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Molecular Subtyping of Breast Cancer from Traditional Tumor Marker Profiles Using Parallel Clustering Methods

Authors' Affiliations: ¹ Unit of Medical Statistics and Biometry, National Cancer Institute of Milano, ² Institute of Medical Statistics and Biometry, University of Milano, Milan, ³ Institute of Pathology, University of Ferrara, Ferrara, and ⁴ Unit of Cancer Pathology, Department of Oncology and Neurosciences and "G. d'Annunzio" Foundation of the University of Chieti, Chieti, Italy

Requests for reprints: Federico Ambrogi, Unità di Statistica Medica e Biometria, Istituto Nazionale per lo Studio e la Cura dei Tumori, via Venezian 1, 20133 Milan, Italy. Phone: 39-2-2390-3282; Fax: 39-2-5032-0866; E-mail: federico.ambrogi{at}istitutotumori.mi.it.

Purpose: Recent small-sized genomic studies on the identification of breast cancer bioprofiles have led to profoundly dishomogeneous results. Thus, we sought to identify distinct tumor profiles with possible clinical relevance based on clusters of immunohistochemical molecular markers measured on a large, single institution, case series.

Experimental Design: Tumor biological profiles were explored on 633 archival tissue samples analyzed by immunohistochemistry. Five validated markers were considered, i.e., estrogen receptors (ER), progesterone receptors (PR), Ki-67/MIB1 as a proliferation marker, HER2/NEU, and p53 in their original scale of measurement. The results obtained were analyzed by three different clustering algorithms. Four different indices were then used to select the different profiles (number of clusters).

Results: The best classification was obtained creating four clusters. Notably, three clusters were identified according to low, intermediate, and high ER/PR levels. A further subdivision in two biologically distinct subtypes was determined by the presence/absence of HER2/NEU and of p53. As expected, the cluster with high ER/PR levels was characterized by a much better prognosis and response to hormone therapy compared to that with the lowest ER/PR values. Notably, the cluster characterized by high HER2/NEU levels showed intermediate prognosis, but a rather poor response to hormone therapy.

Conclusions: Our results show the possibility of profiling breast cancers by means of traditional markers, and have novel clinical implications on the definition of the prognosis of cancer patients. These findings support the existence of a tumor subtype that responds poorly to hormone therapy, characterized by HER2/NEU overexpression.

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