AKT2 amplification

This is the largest molecular profiling analysis of PASC, which is characterized by unique genomic alterations, and is associated with higher PD-L1 expression, immune related gene expression, CD4+ T cell infiltration and IFN gamma signature, and lower MAPK activation. PASC is associated with better OS compared to PSCC. These findings may provide subtype-specific therapeutic opportunities for PASC and PSCC pts.

Material and Methods We analysed preoperative core biopsy samples of 20 patients with MRSTS who received 5×5 Gy radiotherapy combined with three cycles of doxorubicin-ifosfamide chemotherapy in a phase II clinical trial (NCTXXXXXXXX). D Undifferentiated pleomorphic sarcoma CDK4 Amplification - - D Dedifferentiated liposarcoma CDK4 Amplification - - E Undifferentiated pleomorphic sarcoma RB1 Nonsense mutation c.958C>T p.R320* D Myxofibrosarcoma AKT2 Amplification - - D Undifferentiated pleomorphic sarcoma PTEN Gene deletion - - D Undifferentiated pleomorphic sarcoma PTEN Gene deletion - - E Pleomorphic liposarcoma PTEN Gene deletion - - D Myxofibrosarcoma NF1 Nonsense mutation c.3520C>T p.Q1174* D Malignant peripheral nerve sheath tumor NF1 Nonsense mutation c.1278G>A p.W426* D Malignant peripheral nerve sheath tumor Conclusion The detection of known mutations in MRSTS suggests poor pathological response to neoadjuvant radiochemotherapy. Identified mutations may indicate new therapeutic targets in the treatment of MRSTS.

Although more and more patients with ovarian cancer are undergoing tumor-based next-generation sequencing to identify genetic mutations in their tumors, the benefits of such testing are not well established. In a group of over 400 patients with ovarian cancer who underwent tumor-based next-generation sequencing in the course of their treatment, nearly all patients had one or more genetic alterations detected, and one out of four patients had a mutation that qualified them for a personalized treatment option.

Genetic and expression alterations identified by the BostonGene Tumor PortraitTM TestEvent type analyzed in targeted panelsEvent typeCohort (N patients)*% cohort with event or # biomarkersEvents, status, or subtypeYesSNV/IndelMG (21)10%FAT4 Y558_V590delinsCAfs*5 LOF mutation COL2A1 W1348Nfs*13 LOF mutationYesSNV/IndelMD (40)6%KMT2B R1779* LOF mutation KMT2C S143Vfs*3 LOF mutation PRKDC Y4046* LOF mutationYesGermlineMG (21)5%MUTYH rs36053993, germline, pathogenicYesGermlineMD (40)3%BTD rs13078881, germline, pathogenicYesCNAMG (21)43%IGF1R amplification +8 copies MGMT loss FANCA loss MCL1 amplification +10 copies MYOCD amplification +3 copies AKT2 amplification +8 copies AMACR amplification +6 copies YAP1 amplification +7 copies TRAF2 loss EZH2 amplification +2 copies HMGA2 amplification +100 copies FRS2 amplification +61 copies DDIT3 amplification +39 copiesYesCNAMD (40)27.5%ERK1 amplification +2 copies FOXO1 amplification +5 copies HMGA2 amplification +2, +8 copies KMT2C amplification +3 copies NCOR1 amplification +7 copies TERT amplification +6 copies TSPAN31 amplification +30 copies HSF1 lossYesFusionsMG (20)10%MDM2-CR1 MDM2-TXNDC12 AC090825.1-IGF1RYesFusionsMD (39)15%FUS-KIAA1549 KIAA1549-CREB3L2 HMGA2-LRRC37A3 NAB2-STAT6 PPP1R12A-PAWR RB1-ZAR1LNoTMB**MG+MD (61)8%35.67 mut/Mb (Desmoid fibromatosis) 8.48 mut/Mb (Cutaneous angiosarcoma) 8.9 mut/Mb (Sarcoma, NOS) 16.1 mut/Mb (Skin Angiosarcoma) 18.8 mut/Mb (Undifferentiated pleomorphic sarcoma)NoMSI statusMG+MD (61)100%StableNoHLA loss of heterozygosityMG+MD (61)11%HLA-I LOH (Leiomyosarcoma (N=1), Ewing Sarcoma (N=1)) HLA-A (Dedifferentiated liposarcoma (N=1)) HLA-I (Chondrosarcoma (N=3), High-grade sarcoma (N=1))NoTargetable surface molecule overexpressionMG+MD (59)81%CTLA4, EGFR, ERBB2, MAGEA3, PD1, PDL1, TIM3, TROP, ERBB2, FOLR1, NECTIN4, ROR1, TROP2NoMolecular Functional PortraitTM typeMG+MD (59)32%FibroticNoMolecular Functional PortraitTM typeMG+MD (59)17%Immune DesertNoMolecular Functional PortraitTM typeMG+MD (59)24%Immune-Enriched, FibroticNoMolecular Functional PortraitTM typeMG+MD (59)27%Immune-Enriched, Non-fibroticNoMHC deficiencyMG+MD (59)3%MHC class I/II deficiencyNoMHC deficiencyMG+MD (59)3%MHC class II deficiencyNoFDA label biomarkersMG+MD (59)7 biomarkers- Desmoid fibromatosis, TMB 35.67 mut/Mb (Pembrolizumab) - Angiosarcoma, TMB 16.1 mut/Mb (Pembrolizumab); - Undifferentiated pleomorphic sarcoma, MSI, TMB 18.8 mut/Mb (Pembrolizumab); - Cutaneous angiosarcoma, PALB2 pathogenic germline variant (Olaparib); - Chondrosarcoma IDH1 R132L (Ivosidenib)NoTranscriptomic biomarkersMG+MD (59)29 biomarkersCD8+ T cell number; PDL1 expression level; SLFN11 expression level; SMARCB1 expression; CD8+ T cell numberNoDiagnostic biomarkersMG+MD (59)9 biomarkersNAB2-STAT6; MXI1-NUTM1; EWSR1-NR4A3; EWSR1-FLI1; EWSR1-CREB3L1; NAB2-STAT6----*RNA analysis failed for 2 patients. Therefore, any expression based analysis was performed on n=20 and n=39 for the MG and MD cohort, respectively. **Tumor mutational burden is considered high for FFPE samples when TMB>8mut/Mb.

The genomic profiling of Brazilian NSCLC indicated actionable mutations and remarkable genomic amplifications and deletions. Our results may contribute to improve the knowledge about the molecular profile of admixed patients.

Herein, we report a patient presenting with a primary small bowel spindle cell GIST and concurrent peritoneal and liver metastases displaying an imatinib-sensitive KIT exon 11 in-frame deletion. We present the first report of a multi-drug resistant GIST patient who developed an FGFR2 gene fusion as a secondary genetic event to the selective pressure of various TKIs. This case also highlights the heterogeneous escape mechanisms to targeted therapy across various tumor nodules, spanning from both KIT-dependent and KIT-independent off-target activation pathways.