Cytokeratin 5/6 fingerprinting in HER2-positive tumors identifies a poor prognosis and trastuzumab-resistant Basal-HER2 subtype of breast cancer

// Begona Martin-Castillo 1, 2 , Eugeni Lopez-Bonet 2, 3 , Maria Buxo 2, 4, 5 , Joan Dorca 6 , Francesc Tuca-Rodriguez 7 , Miguel Alonso Ruano 7 , Ramon Colomer 8, 9 , Javier A. Menendez 2, 10 1 Unit of Clinical Research, Catalan Institute of Oncology, Girona, Catalonia, Spain 2 Girona Biomedical Research Institute (IDIBGI), Molecular Oncology Group, Girona, Catalonia, Spain 3 Department of Anatomical Pathology, Dr. Josep Trueta Hospital of Girona, Girona, Catalonia, Spain 4 Epidemiology Unit and Cancer Registry of Girona (UERCG), Catalan Cancer Plan, Catalan Health Government, Girona, Catalonia, Spain 5 Department of Nursing, Universitat de Girona (UdG), Girona, Catalonia, Spain 6 Medical Oncology Department, Catalan Institute of Oncology, Girona, Catalonia, Spain 7 Department of Gynecology, Dr. Josep Trueta Hospital of Girona, Girona, Catalonia, Spain 8 Breast Cancer Clinical Research Unit, CNIO-Spanish National Cancer Research Center, Madrid, Spain 9 Medical Oncology Department, Hospital La Princesa, Madrid, Spain 10 Translational Research Laboratory, Catalan Institute of Oncology (ICO), Girona, Catalonia, Spain Correspondence to: Javier A. Menendez, e-mail: jmenendez@iconcologia.net , jmenendez@idibgi.org Keywords: Breast cancer, HER2, basal-like, trastuzumab, cytokeratins Received: December 22, 2014      Accepted: January 08, 2015      Published: January 29, 2015 ABSTRACT There is an urgent need to refine the prognostic taxonomy of HER2+ breast carcinomas and develop easy-to-use, clinic-based prediction algorithms to distinguish between good- and poor- responders to trastuzumab-based therapy. Building on earlier studies suggesting that HER2+ tumors enriched with molecular and morpho-immunohistochemical features classically ascribed to basal-like tumors are highly aggressive and refractory to trastuzumab, we investigated the prognostic and predictive value of the basal-HER2+ phenotype in HER2-overexpressing tumors. Our retrospective cohort study of a consecutive series of 152 HER2+ primary invasive ductal breast carcinomas first confirmed the existence of a distinct subgroup co-expressing HER2 protein and basal cytokeratin markers CK5/6, the so-called basal-HER2+ phenotype. Basal-HER2+ phenotype (≥10% of cells showing positive CK5/6 staining), but not estrogen receptor status, was significantly associated with inferior overall survival by univariate analysis and predicted worsened disease free survival after accounting for strong prognostic variables such as tumor size at diagnosis in stepwise multivariate analysis. In the sub-cohort of HER2+ patients treated with trastuzumab-based adjuvant/neoadjuvant therapy, basal-HER2+ phenotype was found to be the sole independent prognostic marker for a significantly inferior time to treatment failure in multivariate analysis. A CK5/6-based immunohistochemical fingerprint may provide a simple, rapid, and accurate method for re-classifying women diagnosed with HER2+ breast cancer in a manner that can improve prognosis and therapeutic planning in patients with clinically aggressive basal-HER2+ tumors who are not likely to benefit from trastuzumab-based therapy.