










































This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited. 
 © 2021 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada.

Key Words Competing Interests Article Information

Retroperitoneal sarcoma, comprehensive 
genomic profiling, targeted therapy

Dr P Grivas (all unrelated in the last 3 years): 
consulting: AstraZeneca; Bayer; Bristol Myers 
Squibb; Clovis Oncology; Dyania Health, Driver; 
EMD Serono; Exelixis; Foundation Medicine; 
Genentech/Roche; Genzyme; GlaxoSmithKline; 
Heron Therapeutics; Immunomedics, Janssen; 
Merck; Mirati Therapeutics; Pfizer; Seattle 
Genetics; QED Therapeutics. Research Funding 
to Institution: Merck; Pfizer, Clovis Oncology, 
Bavarian Nordic, Immunomedics, Debiopharm, 
Bristol Myers Squibb, QED Therapeutics, 
GlaxoSmithKline, Kure It Cancer Research.  
Dr A Necchi: consultant and advisor, Merck, 
Roche, Astra Zeneca, Janssen, Clovis Oncology, 
Incyte, BioClin Therapeutics; Bayer, Bristol 
Myers Squibb; Research grants (Institution): 
Merck, Astra Zeneca.

Received on March 28, 2021 
Accepted on May 15, 2021

Soc Int Urol J. 2021;2(4):216–228

DOI: 10.48083/ VOGF2319

Primary Adult Retroperitoneal Sarcoma:  
A Comprehensive Genomic Profiling Study

Andrea Necchi,1 Giuseppe Basile,2 Filippo Pederzoli2, Marco Bandini,2 Petros Grivas,3  
Gennady Bratslavsky,4 Philippe E. Spiess,5 J. Keith Killian,6 Douglas I. Lin,6 Erik Williams,6  
Shakti Ramkissoon,6 Eric A. Severson,6 Brian M. Alexander,6 Jeffrey Venstrom,6  
Prasanth Reddy,6 Kimberly McGregor,6 Julia A. Elvin,6 Alexa B. Schrock,6 Dean C. Pavlick,6  
Dexter X. Jin,6 Sally E. Trabucco,6 Natalie Danziger,6 Jeffrey S. Ross5,6

1Department of Medical Oncology, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Milan, Italy  2Urological Research Institute (URI), Unit of Urology, 
IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Milan, Italy  3University of Washington, Fred Hutchinson Cancer Research Center, Seattle Cancer 
Care Alliance, United States  4SUNY Upstate Medical University, Syracuse, United States  5Moffitt Cancer Center and Research Institute, Tampa, United States  
6Foundation Medicine Inc., Cambridge, United States

Abstract

Background Adult primary retroperitoneal sarcomas (RPSs) are a group of heterogeneous tumors with different 
histological subtypes. Comprehensive genomic profiling (CGP) analyses have recently provided significant insights 
into the biology of sarcomas by identifying genomic alterations (GAs) which could benefit from targeted therapies.

Methods RPS were evaluated by CGP using next-generation sequencing of up to 406 cancer-related genes. Tumor 
mutational burden (TMB) was determined on 0.83 to 1.14 mut/Mb of sequenced DNA. Finally, PD-L1 expression was 
determined.

Results Overall, 296 cases of primary RPS were analyzed. Liposarcoma (LPS) subtype had more GA/tumor than 
leiomyosarcoma (LMS) subtypes, with follicular dendritic cell sarcomas harboring the highest and synovial sarcomas 
the lowest. TP53 and Rb1 alterations were the highest in LMS, and CDK4/6 and MDM2 in LPS. However, both the 
TMB and targetable GA rates were low across subtypes. PD-L1 immunostaining was low positive in 21% and high 
positive in 5% of patients, respectively.

Conclusions CGP analysis revealed that potentially actionable genomic targets were rare in our cohort of RPS. 
Moreover, RPSs seem less likely to respond to immune checkpoint inhibitors based on putative biomarkers status. 
Nevertheless, genomic stratification according to histological subtypes led to description of GAs that can inform 
future clinical trials design.

