Targeting the Molecular and Immunologic Features of Leiomyosarcoma

Abstract

Leiomyosarcoma (LMS) is a rare, aggressive mesenchymal tumor with smooth muscle differentiation. LMS is one of the most common histologic subtypes of soft tissue sarcoma; it most frequently occurs in the extremities, retroperitoneum, or uterus. LMS often demonstrates aggressive tumor biology, with a higher risk of developing distant metastatic disease than most sarcoma histologic types. The prognosis is poor, particularly in patients with uterine disease, and there is a need for the development of more effective therapies. Genetically, LMS is karyotypically complex and characterized by a low tumor mutational burden, with frequent alterations in TP53, RB1, PTEN, and DNA damage response pathways that may contribute to resistance against immune-checkpoint blockade monotherapy. The LMS immune microenvironment is highly infiltrated with tumor-associated macrophages and tumor-infiltrating lymphocytes, which may represent promising biomarkers. This review provides an overview of the clinical and pathologic behavior of both soft tissue and uterine LMS and summarizes the genomic and immune characteristics of these tumors and how they may provide opportunities for the development of biomarker-based immune therapies.

Dedifferentiated Leiomyosarcoma of the Uterine Corpus with Heterologous Component: Clinicopathological Analysis of Five Consecutive Cases from a Single Institution and Comprehensive Literature Review

“…LMS encompasses tumors that demonstrate a wide range of differentiation with loss of smooth muscle marker expression, extending from well-differentiated to poorly differentiated LMS, resembling UPS [48]. The vast majority of patients with uterine LMS carry at least one mutation in either tumor protein 53 (TP53), retinoblastoma (RB1), phosphatase and tensin homolog deleted on chromosome 10 (PTEN), or alpha-thalassemia/mental retardation, X-linked (ATRX) [49].…”

A Ten-Year Real-Life Experience with Pazopanib in Uterine Leyomiosarcoma in Two High-Specialized Centers in Italy: Effectiveness and Safety

“…The research reports no substantial differences from a clinical point of view between patients who had an objective response and those who did not. Thus, to better understand any prognostic factors for response, further studies should be conceived from a molecular point of view, as biomarkers predictive of both response and resistance to pazopanib have still not been identified [ 28 , 29 ]. In fact, prospective studies on pazopanib and subsequent subgroup analyses on different types of soft-tissue sarcomas have failed to pick up (baseline) clinical or pathological features that can improve the use of this drug in terms of both response and survival [ 28 , 29 ].…”

The Future of Targeted Therapy for Leiomyosarcoma

“…Targeting macrophages for cancer therapy represents a double-edged sword; on one hand macrophages can promote tumor progression and suppress immune recognition, while on the other hand they can phagocytose cancer cells [ 131 ]. Next, different combinations of immunotherapy can be trialed in an effort to enhance anti-tumor immunity [ 6 ]. For example, it would be interesting to combine macrophage-targeting drugs (e.g., anti-CD47 or anti-CSF-1R) and T-cell immune checkpoint inhibitors (e.g., anti-PD1) to assess for synergy, as macrophage phagocytosis and subsequent antigen presentation to T-cells can augment T-cell-mediated tumor immunity [ 132 ].…”

“…(B) Most common copy number alterations. (C) Tumor mutational burden, divided by low (<2 mutations per megabase), medium (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16), or high (>16). (D) Percent with clinically actionable alterations by OncoKB level.…”

“…Surgery is the mainstay of treatment for localized LMS, with the addition of radiation and chemotherapy depending on the clinical characteristics and associated local and distant recurrence risks [ 6 ]. Treatment of recurrent or metastatic LMS typically involves cytotoxic chemotherapy.…”