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The METTEN study assessed the efficacy, tolerability, and safety of adding metformin to neoadjuvant chemotherapy plus trastuzumab in early HER2-positive breast cancer (BC). Women with primary, non-metastatic HER2-positive BC were randomized (1:1) to receive metformin (850 mg twice-daily) for 24 weeks concurrently with 12 cycles of weekly paclitaxel plus trastuzumab, followed by four cycles of 3-weekly FE75C plus trastuzumab (arm A), or equivalent regimen without metformin (arm B), followed by surgery. Primary endpoint was the rate of pathological complete response (pCR) in the per-protocol efficacy population. pCR rate was numerically higher in the metformin-containing arm A (19 of 29 patients [65.5%, 95% CI: 47.3–80.1]) than in arm B (17 of 29 patients [58.6%, 95% CI: 40.7–74.5]; OR 1.34 [95% CI: 0.46–3.89], P = 0.589). The rate of breast-conserving surgery was 79.3% and 58.6% in arm A and B (P = 0.089), respectively. Blood metformin concentrations (6.2 μmol/L, 95% CI: 3.6–8.8) were within the therapeutic range. Seventy-six percent of patients completed the metformin-containing regimen; 13% of patients in arm A dropped out because of metformin-related gastrointestinal symptoms. The most common adverse events (AEs) of grade ≥3 were neutropenia in both arms and diarrhea in arm A. None of the serious AEs was deemed to be metformin-related. Addition of anti-diabetic doses of metformin to a complex neoadjuvant regimen was well tolerated and safe. Because the study was underpowered relative to its primary endpoint, the efficacy data should be interpreted with caution.

Clinically HER2+ (cHER2+) breast cancer (BC) can no longer be considered a single BC disease entity in terms of trastuzumab responsiveness. Here we propose a framework for predicting the response of cHER2+ to trastuzumab that integrates the molecular distinctions of intrinsic BC subtypes with recent knowledge on cancer stem cell (CSC) biology. First, we consider that two interchangeable populations of epithelial-like, aldehyde dehydrogenase (ALDH)-expressing and mesenchymal-like, CD44+CD24-/low CSCs can be found in significantly different proportions across all intrinsic BC subtypes. Second, we overlap all the intrinsic subtypes across cHER2+ BC to obtain a continuum of mixed phenotypes in which one extreme exhibits a high identity with ALDH+ CSCs and the other extreme exhibits a high preponderance of CD44+CD24-/low CSCs. The differential enrichment of trastuzumab-responsive ALDH+ CSCs versus trastuzumab-refractory CD44+CD24-/low CSCs can explain both the clinical behavior and the primary efficacy of trastuzumab in each molecular subtype of cHER2+ (i.e., HER2-enriched/cHER2+, luminal A/cHER2+, luminal B/cHER2+, basal/cHER2+, and claudin-low/cHER2+). The intrinsic plasticity determining the epigenetic ability of cHER2+ tumors to switch between epithelial and mesenchymal CSC states will vary across the continuum of mixed phenotypes, thus dictating their intratumoral heterogeneity and, hence, their evolutionary response to trastuzumab. Because CD44+CD24-/low mesenchymal-like CSCs distinctively possess a highly endocytic activity, the otherwise irrelevant HER2 can open the door to a type of "Trojan horse" approach by employing antibody-drug conjugates such as T-DM1, which will allow a rapid and CSC-targeted delivery of cytotoxic drugs to therapeutically manage trastuzumab-unresponsive basal/cHER2+ BC. Contrary to the current dichotomous model used clinically, our model proposes that a reclassification of cHER2+ tumors based on the spectrum of molecular BC subtypes might inform on their CSC-determined sensitivity to trastuzumab, thus providing a better delineation of the predictive value of cHER2+ in BC by incorporating CSCs-driven intra-tumor heterogeneity into clinical decisions.

// 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.