216 SIUJ  •  Volume 2, Number 4  •  July 2021 SIUJ.ORG

ORIGINAL RESEARCH

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Introduction

Adult primary retroperitoneal sarcomas (RPSs) are 
rare malignancies that encompass a variety of clinical 
and pathological entities, with distinct histology and 
cancer biology[1]. The reported yearly crude incidence 
rate of soft-tissue sarcomas of the retroperitoneum and 
peritoneum is 0.31 per 100 000 individuals in Europe, 
with a 5-year relative survival rate of 38.8%[2]. RPSs are 
usually classified according to the normal mesenchymal 
tissue t hey most closely resemble. The correct 
identification of the histological subtype constitutes 
a mainstay in the multidisciplinary management of 
RPS, as different entities are more or less responsive 
to systemic therapy and/or radiation, thus influencing 
the therapeutic plan[3,4]. Nevertheless, together with 
traditional histology-based classification of sarcomas, 
novel data about t he genomic, epigenetic, a nd 
immunological landscape of these rare malignancies 
are emerging to potentially guide better stratification. 
Pa r t icu la rly, sa rcomas have been t rad it iona l ly 
grouped into 2 broad categories based on genomic 
alterations: sarcomas with simple karyotypes harboring 
distinct alterations, such as reciprocal chromosomal 
translocations and specific oncogenic mutations, and 
those with more complex, unbalanced karyotypes[5]. 
However, this crude dichotomy does not account for 
the complex heterogeneity within a given histology and 
between different subtypes, highlighting the need for 
a widespread implementation of molecular profiles in 
sarcomas.

In this context, comprehensive genomic profiling 
(CGP) analysis can provide significant insights into 
the biology of several tumors, allowing detection of 

numerous genomic alterations that could help elucidate 
the biolog y and potentially suggest strategies for 
precision oncology clinical trials[6,7]. In this study, we 
profiled a group of 296 RPS and analyzed the frequency 
of genomic alterations (GAs), hypothesizing that we 
would identify distinct therapeutic opportunities for 
patients affected by these rare malignancies.

Methods

Approva l for this study was obtained from the 
Western Institutional Review Board (Protocol No. 
20152817). A retrospective database search of a Clinical 
Laboratory Improvement Amendments certified, and 
College of American Pathologists accredited reference 
molecular laboratory was performed for all available 
primary RPS cases. The cases were previously assayed 
by CGP via both DNA- and RNA-based targeted 
next-generation sequencing (Foundation Medicine, 
Cambridge, MA) during the course of standard clinical 
care at other institutions. Clinicopathological data, 
including patient age and gender, routine histology 
and immunohistochemica l staining results, and 
confirmation that the sarcomas were primary in the 
retroperitoneum and not metastases from other non-
retroperitoneal primary sarcomas, were extracted from 
clinicopathology reports. The pathologic diagnosis of 
primary RPS and associated morphological features 
were centrally re-evaluated on routine H&E slides 
of tissue sections submitted for genomic profiling. 
Particularly, all cases included in this study were 
evaluated by an experienced board-certified pathologist 
at the time of specimen arrival in the laboratory, and 
then reviewed by a single pathologist to confirm the 
diagnosis and origin in the retroperitoneum.

All samples forwarded for DNA and RNA extraction 
contained a minimum of 20% tumor cells. The samples 
were assayed using next-generation sequencing for all 
coding exons from at least 406 cancer-related genes, 
plus additional select introns from up to 31 genes 
frequently rearranged in cancer. Patient samples 
were sequenced and evaluated for genomic alterations 
including base substitutions, insertions, deletions, copy 
number alterations (amplifications and homozygous 
deletions), and gene f usions/rearrangements, as 
previously described[8,9]. RNA-sequencing of 265 
genes was performed for rearrangement analysis. The 
bioinformatics processes used in this study included 
Bayesian algorithms to detect base substitutions, local 
assembly algorithms to detect short insertions and 
deletions, a comparison with process-matched normal 
control samples to detect gene copy number alterations, 
and an analysis of chimeric read pairs to identify gene 
fusions as previously described[8,9]. To visualize 
the sequencing data results, an OncoPrint plot was 

Abbreviations 
CGP comprehensive genomic profiling
FDCS follicular dendritic cell sarcoma
GA genomic alteration
ICI immune checkpoint inhibitor
LMS leiomyosarcoma
LPS liposarcoma
MPNST malignant peripheral nerve sheath tumors
MSI microsatellite instability
OS overall survival
PFS progression-free survival
PLS pleomorphic sarcoma
PRS primary retroperitoneal sarcoma
SFT solitary fibrous tumors
SS synovial sarcomas
TMB tumor mutational burden
TKI tyrosine kinase inhibitor

217SIUJ.ORG SIUJ  •  Volume 2, Number 4  •  July 2021

Primary Adult Retroperitoneal Sarcoma: A Comprehensive Genomic Profiling Study

http://SIUJ.org


generated with the online tools as described by Gao et 
al.[10] and Cerami et al.[11].

