Abstract P6-08-03: Transcriptional profiling of breast cancer metastases identifies liver metastasis-selective genes associated with adverse outcome in luminal A primary breast cancer
Authors: Kimbung Siker , Johansson Ida , Danielsson Anna , Veerla Srinivas , Egyhazi Suzanne , Bergh Jonas , Einbeigi Zakaria , Linderholm Barbro , Lidbrink Elisabet , Loman Niklas , Malmström Per , Söderberg Martin , Walz Thomas M , Fernö Mårten , Hatschek Thomas , Hedenfalk Ingrid ,   the TEX Study Group
Published: May 2015

Background: The site of relapse is associated with the prognosis of metastatic breast cancer, but our understanding of the molecular determinants of organ-specificity of metastasis is incomplete. This study aimed to provide additional insight into the biology of breast cancer liver metastases and to identify liver metastasis-selective genes associated with outcome in primary breast cancer.

Methods: A cohort of 304 women with locally advanced and metastatic breast cancer was studied. Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and Ki67 expression were quantified in primary tumors (N=217) by immunohistochemistry and in situ hybridization on tissue microarrays, and molecular subtypes were assigned according to the 2013 St Gallen guidelines. In addition, fine-needle aspirates of metastases (N=91) were subjected to whole genome transcriptional profiling.

Results: Liver relapse was significantly associated with ER positivity (P&lt;0.002) and the luminal B-like subtype (P&lt;0.01) and was prognostic of an inferior post-relapse survival (P&lt;0.001). Transcriptional profiling revealed that the major variation in the transcriptional landscape of breast cancer metastases was associated with the expression of hormone receptors and the tumor molecular subtype. However, liver metastases displayed unique transcriptional fingerprints, characterized by down-regulation of extracellular matrix (i.e. stromal) genes involved in adhesion and skeletal development. Importantly, we identified a subset of 17 liver metastasis-selective genes that displayed significantly decreased expression in primary tumors of high histological grade (grade 3) and of the luminal B and basal subtypes (P&lt;0.001). This 17-gene signature was significantly and independently prognostic of shorter relapse-free (P =0.001) and overall (P=0.03) survival among patients with ER positive primary tumors. Remarkably, the 17-gene signature remained an independent predictor of shorter relapse-free survival (P=0.004) among patients with luminal A primary tumors.

Conclusion: These results highlight a possible role of stroma-related genes in breast cancer liver metastasis biology and validate the prognostic relevance of extracellular matrix/stromal genes in hormone receptor positive primary breast cancer, specifically of the luminal A subtype.

Citation Format: Siker Kimbung, Ida Johansson, Anna Danielsson, Srinivas Veerla, Suzanne Egyhazi, Jonas Bergh, Zakaria Einbeigi, Barbro Linderholm, Elisabet Lidbrink, Niklas Loman, Per Malmström, Martin Söderberg, Thomas M Walz, Mårten Fernö, Thomas Hatschek, Ingrid Hedenfalk, the TEX Study Group. Transcriptional profiling of breast cancer metastases identifies liver metastasis-selective genes associated with adverse outcome in luminal A primary breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-03.