P2.02-016 Pulmonary Sarcomas: A Comprehensive Genomic Profiling Study

Pulmonary sarcomas (PSRC) are uncommon primary thoracic malignancies that are often clinically aggressive. Comprehensive genomic profiling (CGP) can identify biomarkers for both targeted and immunotherapy. We used CGP to analyze novel treatment options for patients with advanced PSRC. CGP using hybridization-captured, adaptor ligation-based libraries for up to 406 genes plus select introns from 31 genes frequently rearranged in cancer was performed on 19 PSRC; 15 cases also underwent RNA sequencing for enhanced fusion detection in 265 of these genes. All classes of genomic alteration (GA) were assessed simultaneously: base substitutions, indels, rearrangements, and copy number changes. Clinically relevant GA (CRGA) are GA associated with drugs on the market or under evaluation in clinical trials. Tumor mutational burden (TMB) was determined on 1.1 Mb of sequenced DNA. In this cohort were 10 sarcoma NOS, 5 pulmonary artery intimal sarcomas, 2 pleomorphic/MFH sarcomas, 1 primary IMT, and 1 primary SFT, including 1 stage I, 1 stage II, 9 stage III and 8 stage IV tumors. Patient median age was 52 years (range 33–81 years), with 7 female and 12 male patients. The mean GA per sarcoma was 5.7. Notable alterations not presently considered actionable affected TP53 (53%), CDKN2A (32%), CDKN2B (27%), and RB1 (21%). CRGA alterations were detected in PDGFRA, RICTOR, CDK4 and KIT (11% each), and EGFR, TSC2, ALK and BRAF (5% each); 9 (47%) PSRC featured ≥1 CRGA. An ALK fusion was detected in an IMT localized only to the lung and diagnosed as a primary lesion. Inactivation of SMARCA4 through mutation and loss of heterozygosity was found in 1 case. Mean TMB was 8.65 mutations/Mb (16% had TMB >10 mut/Mb, 11% had TMB >20 mut/Mb); cases with TMB >20 mut/Mb lacked characteristically targetable CRGA. All samples tested for MSI (n=7) were microsatellite stable. Assessment of therapeutic intervention and responses is ongoing. PSRC is an extremely rare primary lung malignancy characterized by a relatively high frequency of GA. CGP identified various potentially targetable alterations in this small series, particularly driver mutations or fusions in tyrosine kinases and cell cycle regulatory genes. Furthermore, characteristic genomic profiles can provide diagnostic insight, as for SMARCA loss or ALK fusions. This study also identified a significant number of PSRC with intermediate or high TMB, indicating potential immunotherapy options for these patients. Further study of CGP to help manage patient care and minimize suffering from this rare pulmonary malignancy appears warranted.