Tumor mutational burden (TMB) was determined on 
0.83 to 1.14 Mb of sequenced DNA using an algorithm, 
as previously described[12]. In this study, low TMB 
scores were defined as < 6 mut/Mb, intermediate TMB 
as 6 to 19 mut/Mb, and high TMB as ≥20 mut/Mb. 
The TMB cut-offs used in this study were the levels 
that had been in use prior to the U.S. Food and Drug 
Administration (FDA) approval of pembrolizumab in 
solid tumors featuring a TMB > 10 mut/Mb. Assessment 
of microsatellite instability (MSI) was performed from 
DNA sequencing across 114 significant loci[13]. Each 
microsatellite locus had repeat length of 7 to 39 bp. 
The next-generation sequencing-based microsatellite 
instability score was translated into categorical MSI 
high, MSI intermediate, or microsatellite stable tumors 
by unsupervised clustering of specimens for which 
microsatellite instability status was previously assessed 
via gold standard methods[13]. PD-L1 expression was 
determined on subsets of the tumors using the DAKO 
22C3 assay with low positive tumor cell scoring defined 
as 1% to 49% staining and high positive tumor cell 
scoring defined as ≥ 50% staining. The cut-offs for the 
Dako 22C3 staining are those currently being used in 
the United States for the selection of patients with non-
small cell lung cancer for treatment with single agent 
pembrolizumab.

Results
The clinical and genomic features of the 296 cases 
of primary RPS are shown in Table 1. All cases were 
clinically advanced and frequently resistant to the 
most recent therapy the patient had received at the time 
sequencing was ordered. There were 155 liposarcomas 
(LPS), 74 leiomyosarcomas (LMS), 44 pleomorphic 
sarcomas (PLS), 7 solitary fibrous tumors (SFT),  
6 malignant peripheral nerve sheath tumors (MPNST), 
5 synovial sarcomas (SS), and 5 follicular dendritic 
cell sarcomas (FDCS). Three cases of fibrosarcoma/
fibromyxoid sarcoma were included in the PLS group. 
OncoPrint plots of the most frequent GAs recorded 
in the overall cohort and each subtype is reported in 
Supplementary material 1.

The median age of all patients was 59 years, similar in 
all groups except for MPNST and SS, with significantly 
younger patients. The number of GAs per tumor was 
similar across the overall cohort and ranged from  
5.1 to 7.4. LMS and SS subtypes exhibited the lowest GA/
tumor, while FDCS had the highest (7.4 GA/tumor).

The GAs associated with the RPS as a whole and in 
the 7 individual RPS subtypes are shown in the longtail 
plots reported in Figure 1. Alterations in genes not 
currently linked to possible targeted therapies were 

identified. TP53 inactivation was frequently reported 
in LMS and rarely identified in LPS, SS or FDCS, while 
Rb1 inactivating GA was essentially restricted to LMS. 
Moreover, MDM2 amplification was clearly linked to 
LPS subtype, while FRS2 amplification, identified in 46% 
of all RPS cases, was predominantly associated with the 
LPS and PLS tumor types.

