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. 2024 Nov 4;29(11):e1480-e1491.
doi: 10.1093/oncolo/oyae168.

Genomic, immunologic, and prognostic associations of TROP2 (TACSTD2) expression in solid tumors

Dan Morgenstern-Kaplan  1 , Samuel A Kareff  1 , Asaad Trabolsi  1 , Estelamari Rodriguez  1 , Harris Krause  2 , Jennifer R Ribeiro  2 , Heng Tan  1 , Emmanuel S Antonarakis  3 , Emil Lou  3 , Misako Nagasaka  4 , Sandra Algaze  5 , Heinz-Josef Lenz  5 , Stephen V Liu  6 , Balazs Halmos  7 , Dave S B Hoon  8 , Andreas Seeber  9 , Patrick C Ma  10 , Wafik S El-Deiry  11 , Ari M Vanderwalde  2 , Gilberto Lopes  1
Affiliations

Genomic, immunologic, and prognostic associations of TROP2 (TACSTD2) expression in solid tumors

Dan Morgenstern-Kaplan et al. Oncologist. .

Abstract

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.

Keywords: TROP2; precision oncology; targeted therapy; tumor genetics.

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Conflict of interest statement

E.S.A. reports grants and personal fees from Janssen, Sanofi, Bayer, Bristol Myers Squibb, Curium, Merck, Pfizer, AstraZeneca, and Clovis; personal fees from Astellas, Amgen, Blue Earth, Exact Sciences, Invitae, Eli Lilly, and Foundation Medicine; grants from Novartis, Celgene, and Orion; and has a patent for an AR-V7 biomarker technology that has been licensed to Qiagen. E.L. reports support from the University of Minnesota Clinical Center for the Study of Pancreatic Disease, part of The Chronic Pancreatitis Diabetes Pancreatic Cancer research (CPDPC) consortium funded by the NIDDK (5U01DK126300-03), and research grants from the American Cancer Society (RSG-22-022-01-CDP) 2022-2026; The Randy Shaver Cancer Research and Community Fund; compensation for scientific review of proposed printed content, Elsevier Publishing and Johns Hopkins Press; Institutional Principal Investigator for clinical trials sponsored by Celgene, Novocure, Ltd, Intima Bioscience, Inc., the National Cancer Institute, and University of Minnesota membership in the Caris Life Sciences Precision Oncology Alliance (no financial compensation).

Figures

Figure 1.
Figure 1.
Pan-cancer expression of TACSTD2. (A) TACSTD2 expression in transcripts per million (TPM) between primary and metastatic sites in breast cancer, colorectal, hepatocellular cancer, pancreatic ductal adenocarcinoma, and urothelial carcinoma. (B) TACSTD2 expression in left- and right-sided colorectal tumors and (C) segmented based on CRC consensus molecular subtype (CMS) (D; P < .05).
Figure 2.
Figure 2.
Landscape of TACSTD2-associated genomic alterations. The heat map shows the difference in the prevalence of mutations and copy number alterations between TACSTD2-high and TACSTD2-low tumors. Orange indicates the alteration is associated with TACSTD2-low; blue indicates the alteration is associated with TACSTD2-high. An alteration is included in the heatmap if it has an absolute difference in prevalence of >3% in one of the investigated cancer types. Red asterisks indicate statistical significance (q < .05). Abbreviations: CRC: colorectal cancer; PDAC: pancreatic ductal adenocarcinoma; UC: urothelial carcinoma.
Figure 3.
Figure 3.
Pan-cancer prevalence of immune-oncology biomarkers stratified by TACSTD2 expression. Prevalence of PD-L1 positivity by immunohistochemistry (A), mismatch repair deficiency/microsatellite instability-high (dMMR/MSI-high) (B), and tumor mutational burden-high (TMB-high) (C) tumors segmented by quartile TACSTD2 expression (Q1-Q4). *q < .05. Abbreviations: CRC: colorectal cancer; PDAC: pancreatic ductal adenocarcinoma; UC: urothelial carcinoma.
Figure 4.
Figure 4.
Tumor immune microenvironment of TACSTD2-low versus TACSTD2-high cancer. (A) Immune cell composition based on TACSTD2 quartile gene expression across tumor types. (B) Difference in immune cell composition between TACSTD2-high and TACSTD2-low tumors (*q < .05). (C) Prevalence of inflamed tumors (T-cell inflamed score) segmented by TACSTD2 quartile gene expression (*q < .05). Abbreviations: CRC: colorectal cancer; PDAC: pancreatic ductal adenocarcinoma; UC: urothelial carcinoma.
Figure 5.
Figure 5.
Association of TACSTD2 expression with overall survival (OS) and immune checkpoint inhibitor (ICI) response. Forest plots show log2 hazard ratios (HRs) for OS (A) and post-ICI OS (B) across tumor types. (C) Kaplan-Meier curves for OS and survival on sacituzumab govitecan (SG) for the indicated tumors, higher HRs suggest more favorable OS for TACSTD2-low (*P < .05; **P < .005). OS calculated from tissue collection to last contact; post-ICI OS calculated from first of treatment to last contact and survival on SG calculated from start of treatment to last contact.
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