The breast cancer coagulome in the tumor microenvironment and its role in prognosis and treatment response to chemotherapy

Mari Tinholt; Xavier Tekpli; Lilly Anne Torland; Andliena Tahiri; Jürgen Geisler; Vessela Kristensen; Per Morten Sandset; Nina Iversen

doi:10.1016/j.jtha.2024.01.003

The breast cancer coagulome in the tumor microenvironment and its role in prognosis and treatment response to chemotherapy

J Thromb Haemost. 2024 May;22(5):1319-1335. doi: 10.1016/j.jtha.2024.01.003. Epub 2024 Jan 17.

Authors

Mari Tinholt¹, Xavier Tekpli², Lilly Anne Torland³, Andliena Tahiri⁴, Jürgen Geisler⁵, Vessela Kristensen⁶, Per Morten Sandset⁷, Nina Iversen²

Affiliations

¹ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; Department of Haematology, Oslo University Hospital, Oslo, Norway. Electronic address: mari.tinholt@ous-hf.no.
² Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
³ Department of Research and Innovation, Vestre Viken Hospital Trust, Drammen, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁴ Department of Research and Innovation, Vestre Viken Hospital Trust, Drammen, Norway; Department of Clinical Molecular Biology (EpiGen), Medical Division, Akershus University Hospital, Lørenskog, Norway.
⁵ Department of Oncology, Akershus University Hospital, Lørenskog, Norway; Institute of Clinical Medicine, University of Oslo, Campus Akershus University Hospital, Lørenskog, Norway.
⁶ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
⁷ Department of Haematology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital, Norway.

PMID: 38237862
DOI: 10.1016/j.jtha.2024.01.003

Abstract

Background: The procoagulant phenotype in cancer is linked to thrombosis, cancer progression, and immune response. A novel treatment that reduces the risk of both thrombosis and cancer progression without excess bleeding risk remains to be identified.

Objectives: Here, we aimed to broadly investigate the breast tumor coagulome and its relation to prognosis, treatment response to chemotherapy, and the tumor microenvironment.

Methods: Key coagulation-related genes (n = 35) were studied in a Norwegian cohort with tumor (n = 134) and normal (n = 189) tissue and in the Cancer Genome Atlas (n = 1052) data set. We performed gene set variation analysis in the Norwegian cohort, and in the Cancer Genome Atlas cohort, associations with the tumor microenvironment and prognosis were evaluated. Analyses were performed with cBioPortal, Estimation of Stromal and Immune cells in Malignant Tumors Using Expression Data, Tumor Immune Estimation Resource, the integrated repository portal for tumor-immune system interactions, Tumor Immune Single-cell Hub 2, and the receiver operating characteristic plotter. Six independent breast cancer cohorts were used to study the tumor coagulome and treatment response to chemotherapy.

Results: Twenty-two differentially expressed coagulation-related genes were identified in breast tumors. Several coagulome factors were correlated with tumor microenvironment characteristics and were expressed by nonmalignant cells in the tumor microenvironment. PLAT and F8 were independent predictors of better overall survival and progression-free survival, respectively. F12 and PLAU were predictors of worse progression-free survival. The PROCR-THBD-PLAT signature showed a promising predictive value (area under the curve, 0.75; 95% CI, 0.69-0.81; P = 3.6 × 10^-17) for combination chemotherapy with fluorouracil, epirubicin, and cyclophosphamide.

Conclusion: The breast tumor coagulome showed potential in prediction of prognosis and chemotherapy response. Cells within the tumor microenvironment are sources of coagulome factors and may serve as therapeutic targets of coagulation factors.

Keywords: blood coagulation; breast cancer; chemotherapy; prognostic factors; tumor; tumor microenvironment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Antineoplastic Combined Chemotherapy Protocols / therapeutic use
Biomarkers, Tumor / blood
Biomarkers, Tumor / genetics
Blood Coagulation Factors / genetics
Blood Coagulation* / drug effects
Breast Neoplasms* / drug therapy
Breast Neoplasms* / genetics
Female
Gene Expression Regulation, Neoplastic
Humans
Middle Aged
Norway
Prognosis
Treatment Outcome
Tumor Microenvironment*

Substances

Biomarkers, Tumor
Blood Coagulation Factors