Transcriptional Profiling of Breast Cancer Metastases Identifies Liver Metastasis-Selective Genes Associated with Adverse Outcome in Luminal A Primary Breast Cancer.
OBJECTIVE
The complete molecular basis of the organ-specificity of metastasis is elusive. This study aimed to provide an independent characterization of the transcriptional landscape of breast cancer metastases with the specific objective to identify liver metastasis-selective genes of prognostic importance following primary tumor diagnosis.


METHODS
A cohort of 304 women with advanced breast cancer was studied. Associations between the site of recurrence and clinicopathologic features were investigated. Fine-needle aspirates of metastases (n = 91) were subjected to whole-genome transcriptional profiling. Liver metastasis-selective genes were identified by significance analysis of microarray (SAM) analyses and independently validated in external datasets. Finally, the prognostic relevance of the liver metastasis-selective genes in primary breast cancer was tested.


RESULTS
Liver relapse was associated with estrogen receptor (ER) expression (P = 0.002), luminal B subtype (P = 0.01), and was prognostic for an inferior postrelapse survival (P = 0.01). The major variation in the transcriptional landscape of metastases was also associated with ER expression and molecular subtype. However, liver metastases displayed unique transcriptional fingerprints, characterized by downregulation of extracellular matrix (i.e., stromal) genes. Importantly, we identified a 17-gene liver metastasis-selective signature, which was significantly and independently prognostic for shorter relapse-free (P < 0.001) and overall (P = 0.001) survival in ER-positive tumors. Remarkably, this signature remained independently prognostic for shorter relapse-free survival (P = 0.001) among luminal A tumors.


CONCLUSIONS
Extracellular matrix (stromal) genes can be used to partition breast cancer by site of relapse and may be used to further refine prognostication in ER positive primary breast cancer.
Division of Oncology and Pathology, Department of Clinical Sciences, Lund, Lund University, Sweden. CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
Siker
S
Kimbung
Division of Oncology and Pathology, Department of Clinical Sciences, Lund, Lund University, Sweden. CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
Ida
I
Johansson
Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Anna
A
Danielsson
Division of Oncology and Pathology, Department of Clinical Sciences, Lund, Lund University, Sweden. CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
Srinivas
S
Veerla
Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Sweden.
Suzanne
S
Egyhazi Brage
Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Sweden.
Marianne
M
Frostvik Stolt
Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Sweden.
Lambert
L
Skoog
Department of Oncology, Sundsvall Hospital, Sundsvall, Sweden.
Lena
L
Carlsson
Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Zakaria
Z
Einbeigi
Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Sweden.
Elisabet
E
Lidbrink
Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Barbro
B
Linderholm
Department of Oncology, Skåne University Hospital, Lund/Malmö, Sweden.
Niklas
N
Loman
Department of Oncology, Skåne University Hospital, Lund/Malmö, Sweden.
Per-Olof
PO
Malmström
Department of Oncology, Skåne University Hospital, Lund/Malmö, Sweden.
Martin
M
Söderberg
Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden.
Thomas M
TM
Walz
Division of Oncology and Pathology, Department of Clinical Sciences, Lund, Lund University, Sweden.
Mårten
M
Fernö
Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Sweden.
Thomas
T
Hatschek
Division of Oncology and Pathology, Department of Clinical Sciences, Lund, Lund University, Sweden. CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden. Ingrid.Hedenfalk@med.lu.se.
Ingrid
I
Hedenfalk
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D017326:Clinical Trials, Phase III as Topic; D016000:Cluster Analysis; D015331:Cohort Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000556:secondary*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D063868:Patient Outcome Assessment; D011379:Prognosis; D016032:Randomized Controlled Trials as Topic; D059467:Transcriptome
D014408:Biomarkers, Tumor