The genomic, transcriptomic, and immunological landscape of TROP2 in solid tumors.
Authors: Trabolsi Asaad , Kareff Samuel A. , Rodriguez Estelamari , Krause Harris Benjamin , Tan Heng , Morgenstern-Kaplan DAN , Antonarakis Emmanuel S. , Lou Emil , Nagasaka Misako , Algaze Sandra , Lenz Heinz-Josef , Liu Stephen V. , Halmos Balazs , Hoon Dave S. , Seeber Andreas , Ma Patrick C. , El-Deiry Wafik S. , Vanderwalde Ari M. , Sledge George W. , Lopes Gilberto 
Published: June 2023

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Background: TROP2 expression is associated with decreased overall survival in colorectal and pancreatic cancers. The antibody drug conjugate sacituzumab delivers a SN38 toxic payload to TROP2-expressing cells and is approved for the treatment of breast cancer and urothelial carcinoma. We aimed to explore the genomic and immunological landscape of TACSTD2 (TROP2-encoding gene) in different solid tumors. Methods: Tumors from breast cancer (BC, N=11,246), colorectal carcinoma (CRC, N= 15,425), liver cancer (LC, N=433), pancreatic cancer (PC, N=5,488) and urothelial carcinoma (UC, N=5,488) were assessed at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing of DNA (592-gene or whole exome) and RNA (whole transcriptome). PD-L1 (SP142; Positive (+): ≥2+, ≥5%) expression was assessed by IHC. When investigating the genomic landscape, mutation prevalence was calculated for pathogenic SNVs/indels. TACSTD2-High (H) and -Low (L) expression was defined as top and bottom quartile of TACSTD2 transcripts per million, respectively. A transcriptomic signature predictive of response to immunotherapy was applied (T cell-inflamed score [Bao, 2020]). tests were applied as appropriate, with P-values adjusted for multiple comparisons ( p < .05). Real-world overall survival data was obtained from insurance claims and Kaplan-Meier estimates were calculated for molecularly defined subpopulations of patients. Results: Compared to TACSTD2-L, TACSTD2-H tumors had a higher prevalence of TP53 mutations in BC ( TACSTD2-H 59% vs -L 48%), CRC (77% vs 71%), LC (43% vs 23%) and PC (83% vs 69%), whereas UC TACSTD2-H had a lower prevalence (54% vs 67%, p < .05 for all). TACSTD2-H tumors had a higher rate of KRAS mutations in CRC (55% vs 38%, p < .05) and PC (96% vs 78%, p < .05). In CRC, the percentage of KRAS mutations that were G12C was higher in TACSTD2-H (7.3% vs 6.4%, p < .05). TACSTD2-H tumors had a higher rate of ARID1A mutations in CRC (6.7% vs 10%, p < .05) and UC (29 vs 20%, p < .05). A higher prevalence of PD-L1+ tumors was observed in CRC TACSTD2-H (6.4 vs 3.9%, p < .05) and the opposite pattern was observed in UC (16% vs 37%, p < .05). TACSTD2-H tumors were more frequently T cell-inflamed across investigated cancers (BC: TACSTD2-H 36% vs -L 19%, CRC: 29% vs 14%, LC: 54% vs 10%, PC: 42% vs 20%, UC: 32% vs 28%, all p < .05). TACSTD2-H was associated with worse overall survival in PC (HR 1.31 [1.19-1.44], p < .001), BC (HR 1.13 [1.03-1.23], p < .007) and CRC (HR 1.33 [1.24-1.42], p < .001), while this association was not observed in UC (HR .98 [.86-1.12], p = .75) or LC (HR 1.14[.82-1.57], p = .44). Conclusions: The association of TACSTD2 expression with KRAS, TP53 and ARID1A mutations and T cell-inflamed tumors (ICI responsive) should be considered as possible combination therapies with TROP2 targeting antibody drug conjugates are investigated.