Alterations potentially linked to targeted therapy 
selection were identified throughout the RPS cases in 
limited frequencies. Examples included inactivating 
NF1/NF2 GA in MPNST, PIK3CA activating mutations 
and PTEN inactivating mutations and deletions. 
Moreover, potentially impacting the evaluation of cell 
cycle inhibitors were the high frequencies of CDK4/6 
amplifications, mostly restricted to LPS and PLS, and 
the CDKN2A/B loss identified in PLS, and relatively 
frequently in MPNST. It should be noted that MTAP loss, 
which is nearly restricted to tumors with CDKN2A/B 
loss and potentially associated with potential targeted 
therapies focused on tumor cells arginine metabolism, 
was not tested for in the current study. Tumor-defining 
gene fusions included the HMGA2 fusions for the LPS 
and PLS groups, the STAT6 fusions in SFT type, and 
SS18 fusions in the SS cases. Rare gene fusions that 
activate targetable gene kinase domains included very 
rare detection of ALK, NTRK, and ROS1 fusions, all 
identified at 1% of LPS and PLS, 2% of PLS and in 1 out 
of 6 cases of MPNST.

Biomarkers currently associated with response 
to immune checkpoint inhibitors (ICIs) were also 
evaluated. No tumor featured MSI high status. TMB 
was low throughout this group of tumors, with MPNST 
having the highest median TMB at 4.8 mut/Mb and SS, 
SFT, and FDCS all having a median TMB of < 1 mut/Mb. 
Low tumor cell PD-L1 expression (< 49%) was detected 
in 21% of RPS cases, with PLS having the highest 
frequency at 33%, and SFT, MPNST, SS, and FDCS all 
having no low positive cases. High positive staining (≥ 
50%) was present in only 5% of our cohort and mostly 
identified in PLS (16%) and FDCS (20%) subtypes. 
Boxplot of TMB analysis of all RPS included and each 
subtype is reported in Supplementary material 2.

Case examples of genomically profiled RPS are shown 
in Figures 2 and 3. In Figure 2, a PLS in a 77-year-old 
woman featured an activating fusion in the NTRK3 gene 
with the STRN3 gene [5'-STRN3(ex1-3 NM_014574)-
(B)NTRK3(ex12-19 NM_002530)]. In Figure 3, a well-
differentiated retroperitoneal LPS showed significant 
amplification of the CDK4 gene, which has potential to 
drive therapy selection using specific CDK4 inhibitors 
in clinical trials. Figure 4 shows a retroperitoneal 
dedifferentiated liposarcoma which presented with 
pulmonary metastases and was found to contain an 
MDM2 amplification and an HMGA2-TSFM fusion. This 

218 SIUJ  •  Volume 2, Number 4  •  July 2021 SIUJ.ORG

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TABLE 1. 

Clinical and genomic features in adult retroperitoneal sarcomas

All Cases LPS LMS PLS SFT MPNST SS FDCS

Number of cases, n 296 155 74 44 7 6 5 5

Female gender, % 53 42 78 49 57 33 60 60

Median age in years, range
59

(20–88)
60

(29–88)
60

(31–86) 
57

(20–85)
52

(31–71)
28 

(20–53)
39

(22–46)
56

(30–71)

GA/tumor 5.1 6 3.4 5.2 6 5.7 2.6 7.4

TP53 Inactivating  
SV mutation, %

24 5 66 26 29 33 0 0

RB1 Inactivating  
SV  mutation, %

10 1 32 5 0 0 0 0

FRS2 Amplification 46 78 0 28 14 0 0 0

NF1/NF2 Inactivating  
SV mutation, %

4 1 1 4 0 83 0 0

PIK3CA Activating 
SV mutations and 
amplifications, %

3 2 4 0 0 17 0 0

ESR1 Inactivating  
SV mutation, %

7 12 0 0 14 0 0 0

CDKN2A Deletion, % <1 <1 1 15 0 83 0 0

CDKN2B Deletion, % <1 <1 1 11 0 83 0 0

CDK4/6 Amplification, % 52 89 0 28 14 0 0 20

PTEN Deletion/ inactivating 
SV mutation, %

4 2 12 9 0 0 0 20

MDM2 Amplification, % 54 91 1 30 14 17 0 20

ALK Kinase activating 
fusions, %

<1 1 0 0 0 0 0 0

ROS1 Kinase activating 
fusions, %

<1 1 1 0 0 0 0 0

NTRK1-3 Kinase activating 
fusions, %

1 1 1 2 0 17 0 0

STAT6 Fusions, % 2 0 0 0 86 0 0 0

HMGA2 Fusions, % 17 28 1 11 0 0 0 0

SS18 Fusions, % <1 0 0 0 0 0 100 0

MSI-High, % 0 0 0 0 0 0 0 0

Median TMB (mut/Mb) 2.4 1.6 3.2 2.4 0.8 4.8 0.8 0.8

PD-L1 IHC low positive 21 25 10 33 0 0 0 0

PD-L1 IHC high positive 5 3 0 16 0 0 0 20

FDCS: follicular dendritic cell sarcoma; LPS: liposarcoma; LMS: leiomyosarcoma; MPNST: malignant peripheral nerve sheath tumor;  
PLS: pleomorphic sarcoma; SFT: solitary fibrous tumors; SS: synovial sarcoma. 

