AUTHOR=Tutzauer Julia , Larsson Anna-Maria , Aaltonen Kristina , Bergenfelz Caroline , Bendahl Pär-Ola , Rydén Lisa 

TITLE=Gene expression in metastatic breast cancer—patterns in primary tumors and metastatic tissue with prognostic potential

JOURNAL=Frontiers in Molecular Biosciences

VOLUME=10

YEAR=2024

URL=https://www.frontiersin.org/journals/molecular-biosciences/articles/10.3389/fmolb.2023.1343979

DOI=10.3389/fmolb.2023.1343979

ISSN=2296-889X

ABSTRACT=<p><bold>Background:</bold> Metastatic breast cancer (MBC) is the main cause of breast cancer-related death. The outcome of MBC varies, and there is a lack of biomarkers to aid in prognostication. The primary aim of this study was to evaluate the prognostic value of gene expression (GEX) signatures in the primary tumor (PT) and distant metastasis (DM) for progression-free survival (PFS) and overall survival (OS). The secondary aim was to describe GEX changes through MBC evolution and to identify MBC subtypes.</p><p><bold>Methods:</bold> RNA was extracted from the PT, lymph node metastasis (LNM), and DM from MBC patients in a prospective observational study (<italic>n</italic> = 142; CTC-MBC NCT01322893) and was subjected to GEX analysis retrospectively using the NanoString Breast Cancer 360™ panel. 31 continuous GEX variables in DMs and PTs were analyzed for PFS and OS by Cox regression analysis and Kaplan-Meier estimates. Multivariable Cox regressions were adjusted for number of DM sites and CTCs, visceral metastasis, ECOG status, age at MBC diagnosis and, in additional analyses, PAM50 subtype. Differential GEX analyses and Euclidean distances were used to describe subgroup differences and visualize within-patient heterogeneity.</p><p><bold>Results:</bold> Compared to DM GEX, GEX of the PT was at least equally useful for predicting MBC outcome. The strongest marker for a favorable PFS, both when expressed in the PT and the DM was <italic>AR</italic>, even after adjustment for prognostic markers including PAM50. GEX signatures related to hormone responsiveness, including <italic>ESR1</italic>, <italic>FOXA1</italic>, <italic>PGR</italic>, and <italic>AR</italic> were favorable prognostic markers, and the p53 signature was unfavorable for PFS when expressed in PT or DM. The previously published PAM50MET signature was prognostic for both PFS and OS. We established five distinct DM GEX profiles where two associated with liver and bone metastases, respectively. Finally, we identified four DM GEX profiles able to identify MBCs with poor OS in this cohort.</p><p><bold>Conclusion:</bold> GEX of both DM and PT are useful in MBC prognostication. GEX of <italic>AR</italic> adds prognostic information for MBC. Our descriptive analyses illuminate the biological differences between MBCs in relation to outcome and metastatic site.</p>