TY - JOUR
T1 - Genomic, immunologic, and prognostic associations of TROP2 (TACSTD2) expression in solid tumors
AU - Morgenstern-Kaplan, Dan
AU - Kareff, Samuel A.
AU - Trabolsi, Asaad
AU - Rodriguez, Estelamari
AU - Krause, Harris
AU - Ribeiro, Jennifer R.
AU - Tan, Heng
AU - Antonarakis, Emmanuel S.
AU - Lou, Emil
AU - Nagasaka, Misako
AU - Algaze, Sandra
AU - Lenz, Heinz Josef
AU - Liu, Stephen V.
AU - Halmos, Balazs
AU - Hoon, Dave S.B.
AU - Seeber, Andreas
AU - Ma, Patrick C.
AU - El-Deiry, Wafik S.
AU - Vanderwalde, Ari M.
AU - Lopes, Gilberto
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/11/1
Y1 - 2024/11/1
N2 - 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.
AB - 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.
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U2 - 10.1093/oncolo/oyae168
DO - 10.1093/oncolo/oyae168
M3 - Article
C2 - 38986529
AN - SCOPUS:85208772990
SN - 1083-7159
VL - 29
SP - e1480-e1491
JO - Oncologist
JF - Oncologist
IS - 11
ER -
