A review of soft-tissue sarcomas: translation of biological advances into treatment measures

Figures & data

Table 1 Soft-tissue sarcoma genomic landscape

Sarcoma type/sub-type	Gene/chromosome alteration	Frequency
LPS (WDLS, DDLS)	HMGA2 amplification	76%
	MDM2 amplification	87%
	CDK4 amplification	95%
LPS (MLS)	13q21–13q32 amplifications	24%
	Telomerase reactivation	69%
	Telomerase reactivation	39%
	C228T TERT mutation	74%
AS	TP53 mutation	4%
	8q24.21 amplification	50%
	10p12.33 amplification	33%
	5q35.3 amplification	11%
	VEGF overexpression	21%–25%
	Inactivating PTPRB mutations	26%
	Likely activating PLCG1 mutations	9%
	PIK3CA mutations	3%
	FLT4 mutations	3%
	H/K/NRAS mutations	13%
LMS	Genomic imbalances	88%
	Aberrant chromosome numbers and structures	60%
	Promoter hypermethylation of RASSF1A	39%
LMS (ULMS)	X-chromosome gains	48%
	10q chromosome region loss	62%
	13q chromosome region loss	Most
RMS	Ras pathway mutations	35%–45%
	TP53 mutations	5%–22%
	MDM2 amplification	10%–17%
RMS (ERMS)	CDKN2A/B focal deletion	23%
	FGFR4 activating mutations	20%
	NF1 locus deletions	15%
	Ras family activating mutations	12%–42%
	High GLI1 expression	21%
	FGFR4 mutations	9%
	PIK3CA mutations	5%
RMS (ARMS)	PAX3–FOXO1 gene fusions	55%
	PAX7–FOXO1 gene fusions	22%
ES	EWS–FLI1 translocation	Characteristic
SS	SYT–SSX1 translocation fusion	Characteristic
Monophasic SS	Genetic aberrations	78%
Poorly differentiated SS	Genetic aberrations	5%
Biphasic SS	Genetic aberrations	16%
	Overexpression: KRT5, KRT7, KRT8, KRT14	Preferentially expressed in biphasic samples
	Overexpression: EST, ELF3	Preferentially expressed in biphasic samples

Abbreviations: LPS, liposarcoma; WDLS, well-differentiated liposarcoma; DDLS, dedifferentiated liposarcoma; MLS, myxoid liposarcoma; AS, angiosarcoma; LMS, leiomyosarcoma; ULMS, uterine leiomyosarcoma; RMS, rhabdomyosarcoma; ERMS, embryonic rhabdomyosarcoma; ARMS, alveolar rhabdomyosarcoma; ES, Ewing’s sarcoma; SS, synovial sarcoma.