219SIUJ.ORG SIUJ  •  Volume 2, Number 4  •  July 2021

Primary Adult Retroperitoneal Sarcoma: A Comprehensive Genomic Profiling Study

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tumor featured 100% tumor cell immunohistochemical 
staining for PD-L1 using the Dako 22C3 assay.

Discussion
Adult RPSs are a group of rare and heterogeneous 
tumors marked by aggressive behavior and poor 
prognosis. Thus, the multidisciplinary management 
based on surgery, systemic therapy, and/or radiation 
has been the cornerstone of RPS treatment for several 
years. However, a great number of patients still have 
poor outcomes despite t he implementation and 
continuous optimization of multimodal therapies[14]. 
The negative findings of the STRASS trial[15], which 
examined the effect of preoperative radiotherapy in 
RPS, suggested the idea that treatment efficacy is deeply 
inf luenced by the intrinsic biological characteristics 
of the different sarcomas, thus highlighting the need 

for a better molecular understanding of these entities.  
In this context, the spread of novel genomic techniques 
has advanced the field in this direction, also revealing 
several potential molecular targets and biomarkers that 
could offer novel opportunities in the management 
of these malignancies. The PALETTE trial was the 
landmark study to evaluate the effectiveness of a multi-
target tyrosine kinase inhibitor (TKI), pazopanib, over 
placebo in 362 non-adipocytic soft-tissue sarcomas. 
The authors reported significantly prolonged median 
progression-free survival (PFS) in the intention-to-
treat cohort (4.6 versus 1.6 months) resulting in FDA 
approval of pazopanib in 2012 for advanced LPS 
refractory to systemic chemotherapy[16]. Similarly, the 
FDA approved eribulin for the treatment of inoperable 
LPS after chemotherapy, based on a phase III study that 
compared eribulin and dacarbazine for LPS and LMS. 
Although no difference was achieved in the overall 

FIGURE 1. 

Longtail plots of the frequencies and types of genomic alterations in all cases of primary retroperitoneal sarcomas

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All	Adult	Retroperitoneal	Sarcomas	

	

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Retroperitoneal	LPS	

	

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Retroperitoneal	SFT	

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T
6

A
 

Retroperitoneal	PLS	

0% 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 

100% 

F
G

F
2

3
 

C
C

N
D

2
 

K
D

M
5

A
 

F
G

F
6

 
N

R
A

S
 

Z
N

F
2

1
7

 
N

O
T

C
H

2
 

S
F

3
B

1
 

A
T

R
X

 
C

D
K

4
 

C
D

K
N

2
A

 
R

B
1

 
A

R
F

R
P

1
 

L
R

P
1

B
 

N
C

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1
 

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A
U

R
K

A
 

C
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E
B

B
P

 
H

IS
T

1
H

2
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M
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M

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F

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1

1
 

Retroperitoneal	FDCS	

0% 
10% 
20% 
30% 
40% 
50% 
60% 
70% 
80% 
90% 

100% 

SS18 PALB2 IKZF3 SGK1 PDGFRA PIK3CA CD36 MLL2 

Retroperitoneal	SS	

	

FDCS: follicular dendritic cell sarcoma (n = 5); LPS: liposarcoma (n = 155); LMS: leiomyosarcoma (n = 74); MPNST: malignant peripheral nerve sheath 
tumor (n = 6); PLS: pleomorphic sarcoma (n = 44); SFT: solitary fibrous tumor (n = 7); SS: synovial sarcoma (n = 5)

