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Page 6 of 9 Keung et al. J Transl Genet Genom 2019;3:8. I https://doi.org/10.20517/jtgg.2019.03

as melanoma, non-small cell lung carcinomas, urothelial cancers, and microsatellite instability-high or
mismatch repair-deficient solid tumors. Interestingly, immunotherapy was first reported as a potential
[71]
therapeutic strategy for sarcomas by William Coley in 1891, when he noted spontaneous regression of a
recurrent malignant sarcoma in a patient after a serious bout of infection.

Recent evidence suggests that immune checkpoint inhibitors may have activity in particular subtypes of
soft tissue sarcomas [72,73] and in histologic subtypes such as undifferentiated pleomorphic sarcoma (UPS)
[11]
and DDLPS that have mutational and copy number heterogeneity . Two multicenter phase II clinical trials
examining the efficacy of anti-PD-1 therapy in advanced metastatic sarcoma included patients with DDLPS
have been reported in recent years [72,73] . The first study, SARC028, enrolled 86 patients with advanced STS
[72]
and bone sarcomas to receive pembrolizumab (anti-PD-1) . Of the 80 patients evaluable for response,
10 had DDLPS with 2 of these patients (20%) achieving disease control (stable disease or partial response)
after only 8 weeks of treatment with pembrolizumab. The second study, Alliance A091401, enrolled and
randomized 85 patients with locally advanced, unresectable, or metastatic sarcoma to receive nivolumab
[73]
(anti-PD-1) monotherapy or nivolumab plus ipilimumab (anti-CTLA-4) . No responses were observed in
the 5 patients with LPS, although patients with both WDLPS and DDLPS were enrolled in this study. Both
SARC028 and A091401 have been expanded to include additional patients with UPS and LPS; results from
these expansion cohorts are eagerly anticipated.

Although immune checkpoint therapy offered significant and durable responses for some patients with
DDLPS in the SARC028 study, most failed to respond to immunotherapy or had short-lived responses.
At baseline, both the tumor immune microenvironment and the poor antigenicity of these tumors may
facilitate escape of immune recognition. There are considerable ongoing efforts in other malignancies to
identify predictors of response to immune checkpoint blockade and elucidate mechanisms of resistance to
immunotherapy. In STS, ongoing studies include those combining immunotherapies with other systemic
therapies (cytotoxic) or local treatment modalities (RT, injectables) in advanced disease or applying
immunotherapy for earlier stage sarcoma, such as in the neoadjuvant setting [65,66,72] .

Patients with myxoid LPS often overexpress the cancer testis antigen, NY-ESO-1, which is being targeted
[4]
by investigational immunotherapies including adoptive cell therapies and peptide vaccines . The adoptive
transfer of T-cells genetically modified to express a T-cell receptor recognizing NY-ESO-1, has shown
[74]
promising responses in a heavily pre-treated MRCLS patients in a pilot study .

CONCLUSION
LPS is classified into 3 biologic groups encompassing 5 histologic subtypes characterized by specific
genomic and genetic alterations and variable clinical behavior and prognosis. Both WDLPS and DDLPS
are characterized by the presence of chromosomal amplification of 12q13-15 with associated amplification
of oncogenes MDM2, CDK4, and HMGA2. DDLPS is notable for having additional and more complete
genetic alterations compared to WDLPS. Myxoid/round cell LPS are nearly uniformly characterized by
the presence of a chromosomal translocation, most commonly t(12;16)(q13;p11) resulting in the fusion
protein FUS-DDIT3, with mutations in PIK3CA more common in high grade tumors. Lastly, pleomorphic
LPS is notable for diverse complex genomic changes and chromosomal rearrangements without unifying
molecular alterations nor targetable aberrations. To date, achieving a comprehensive understanding of
LPS biology has been challenging, in part due to the rarity of these tumors and relative dearth of in vitro
and in vivo experimental model systems. Many of the ongoing clinical trials are testing novel therapeutic
targets, with correlative analyses of associated biospecimens, which should help shed light on molecular
mechanisms behind response and resistance to these novel therapies, and lead to future advancements in the
multimodality treatment for patients with LPS.