Diagnosis, Prognosis, and Treatment of Alveolar Soft-Part Sarcoma

Abstract

IMPORTANCE Alveolar soft-part sarcoma (ASPS) is a rare, translocation-driven sarcoma of the soft tissues. Alveolar soft-part sarcoma often affects young adults and is characterized by indolent behavior but early evidence of metastatic spread. After recognition of ASPS as a specific entity in 1952, retrospective data indicated prolonged survival in patients with metastases, despite inherent resistance to conventional doxorubicin-based chemotherapy. Tyrosine kinase inhibitors and immune checkpoint inhibitors have provided unexpected new treatment strategies for ASPS.OBSERVATIONS This review includes articles published between 1952 and March 1, 2018. With the introduction of new molecular diagnostic tools and therapies, the distinctive features of ASPS have become more evident. The identification and better understanding of molecular pathways activated by the characteristic t(X;17)(p11;q25) translocation and its correspondent chimeric ASPSCR1-transcription factor E3 (TFE3) fusion protein open new paths to drug development. The associations of TFE3 and facilitation of an immunosuppressive microenvironment provide a rationale for exploring treatments that affect the balance between T-effector cells and T-regulatory cells. Tyrosine kinase inhibitors, such as sunitinib, cediranib, and pazopanib, show activity with either tumor responses or disease stabilization in more than 50% of the cases. Given the association of new agents with patient outcomes, it is too early to say whether metastatic ASPS should still be considered incurable in all patients. CONCLUSIONS AND RELEVANCEThe biologic outcomes of the canonical genomic event in ASPS remain under investigation; a better understanding of the tumor microenvironment and the multiple pathways activated in this sarcoma, including unusual bioenergetics, MET signaling, and angiogenesis, should lead to more rational therapy. Basket trials and related prospective studies focusing on the intersection of specific signaling pathways and diseases with unique genomic features, such as ASPS, will provide an understanding of new options for care.

Genomics, Morphoproteomics, and Treatment Patterns of Patients with Alveolar Soft Part Sarcoma and Response to Multiple Experimental Therapies

“…This highlights the possibility that TKI activity in ASPS goes beyond simple VEGF inhibition. Other authors have similarly proposed that TKIs with multikinase activity are more efficacious in ASPS (2), and our experience supports this hypothesis. A similar duration of stable disease (22 months) was seen in a patient on a phase II trial of pazopanib in patients with ASPS, but limited data are available regarding the patient's genomics (12).…”

“…This indolent disease course is paramount in understanding and interpreting any trial results. Chemotherapy does not have activity in this disease (8), and for decades the standard-of-care was surgical resection including metastatectomy (2). The above mentioned upregulation of angiogenesis transcripts provided evidence for using tyrosine kinase inhibitors (TKI) directed at VEGF.…”

Precision Medicine in Soft Tissue Sarcoma Treatment

“…On the other hand, there is an exceptional STS histological subtype immune checkpoint inhibitors are highly effective, i.e., alveolar soft part sarcoma (ASPS) [85,86]. ASPS is characterized by the specific chromosomal translocation t(X;17)(p11.2;q25) and is a vascular-rich sarcoma [87], but the mechanism underlying its response to immune checkpoint inhibitors is unknown; PD-L1 expression, the TMB, and the MSI-high status do not explain the high response rate of ASPS patients to immune checkpoint inhibitors.…”

Are Targeted Agents the Key to Unlock the Code for Immune Checkpoint Inhibitors in Soft-Tissue Sarcomas?

“…Exciting findings from this study is that patients with high neutrophil-to-lymphocyte ratio and high plasma baseline angiogenic activity were associated with increased response to ICIs and axitinib [24]. On the other hand, ASPS, a rare subtype of STS characterized by an unbalanced translocation t(X;17), have demonstrated increased sensitivity to tyrosine kinase inhibitors such as cediranib, pazopanib or sunitinib [25]. Also, Atezolizumab, an anti-PD-L1 agent, successfully induced significant responses in 8 (42%) out of 19 ASPS patients [26].…”