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PFS between the 2 arms, eribulin demonstrated a 
statistically significant improvement in overall survival 
(OS) (13.5 versus 11.5 months), especially for LPS (15.6 
versus 8.4 months)[17]. Following these results, our 
study focused on a large cohort of patients with RPS 
and explored targetable genomic alterations through 
CGP analysis. CGP analyses revealed that possible 
genomic targets were uncommon in our cohort of 
patients with RPS. In particular, RPSs were genomically 
stable tumors with low GA rate, low expression of PD-
L1 and low median TMB, suggesting low efficacy for 
ICI approaches. Nevertheless, genomic stratification 
according to histological subtypes led to the discovery 
of GAs that might predict patient benefit from targeted 
therapy testing in clinical trials. Co-amplification of 
MDM2 and CDK4 is thought to be the main driving 
factor in LPS development, leading to TP53 inactivation 

and uncontrolled cell cycle progression[18]. MDM2 and 
TP53 are within the same pathway, in which MDM2 
ubiquitinates TP53 and targets it for proteasomal 
degradation. In our cohort, LPS cases showed higher 
GA/tumor rate than LMS subtype, and MDM2 and 
CDK4 aberrations were the most frequent GAs, detected 
in 91% and 89% of the specimens, respectively. Similar 
results were recently reported by The Cancer Genome 
Atlas (TCGA) Research Network analysis of 206 adult 
sarcomas, in which the median TMB was low (1.06 
mut/Mb) across the different subtypes[19]. Moreover, 
MDM2 or CDK4 amplification was found as the 
highest frequent GAs in LPS subtype, as reported by 
other series[20,21]. Therefore, several clinical trials 
were launched testing MDM2/CDK4 antagonists[22]. 
Phase I trials of MDM2 inhibitor AMG-232 alone[23] 
or combined with radiation therapy (NCT03217266) 

FIGURE 2.

Pleomorphic sarcoma of the retroperitoneum in a 77-year-old woman 

A	

C	

B	

Low magnification (Figure 2A) and high magnification (Figure 2B) of a pleomorphic sarcoma. This tumor had a very high mitotic rate (20 mitoses per 
hpf), extensive necrosis, and stained positively for S100, SOX-10, caldesmon, and BCL2. The tumor was negative for EMA, desmin, myo-D1, CD99, 
CD31, CD34, pankeratins and pan melanoma markers. Comprehensive genomic profiling revealed an MSI stable tumor with intermediate TMB at  
7 mutations/Mb. There was a deletion in CDKN2A/B, a short variant mutation in PBRM1 and an activating fusion in the NTRK3 gene with the STRN3 
gene (5'-STRN3(ex1-3 NM_014574) (B)-NTRK3(ex12-19 NM_002530) (Figure 2C). NTRK fusions, although extremely rare, are widely distributed in solid 
tumors and some hematologic malignancies. This fusion has been previously described in sarcomas. Tyrosine kinases that target NTRK fusions have 
been approved by the regulatory agencies and include the drugs larotrectinib and entrectinib.

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showed acceptable safety in solid tumors, as well as 
in a cohort of dedifferentiated-LPS and SS subtypes 
treated with DS-3032b (NCT01877382). Similarly, 
encouraging results have been reported for CDK4/6 
antagonists alone or in combination with doxorubicin, 
showing a 12-week PFS rate between 57.2% and 66% in 
retroperitoneal LPS[24–26]. The second most common 
RPS subtype in our cohort was LMS. Our results 
confirmed that LMS is usually characterized by GA of 
tumor suppressors including TP53 (66%) and Rb1 (32%)
[19,20,27], but low frequency of GA in PTEN (12%), 
which underlie potential mechanisms of resistance to 
ICI in LMS subtypes[28]. Conversely, MPNST subtype 
had the highest TMB compared with other subtypes. 
Nevertheless, MPNST specimens were found to be 
CDKN2A/B rearranged, which is a biomarker often 
associated with poor prognosis and low expression 

of “druggable” target GA[29]. Other “targetable” 
gene fusions, such as ALK and ROS1, were rare in our 
population, while NTRK 1-3 gene rearrangements were 
mainly found in the MPNST cohort. NTRK fusions, 
although rare, have been described in sarcoma, and 
novel opportunities for patients with NTRK fusion-
positive solid tumors have recently been introduced[30]. 
Furthermore, another GA potentially linked to targeted 
therapy selection is NF1 in MPNST subtype, while 
deletion was recently associated with MEK inhibitors 
response[31]. In this context, novel opportunities for 
RPS treatment could arise from TAPUR (NCT02693535) 
and NCI-MATCH and the new Combo-MATCH trials 
testing several multi-target inhibitors according to the 
genomic variants expressed.

