1Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institutet and University Hospital, Stockholm, Sweden2Department of Genetics and Pathology, Lineberger Comprehensive Cancer Center, University of North Carolina-Chapel Hill, Chapel Hill, USA3Department of Oncology, Sundsvall General Hospital, Sundsvall4Department of Oncology, Sahlgrenska University Hospital, Gothenburg5Department of Oncology, Skåne University Hospital, Lund6Department of Oncology, Skåne University Hospital, Helsingborg7Division of Oncology, Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping8Department of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden9Department of Surgery, University of California at San Francisco (UCSF), San Francisco, USA10Department of Biosciences and Nutrition, Karolinska Institutet and University Hospital, Stockholm, Sweden
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BackgroundWe and others have recently shown that tumor characteristics are altered throughout tumor progression. These findings emphasize the need for re-examination of tumor characteristics at relapse and have led to recommendations from ESMO and the Swedish Breast Cancer group. Here, we aim to determine whether tumor characteristics and molecular subtypes in breast cancer metastases confer clinically relevant prognostic information for patients.Patients and methodsThe translational aspect of the Swedish multicenter randomized trial called TEX included 111 patients with at least one biopsy from a morphologically confirmed locoregional or distant breast cancer metastasis diagnosed from December 2002 until June 2007. All patients had detailed clinical information, complete follow-up, and metastasis gene expression information (Affymetrix array GPL10379). We assessed the previously published gene expression modules describing biological processes [proliferation, apoptosis, human epidermal receptor 2 (HER2) and estrogen (ER) signaling, tumor invasion, immune response, and angiogenesis] and pathways (Ras, MAPK, PTEN, AKT-MTOR, PI3KCA, IGF1, Src, Myc, E2F3, and β-catenin) and the intrinsic subtypes (PAM50). Furthermore, by contrasting genes expressed in the metastases in relation to survival, we derived a poor metastasis survival signature.ResultsA significant reduction in post-relapse breast cancer-specific survival was associated with low-ER receptor signaling and apoptosis gene module scores, and high AKT-MTOR, Ras, and β-catenin module scores. Similarly, intrinsic subtyping of the metastases provided statistically significant post-relapse survival information with the worst survival outcome in the basal-like [hazard ratio (HR) 3.7; 95% confidence interval (CI) 1.3–10.9] and HER2-enriched (HR 4.4; 95% CI 1.5–12.8) subtypes compared with the luminal A subtype. Overall, 25% of the metastases were basal-like, 32% HER2-enriched, 10% luminal A, 28% luminal B, and 5% normal-like.ConclusionsWe show that tumor characteristics and molecular subtypes of breast cancer metastases significantly influence post-relapse patient survival, emphasizing that molecular investigations at relapse provide prognostic and clinically relevant information.ClinicalTrials.govThis is the translational part of the Swedish multicenter and randomized trial TEX, clinicaltrials.gov identifier nct01433614 (http://www.clinicaltrials.gov/ct2/show/nct01433614).