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Genomic, immunologic, and prognostic associations of TROP2 (TACSTD2) expression in solid tumors
Dan Morgenstern-Kaplan1, Samuel A Kareff1, Asaad Trabolsi1
1Department of Medicine, Division of Medical Oncology, University of Miami Sylvester Comprehensive Cancer Center/Jackson Memorial Hospital, Miami, FL 33131, United States.
Background:
TROP2 (TACSTD2) expression is associated with decreased overall survival (OS) in some solid tumors, and the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan has been approved in breast and urothelial carcinomas. We aimed to explore the multi-omic landscape associated with TACSTD2 gene expression in various solid tumors to identify patients most likely to benefit from this approach.
Methods:
Breast (N = 11 246), colorectal (N = 15 425), hepatocellular (N = 433), pancreatic (N = 5488), and urothelial (N = 4125) tumors were stratified into quartiles by TACSTD2 gene expression, analyzed by next-generation DNA sequencing, whole transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Survival data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined cohorts.
Results:
Several pathogenic mutations were associated with TACSTD2-high tumors, including TP53 in breast, colorectal (CRC), pancreatic, and hepatocellular cancers; KRAS in pancreatic and CRC cancers; ARID1A and FGFR3 in urothelial cancer; and CTNNB1 in hepatocellular cancer. TACSTD2-low breast tumors were enriched for copy number amplifications in CCND1 and FGF/R family member genes. TACSTD2 high was generally associated with more immune cell infiltration and greater T-cell inflammation scores. Patients with TACSTD2-high breast, CRC, and pancreatic cancers demonstrated a significantly shorter OS than TACSTD2-low tumors. This was restricted to CRC with microsatellite stable tumors and patients with pancreatic cancer with KRAS-mutant tumors. Patients with breast cancer with TACSTD2-high tumors also experienced significantly worse OS following immune checkpoint inhibitors.
Conclusions:
TACSTD2 expression is associated with key driver alterations and a more active immune microenvironment, suggesting possible combinatorial strategies with TROP2-targeting ADCs plus immunotherapy in various solid tumors.
Insights
High TROP2 (TACSTD2) expression in solid tumors correlates with specific mutations and a more active immune microenvironment, impacting overall survival and response to therapies.
Area of Science:
- Oncology
- Genomics
- Immunotherapy
Background:
- TROP2 (TACSTD2) expression is linked to poorer survival in several solid tumors.
- TROP2-targeting antibody-drug conjugates (ADCs) are approved for breast and urothelial cancers.
Purpose of the Study:
- To investigate the multi-omic landscape of TACSTD2 expression across diverse solid tumors.
- To identify patient subgroups likely to benefit from TROP2-targeted therapies.
Main Methods:
- Analysis of over 26,000 tumors (breast, colorectal, hepatocellular, pancreatic, urothelial) using next-generation sequencing and whole transcriptome sequencing.
- Stratification of tumors into quartiles based on TACSTD2 gene expression.
- Correlation of molecular data with survival outcomes and immune microenvironment characteristics.
Main Results:
- TACSTD2-high tumors frequently harbored mutations in TP53, KRAS, ARID1A, FGFR3, and CTNNB1.
- TACSTD2-low breast tumors showed amplifications in CCND1 and FGF/R genes.
- Higher TACSTD2 expression was associated with increased immune cell infiltration and T-cell inflammation.
- Patients with TACSTD2-high breast, colorectal, and pancreatic cancers had significantly shorter overall survival, particularly in microsatellite-stable colorectal and KRAS-mutant pancreatic cancers.
- Breast cancer patients with TACSTD2-high tumors experienced worse outcomes with immune checkpoint inhibitors.
Conclusions:
- TACSTD2 expression is associated with key driver mutations and an active immune microenvironment.
- Findings suggest potential for combining TROP2-targeting ADCs with immunotherapy for various solid tumors.
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