Finally, when considering PD-L1 status, 21% of 
RPS in our cohort had a low expression, while only 5% 

Amplifica)on	of	ERBB3	(7	copies),	CDK	4	(41	copies),	MDM2	(90	copies),	FRS2	(46	copies	
and	ZNF217	(12	copies)				

A	

C

B	

FIGURE 3.

Retroperitoneal well-differentiated liposarcoma in a 62-year-old man 

Low magnification (Figure 3A) and high magnification (Figure 3B) of a retroperitoneal well-differentiated liposarcoma. This tumor was MSI stable and 
featured a low TMB of 2 mut/Mb. Comprehensive genomic profiling revealed (Figure 3C) amplifications of multiple genes on chromosome  
12 including ERBB3 (7 copies), CDK4 (41 copies), MDM2 (90 copies), FRS2 (46 copies), and ZNF217 (12 copies). CDK4 encodes the cyclin-dependent 
kinase 4, which regulates the cell cycle, senescence, and apoptosis. CDK4 and its functional homolog CDK6 are activated by D-type cyclins and 
promote cell cycle progression by inactivating the tumor suppressor RB1. Amplification of CDK4 has been reported in lung cancer, glioblastoma,  
and liposarcoma.Amplification of the CDK4 and MDM2 genes, is a hallmark genetic alteration in well-differentiated liposarcoma. CDK4 amplification  
or activation may predict sensitivity to CDK4/6 inhibitors such as abemaciclib, palbociclib, and ribociclib.

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could be considered “high PD-L1,” with PLS and FDCS 
subtypes associated with the highest PD-L1 expression 
rates. Although sarcoma is generally considered a non-
immunogenic tumor, high heterogeneity of PD-L1 
expression was found across different subtypes (0% to 
65%), suggesting that each histological subtype should 
be considered as a separate therapeutic challenge[32,33]. 
Preliminary results from the phase II SARC028 trial 
testing pembrolizumab for soft-tissue sarcomas reported 
an objective response rate of 18% and a 12-week PFS 
rate of 55%, although the subgroup analysis identified 
no response in the LMS cohort[34]. Conversely, 
combination of nivolumab plus ipilimumab has provided 
promising efficacy for LMS and PLS subtypes[35]. To 
further advance the research and understanding of RPS, 
it is crucial to establish joint networks to share clinical 
data, create centralized biobanks and prospective 
registries, and organize collaborative novel clinical 

trials. For instance, based on the increasing number of 
genomic alterations specifically associated with sarcoma 
subtypes, the design of histology- and genomic-based 
trials, irrespective of the tissue of origin of the sarcoma, 
appears a promising approach to test rational targeted 
agents or particular combinations. Further prospective 
studies are needed to confirm safety, feasibility, and 
efficacy of these precision oncology approaches.

This study is not devoid of limitations inherent in 
its nature. This was a retrospective study including 
available cases with a descriptive analytical approach 
without granular demographic and clinicopathologic 
features and clinical outcomes. The presence of selection 
and confounding biases is very likely. There was 
variability of tumor size, source, and viable content, and 
there was no central pathology review of the original 
tumor block; however, H&E sections were reviewed 

A B	

C	

FIGURE 4.

Dedifferentiated liposarcoma of the retroperitoneum in a 74-year-old man

Figure 4A shows a dedifferentiated liposarcoma on hematoxylin and eosin staining at 10X magnification. Figure 4B shows diffuse positive 
membranous immunohistochemical staining for PD-L1 using the Dako 22C3 antibody at 10X magnification. On comprehensive genomic profiling, this 
MS-stable tumor has a low TMB at 3 mutations/Mb. MDM2 amplification characteristic of liposarcoma was found along with amplifications of 
CDK4, CCND3, FRS2 and JUN. This tumor also featured a HMGA2-TSFM fusion [Fusion:5'-HMGA2(ex1-3 NM_003483)-TSFM(ex2-6 NM_005726)] 
(Figure 4C). HMGA2 rearrangements and fusions have been most frequently identified in benign neoplasms such as lipomas, uterine leiomyomas, 
angiomyxomas, as well as in malignant tumors such as well-differentiated liposarcomas and inflammatory myofibroblastic tumors.