Table 2 Soft-tissue sarcoma targets, therapeutics, and clinical status

	Target(s)	Therapeutic	Status	Trial ID
LPS	CDK4/6	Palbociclib (PD0332991)	Phase II trial completed (2017)	NCT01209598
LPS	VEGFR and PDGFR	Pazopanib	Phase II trial completed (2017)	NCT01506596
LPS (MLS)	NY-ESO1	CAR T cells	Phase II trial ongoing	NCT02992743
LPS (MLS), SS	Class I MHC expression	Recombinant IFNγ	Pilot study ongoing	NCT01957709
LPS (DDLS), LMS	mTOR and CDK4/6	Everolimus + ribociclib	Phase II trial ongoing	NCT03114527
LPS, LMS	PDL1 and DNA repair	Avelumab (PDL1 mAb) + trabectedin	Phase II trial ongoing	NCT030743
LPS, ES, AS (UPS)	PD1 and mTOR	Nivolumab (PD1 mAb) + ABI009 (mTOR inhibitor)	Phase II trial ongoing	NCT0319017
AS	VEGF	Bevacizumab (VEGF mAb)	Phase II trial ongoing	NCT00288015
LMS, SS	EGFR	Anlotinib (AL3818)	Phase III trial ongoing	NCT03016819
RMS	NY-ESO1, MAGEA4, PRAME, survivin, and SSX	TAA-specific CTLs	Phase I trial ongoing	NCT02239861
RMS, ES	Immunomodulated lysis	Recombinant vaccinia GM-CSF (JX594)	Phase I trial completed	NCT01169584
RMS, SS	CD56 and tubulin	Lorvotuzumab mertansine	Phase II trial ongoing	NCT02452554
ES	EWS-FLI1	TK216	Phase I trial ongoing	NCT02657005
SS	G6PD	DHEA	Phase II trial ongoing	NCT02683148
SS	mTOR, c-Kit, and PDGFR	Everolimus + imatinib mesylate	Phase II trial completed	NCT01281865
SS	NY-ESO1-expressing tumor cells	Autologous dendritic cells loaded with allogeneic tumor lysate expressing NY-ESO1	Phase I/II ongoing	NCT01883518
Advanced STS postchemotherapy	VEGFR1 and VEGFR2, VEGFR3, PDGFR, and c-Kit	Pazopanib	FDA-approved (2012)	—
Several	Immunomodulated lysis	HSV1716	Phase I trial ongoing	NCT00931931
Several	Tubulin and mitotic spindle	Eribulin	FDA-approved (2015)	—
Several	DNA repair	Trabectedin	FDA-approved (2016)	—
Several	PD1 and CTLA4	Nivolumab ± ipilimumab (CTLA4 mAb)	Phase II trial ongoing	NCT02500797
Several	mTOR	Ridaforolimus	Phase II trial completed (2015)	NCT00112372
Several	VEGFR, PDGFR, and DNA replication	Pazopanib + topotecan	Phase II trial ongoing	NCT02357810
Several	Topoisomerase 2 and PDGFR	Dexrazoxane + doxorubicin + olaratumab	Phase II trial ongoing	NCT025843
Several	Raf, VEGFR1, VEGFR2, VEGFR3, PDGFR B, and c-Kit	Sorafenib	Phase II trial completed	NCT00217620
Several	PDL1 and NY-ESO1	Atezolizumab (PDL1 mAb) + CMB305	Phase II trial ongoing	NCT026099
Several	Histone-lysine methyltransferase EZH2	Tazemetostat	Phase II trial ongoing	NCT02601950

Abbreviations: LPS, liposarcoma; MLS, myxoid liposarcoma; SS, synovial sarcoma; DDLS, dedifferentiated liposarcoma; LMS, leiomyosarcoma; mAb, monoclonal antibody; ES, Ewing’s sarcoma; AS, angiosarcoma; UPS, undifferentiated pleomorphic sarcoma; RMS, rhabdomyosarcoma.

Figure 1 Genomic changes in soft-tissue sarcoma.

Notes: Liposarcomas consist of four subtypes: well-differentiated liposarcoma (WDLS), dedifferentiated liposarcoma, myxoid liposarcoma (MLS), and pleomorphic liposarcoma (PLS). A common characteristic of WDLS, DDLS, and PLS is amplifications in HMGA2, MDM2, and CDK4. PLS bears additional CCND1 amplifications. MLS, on the other hand, harbors a fusion of TLS/FUS–CHOP, which is responsible for pathogenesis. Angiosarcomas are diverse malignancies and bear aberrations in MYC, VEGF/VEGFR, PTPRB, and PLCG1. Leiomyosarcomas have frequent X-chromosome (Chr) gains, constitutively activated Akt and losses in Chr 10, which bears the PTEN gene. The two latter aberrations lead to mTOR activation via TSC2 and are instrumental in disease pathology. Rhabdomyosarcoma can be subtyped into alveolar rhabdomyosarcoma (ARMS) and embryonic rhabdomyosarcoma (ERMS). The former is associated with PAX3/7–FOXO1 fusions and cause Hippo-pathway dysregulation accompanied by bypass of cellular senescence, and the latter is distinguished by losses in Chr 11, along with gene mutations in the Ras pathway. Other pathways involved include Hedgehog, PI3K, and p53. Ewing’s sarcoma is characterized by EWS–ETS gene fusion, and this potent transcription factor induces genes associated with proliferation, apoptosis inhibition, and metabolic changes to favor biosynthesis and cell division. Synovial sarcoma (SS) is associated with SYT–SSX fusions: SYT–SSX2 for monophasic SS and SYT–SSX1/2 for biphasic SS. Arrows indicate gene transcription.