Abstract PO5-14-10: Dynamics and prognostic value of subtype specific TROP2 expression in matched pair samples of primary (PBC) and metastatic breast cancer (MBC) tissues
Authors: Deutsch Thomas , Wirtz Ralph , Stefanovic Stefan , Hartkopf Andreas , Sinn Hans-Peter , Schneeweiss Andreas , Wallwiener Markus 
Published: May 2024

Abstract
Background: The genotype and phenotype of breast cancer may change during disease progression. This is of particular interest in the advent of targeted treatment adressing extracellular targets such as TROP2, which serves as chemotherapy carrier rather than being required for tumor cell survival. In addition, technical issues may affect biomarker assessment when comparing primary breast cancer (PBC) tissues with biopsies of metastatic breast cancer (MBC) tissues at distant sites. Here we analyzed TROP2 expression on mRNA level by RT-qPCR in primary tumor and metastatic tissues on basis of molecular subtyping to determine subtype specificity and target gene stability/dynamics.
Methods: The tumor bank of a single institution was screened for paraffin-embedded pairs of PBC and MBC tissue samples and a total of 34 matched PBC and MBC pairs were retrieved. RNA was extracted using a bead-based extraction method (RNXtract® IVD kits, Cerca Biotech). Multiplex RT-qPCR was performed using TaqMan® based primer probe sets for ESR1/PGR/ERBB2 and MKI67 (MammaTyper® IVD kits, Cerca Biotech) as well as TROP2 (TargetTyper RUO kits, STRATIFYER Molecular Pathology GmbH). Correlation analysis, Scatter Plots, Partitioning tests and Kaplan Meier analysis were performed using the SAS JMP® 9.0.0 software.
Results: Samples from 34 patients with MBC and PBC were available. Positivity of PBC RT-qPCR for ESR1, PGR and HER2 was 78%, 70% and 3%. The overall agreement between matched primary and metastatic lesions 90%, 70% and 100% for RT-qPCR of ESR1, PGR and HER2. Median expression of TROP2 was 2 fold lower in metastatic tissues compared to matched primary tumor tissues, while the lower quartile of mRNA expression dropped 4 fold. In primary tumor tissues TROP2 expression was significantly associated with PGR and HER2 expression (Spearman r=0.5284 p=0.0013 and r=0.3950 p=0.0208; respectively), while no significant association was found for ESR1 and MKI67. In contrast, no significant association with neither PGR nor HER2 was found (Spearman r=0.0461 p=0.8041 and r=0.0461 p=0.7955; respectively), while TROP2 trended to be associated with MKI67 in metastatic lesions (Spearman r=0.3247 p=0.0610). In line with the strong positive association of TROP2 with PGR in primary tumor tissues, elevated TROP2 levels were associated with substantially longer median distant metastasis free survival of 72 months, while TROP2 negative tumors exhibited a median DDFS of only 24 months (p=0,0091). In contrast, no prognostic value for TROP2 mRNA level could be determined from metastatic lesions and determining the time from initial metastasis until death.
Conclusion: In this selected matched pair, metastatic cohort, TROP2 mRNA in primary tumors is strongly associated with luminal type of breast cancer expressing higher levels of PGR mRNA, while no such correlation was found in matched metastatic tissues. Moreover, TROP2 is significantly downregulated in metastatic lesions. As TROP2 is expressed in luminal tumors, it may serve as a valuable target for luminal tumors of higher progression risk. However, TROP2 expression is unstable and requires careful decision making on actual biopsies rather than archival tissue samples.
Citation Format: Thomas Deutsch, Ralph Wirtz, Stefan Stefanovic, Andreas Hartkopf, Hans-Peter Sinn, Andreas Schneeweiss, Markus Wallwiener. Dynamics and prognostic value of subtype specific TROP2 expression in matched pair samples of primary (PBC) and metastatic breast cancer (MBC) tissues [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-14-10.