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Subtypes of Breast Cancer Show Preferential Site of Relapse

¹ Department of Medical Oncology, Erasmus MC, Josephine Nefkens Institute; ² Cancer Genomics Centre, Rotterdam, the Netherlands; and ³ Veridex LLC, a Johnson & Johnson Company, San Diego, California

Requests for reprints: John W.M. Martens, Erasmus MC, Josephine Nefkens Institute, Department of Medical Oncology, Room Be400 P.O. Box 2040, 3000 CA Rotterdam, the Netherlands. Phone: 31-0-10-4088372; Fax: 31-0-10-4088377; E-mail: j.martens{at}erasmusmc.nl.

Key Words: breast cancer • molecular subtypes • site of relapse • metastasis • pathway analysis

We explored whether the five previously reported molecular subtypes in breast cancer show a preference for organ-specific relapse and searched for molecular pathways involved. The "intrinsic" gene list describing the subtypes was used to classify 344 primary breast tumors of lymph node–negative patients. Fisher exact tests were used to determine the association between a tumor subtype and a particular site of distant relapse in these patients who only received local treatment. Modulated genes and pathways were identified in the various groups using Significance Analysis of Microarrays and Global Testing. Bone relapse patients were most abundant in the luminal subtypes but were found less than expected in the basal subtype. The reverse was true for lung and brain relapse patients with the remark that absence of lung relapse was luminal A specific. Finally, a pleura relapse, although rare, was found almost exclusively in both luminal subtypes. Many differentially expressed genes were identified, of which several were in common in a subtype and the site to which the subtype preferentially relapsed. WNT signaling was up-regulated in the basal subtype and in brain-specific relapse, and down-modulated in the luminal B subtype and in bone-specific relapse. Focal adhesion was found up-regulated in the luminal A subtype but down-regulated in lung relapse. The five major molecular subtypes in breast cancer are evidently different with regard to their ability to metastasize to distant organ(s), and share biological features and pathways with their preferred distant metastatic site. [Cancer Res 2008;68(9):3108–14]