Comprehensive molecular profiling of sarcomas in adolescent and young adult patients: Results of the EORTC SPECTA-AYA international proof-of-concept study

Genomic Profiling and Clinical Outcomes of Targeted Therapies in Adult Patients with Soft Tissue Sarcomas

“…These reports include mainly retrospective studies on NGS in sarcoma patients from comprehensive cancer centers in the USA (n = 6) [7][8][9][10][11][12] and also from China [13] and Portugal [14]. In addition, five prospective studies provide data on genomic alterations and matched treatments: one from the USA [15] and four from Europe [16][17][18][19]. Furthermore, a limited number of case reports illustrating clinical benefits from targeted therapies in STS patients were also identified [20][21][22][23].…”

“…Furthermore, composite biomarkers are also interrogated through NGS, such as tumor mutational burden (TMB). Genomic aberrations detected in STS can be assigned to the following cellular pathways and processes: (i) tyrosine kinase (TK) activation or inactivation, including FGFR amplification or fusion, VEGF amplification, RET amplification, BRAF mutation, MET amplification, FGF amplification, and FRS2 amplification; (ii) PI3K-AKT-mTOR (PAM) pathway, including TSC2 deletion or base substitution, VHL deletion, NF2 deletion, TSC1 deletion or base substitution or amplification, and PTEN deletion; (iii) RAF-MEK-ERK (RME) pathway, such as KRAS amplification or base substitution, NRA base substitution, NF1-inactivating mutation or deletion, NF2 deletion, and MAP2K2 amplification; (iv) cell cycle, such as MDM2 amplification, CDK4 amplification, CDKN2A deletion or base substitution, CDKN2B deletion, MYC amplification, CDK6 amplification, CCNE1 amplification, and ARID1A base substitution; (v) DNA damage repair (DDR), such as BRCA1 and BRCA2 deletions, PTEN deletion, BAP1 deletion, FANCE fusion, ATM base substitution, and mismatch repair (MMR) deficiency (defined as loss or inactivation of MLH1, MSH2, MSH3, MSH6, PMS2); and (vi) immune evasion, including TCTLA4 amplification, PDCD1 amplification, and TMB [6][7][8]10,12,16,17,19,27,28,30]. As mentioned above, there are some associations of genomic alterations with specific STS subgroups.…”

“…Alterations in cell cycle genes are more common in liposarcomas [17], MPNST harbor alterations in the RME pathway [30], and angiosarcoma in angiogenesis-related genes (TK family) [31]. TMB has been assessed across STS and has been found high in some histotypes, such as rhabdomyosarcomas [16], UPS [12], MPNST [12], and leiomyosarcomas [17]. Anecdotal cases of high TMB have also been reported in patients with angiosarcoma, fibrosarcoma, and unclassified sarcoma [15,28].…”

“…In a smaller retrospective study in Portugal (N = 30), 10% of sarcoma patients were treated with a genome-targeted drug [14]. In the prospective European EORTC proof-of-concept study of 71 adolescent and young adults with sarcoma, 2.8% of all patients received targeted therapy [16]. Finally, among 65 STS patients in China, 9.2% received matched therapy in a clinical trial [13].…”

Proteomic features of soft tissue tumours in adolescents and young adults

“…Furthermore, these aggregate analyses do not consider well-established differences in the spectrum of STS histological subtypes in AYA versus OA patients 21 . Prior studies that have undertaken molecular profiling of AYA sarcoma specimens including a recent EORTC SPECTA-AYA study have focused exclusively on genomic and transcriptomic data 20 , 22 , 23 . While informative, these technologies do not provide a direct measure of proteins which are key mediators of tumour cell signalling and the largest class of targets for oncology drugs 24 – 27 , making it challenging to bridge the translational gap towards clinical applications.…”