrations.

Treatment Landscape and Unmet Need

Classically, abdominal retroperitoneal tumors are fairly extensive, insinuating around other critical structures and making complete resection an impossibility in many instances. Surgical options may require multi-visceral organ resection, for example, of the kidney, to achieve gross total resection of the tumor. In contrast, localized extremity liposarcomas can, in most cases, be resected with limb-sparing operations. The curative management for localized disease remains surgical resection combined with or without radiation.

Unfortunately, even with complete surgical resection, rate of recurrence is high,¹ and the need for a safe, effective systemic therapy remains a priority. Historically, chemotherapy has represented the conventional anthracycline-based systemic therapy of choice but with limited benefit and often significant toxicities. Newer approved drugs such as trabectedin (Yondelis) and eribulin (Halaven) are important additions, albeit with limited benefit.² An efficacious treatment that is better tolerated and that provides patients with a better quality of life would be welcomed by patients, their families and their healthcare providers.

Capitalizing on Molecular Characteristics

Targeting the molecular characteristics of WDL/DDL has become of great interest to researchers and drug developers. Investigators at Memorial Sloan Kettering have conducted clinical trials with CDK4 inhibitors in DDL. In one trial including 30 patients with advanced progressive DDL who were treated with abemaciclib, the reported median PFS was 30.4 weeks with 1 partial response. Three other patients had more than a 10% decrease in tumor size by RECIST but didn’t meet the criteria for partial response. All treated participants had manageable grade 3-4 toxicity, which included anemia, neutropenia, thrombocytopenia and diarrhea.³A previous trial of palbociclib, a CDK4/6 inhibitor in the treatment of advanced CDK4-positive WDL/DDL reported a median PFS of 18 weeks.²

The level of interest to target MDM2 is also high and preliminary data on MDM2 inhibitors has been available since 2012 when Ray-Coquard et al.⁴ used RG7112, an MDM2 antagonist, to treat 20 patients with proof-of-principle clinical efficacy, including a complete response for one patient and stable disease for 14 patients.²

Another MDM2 inhibitor, milademetan has also been investigated in a phase 1 study, reporting a promising PFS of 8.0 months in patients with WDL/DDL that was progressing on prior therapy.⁵ A phase 3 trial is therefore planned randomizing patients to milademetan versus trabectedin to try to improve the therapeutic armamentarium and outcomes for this patient population.

In addition to CDK4/6 and MDM2 inhibitors, investigators are looking at additional targets including FSR2, PDL-1, NY-ESO-1, and other biomarkers. It will be of great importance to continue expanding targeted therapy and immunotherapy clinical trials in order to expand the availability of safe, effective treatment options for this patient population.

Conclusion

Even a seemingly uniform and homogeneous diagnosis of DDL can be heterogeneous with variable clinical behavior. The need for additional systemic therapies with improved therapeutic index is paramount. Targeting the molecular markers – MDM2 and CDK4/6 amongst others, with newer generation molecules is of great interest.

_REFERENCES:

_{1. Livingston JA, Bugano D, Barbo A, et al. Role of chemotherapy in dedifferentiated liposarcoma of the retroperitoneum: defining the benefit and challenges of the standard Sci Rep. 2017;7(1):11836 (2017). doi: 10.1038/s41598-017-12132-w}

_{2. Chemotherapy for soft tissue sarcomas. American Cancer Society. Accessed August 12, 2021.}

_{3. Dickson MA, Koff A, D'Angelo SP, et al. Phase 2 study of the CDK4 inhibitor abemaciclib in dedifferentiated liposarcoma. J Clin Oncol. 2019;37(15_suppl):11004-11004. doi: 10.1200/JCO.2019.37.15_suppl.11004}

_{4. Ray-Coquard I, Blay JY, Italiano A, et al. Effect of the MDM2 antagonist RG7112 on the P53 pathway in patients with MDM2-amplified, well-differentiated or dedifferentiated liposarcoma: an exploratory proof-of-mechanism study. Lancet Oncol. 2012;13(11):1133-1140. doi:10.1016/S1470-2045(12)70474-6}

_{5. Gounder M, Bauer T, Schwartz G, et al. Milademetan (DS-3032B or RAIN032), An Oral MDM2 Inhibitior, In Well-differentiated/Dedifferendiated Liposarcoma: Results from a Phase 1 Study in Patients with Solid Tumors or Lymphomas. ENA 202, EORTC NCI AACR 32nd Symposium.}