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by an expert pathologist. RPS included have different 
stages and grades which could inf luence the results, 
since the degree of tumor aggressiveness may underlie 
a distinct biology. We did not consider prior therapies 
before tumor tissue collection, which could facilitate 
the selection of cell clones with specific GAs and gene 
expression patterns. Moreover, CGP explored only a 
limited variety of GAs,  leaving out methylomic and 
proteomic profile, which could possibly reveal additional 
important information about RPS biology. We did not 
evaluate circulating cell-free tumor DNA and did not 
pursue composite biomarker analysis.

Conclusions
Our study revealed very few potentially actionable 
genomic targets, suggesting that RPSs seem unlikely 
to respond to targeted therapies or ICI, at least based 
on putative molecular biomarker status. However, 
uncommon “targetable” kinase fusions were found 
depending on RPS subtypes. Further research in the 
different RPS subtypes is needed to explore the biology, 
as well as the safety and efficacy of systemic treatment 
regimens according to the underlying biolog y in 
attempting a precision oncology strategy.

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ESR1

CDKN2A

JUN

ATRX

HMGA2

RB1

TP53

FRS2

CDK4

MDM2

Number of Samples: 296

Variant Type Point Mutation/Indel
Amplification
Deletion

Truncation
Fusion/Rearrangement

Other Multiple
0% 50%100%

A
lteration

Frequency

SUPPLEMENTARY MATERIAL 1A.

ROS1

FGF23

CCND2

ESR1

JUN

ATRX

HMGA2

FRS2

CDK4

MDM2

Number of Samples: 155

Variant Type Amplification
Deletion
Truncation

Fusion/Rearrangement
Other Multiple

0% 50%100%

A
lteration

Frequency

SUPPLEMENTARY MATERIAL 1B.

MYC

PIK3CA

RICTOR

KMT2C

KMT2D

GID4

PTEN

ATRX

RB1

TP53

Number of Samples: 74

Variant Type Point Mutation/Indel
Amplification
Deletion

Truncation
Fusion/Rearrangement

Other Multiple
0% 50%100%

A
lteration

Frequency

SUPPLEMENTARY MATERIAL 1C.

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CDKN2B

HMGA2

RB1

RICTOR

CDKN2A

ATRX

TP53

FRS2

CDK4

MDM2

Number of Samples: 44

Variant Type Point Mutation/Indel
Amplification
Deletion

Truncation
Fusion/Rearrangement

0% 50%100%

A
lteration

Frequency

SUPPLEMENTARY MATERIAL 1D.

CDK4

AKT1

BIRC3

MDM2

FRS2

ATR

PALB2

NOTCH4

TP53

STAT6

Number of Samples: 7
Variant Type Point Mutation/Indel Amplification Truncation Fusion/Rearrangement

0% 50%100%

A
lteration

Frequency

SUPPLEMENTARY MATERIAL 1E.

PTPN11

NBN

LRP1B

AKT2

SUZ12

EED

TP53

CDKN2B

NF1

CDKN2A

Number of Samples: 6
Variant Type Point Mutation/Indel Amplification Deletion Truncation

0% 50%100%

A
lteration

Frequency

SUPPLEMENTARY MATERIAL 1C.

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IKZF3

KMT2D

PALB2

PDGFRA

PIK3CA

SGK1

ZNF703

SSX2

SSX1

SS18

Number of Samples: 5

Variant Type Point Mutation/Indel
Amplification
Truncation

Fusion/Rearrangement
Variant Present in sample

0% 50%100%

A
lteration

Frequency

SUPPLEMENTARY MATERIAL 1G.

CDK4

ATRX

SF3B1

NOTCH2

ZNF217

NRAS

FGF6

KDM5A

CCND2

FGF23

Number of Samples: 5
Variant Type Point Mutation/Indel Amplification Truncation

0% 50%100%

A
lteration

Frequency

SUPPLEMENTARY MATERIAL 1H.

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