Contrasting breast cancer molecular subtypes across serial tumor progression stages: biological and prognostic implications
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Siker Kimbung1,2, Anikó Kovács3, Anna Danielsson4, Pär-Ola Bendahl1, Kristina Lövgren1, Marianne Frostvik Stolt5, Nicholas P. Tobin5, Linda Lindström6,7, Jonas Bergh5, Zakaria Einbeigi4, Mårten Fernö1, Thomas Hatschek5, Ingrid Hedenfalk1,2
1Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden
2CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden
3Department of Clinical Pathology and Cytology, Sahlgrenska University Hospital, Gothenburg, Sweden
4Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
5Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Sweden
6Department of Surgery, University of California at San Francisco (UCSF), San Francisco, CA, USA
7Department of Biosciences and Nutrition, Karolinska Institutet and University Hospital, Solna, Sweden
Ingrid Hedenfalk, e-mail: [email protected]
Keywords: metastatic breast cancer, estrogen receptor, molecular subtype, biomarker conversion, post recurrence mortality
Received: June 12, 2015 Accepted: August 28, 2015 Published: September 08, 2015
The relevance of the intrinsic subtypes for clinical management of metastatic breast cancer is not comprehensively established. We aimed to evaluate the prevalence and prognostic significance of drifts in tumor molecular subtypes during breast cancer progression. A well-annotated cohort of 304 women with advanced breast cancer was studied. Tissue microarrays of primary tumors and synchronous lymph node metastases were constructed. Conventional biomarkers were centrally assessed and molecular subtypes were assigned following the 2013 St Gallen guidelines. Fine-needle aspirates of asynchronous metastases were transcriptionally profiled and subtyped using PAM50. Discordant expression of individual biomarkers and molecular subtypes was observed during tumor progression. Primary luminal-like tumors were relatively unstable, frequently adopting a more aggressive subtype in the metastases. Notably, loss of ER expression and a luminal to non-luminal subtype conversion was associated with an inferior post-recurrence survival. In addition, ER and molecular subtype assessed at all tumor progression stages were independent prognostic factors for post-recurrence breast cancer mortality in multivariable analyses. Our results demonstrate that drifts in tumor molecular subtypes may occur during tumor progression, conferring adverse consequences on outcome following breast cancer relapse.
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