title: Contrasting breast cancer molecular subtypes across serial tumor progression stages: biological and prognostic implications.
abstract: 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.
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.|CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Siker
authors.initials: S
authors.lastname: Kimbung
authors.affiliation: Department of Clinical Pathology and Cytology, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Anikó
authors.initials: A
authors.lastname: Kovács
authors.affiliation: Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Danielsson
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Pär-Ola
authors.initials: PO
authors.lastname: Bendahl
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Lövgren
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Sweden.
authors.forename: Marianne
authors.initials: M
authors.lastname: Frostvik Stolt
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Sweden.
authors.forename: Nicholas P
authors.initials: NP
authors.lastname: Tobin
authors.affiliation: Department of Surgery, University of California at San Francisco (UCSF), San Francisco, CA, USA.|Department of Biosciences and Nutrition, Karolinska Institutet and University Hospital, Solna, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Lindström
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Bergh
authors.affiliation: Department of Oncology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Zakaria
authors.initials: Z
authors.lastname: Einbeigi
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Mårten
authors.initials: M
authors.lastname: Fernö
authors.affiliation: Department of Oncology and Pathology, Karolinska Institutet and Karolinska University Hospital, Sweden.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hatschek
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences, Lund University, Lund, Sweden.|CREATE Health Strategic Center for Translational Cancer Research, Lund University, Lund, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hedenfalk
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D001943:Breast Neoplasms / Q000145:classification / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D016019:Survival Analysis; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor
keywords: biomarker conversion; estrogen receptor; metastatic breast cancer; molecular subtype; post recurrence mortality