Association of HER2/CEP17 ratio with pCR after HER2-directed neoadjuvant treatments in the phase III NeoALTTO trial.

person Christian F. Singer Klinische Abteilung für Allgemeine Gynäkologie und Gynäkologische Onkologie, Comprehensive Cancer Center - Universitätsklinik für Frauenheilkunde Medizinische Universität Wien / AKH, Wien, Vienna, Austria info_outline Christian F. Singer, Franz König, Stephanie Kacerovsky-Strobl, Sabine Danzinger, Christine Brunner, Christoph Suppan, Christine Deutschmann, Marija Balic, Richard Greil, Daniel Egle, Evandro de Azambuja, Serena Di Cosimo, Michael Gnant

Authors person Christian F. Singer Klinische Abteilung für Allgemeine Gynäkologie und Gynäkologische Onkologie, Comprehensive Cancer Center - Universitätsklinik für Frauenheilkunde Medizinische Universität Wien / AKH, Wien, Vienna, Austria info_outline Christian F. Singer, Franz König, Stephanie Kacerovsky-Strobl, Sabine Danzinger, Christine Brunner, Christoph Suppan, Christine Deutschmann, Marija Balic, Richard Greil, Daniel Egle, Evandro de Azambuja, Serena Di Cosimo, Michael Gnant Organizations Klinische Abteilung für Allgemeine Gynäkologie und Gynäkologische Onkologie, Comprehensive Cancer Center - Universitätsklinik für Frauenheilkunde Medizinische Universität Wien / AKH, Wien, Vienna, Austria, Medical University of Vienna, Vienna, Austria, Dept of OB/GYN, Karl Landsteiner Medical University, St. Pölten, Austria, Department of Gynecology and Obstetrics, Medical University of Innsbruck, Innsbruck, Austria, Department of Oncology, Medical University of Graz, Graz, Austria, AKH Wien, Wien, Austria, Medical University Graz, Graz, Austria, Hospital Salzburg Paracelus University, Salzburg, Austria, Medical University of Innsbruck, Innsbruck, Austria, Jules Bordet Institute, Brussels, Belgium, Department of Advanced Diagnostics, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, MI, Italy Abstract Disclosures Research Funding Pharmaceutical/Biotech Company The NeoALTTO trial received financial support from GlaxoSmithKline (until January 2015) and Novartis Pharma AG (as of January 2015). Background: HER2-directed therapies are approved for the treatment of patients with HER2-positive invasive breast cancer as defined by HER2 protein overexpression, or HER2 gene amplification based on HER2/chromosome enumeration probe (CEP17) ratio ≥ 2.2. Above this accepted HER2 status determination, however, it is still unknown whether the efficacy of HER2-directed therapy in early breast cancer increases with increasing HER2/CEP17 ratios. Therefore, the purpose of the presented work is to evaluate whether quantitative assessment of the HER2/CEP17 ratio predicts pathological complete response (pCR) and event-free survival (EFS) of patients treated with neo-adjuvant HER2-based regimen in the prospective phase III NeoALTTO trial. Methods: 455 women with HER2-positive early breast cancer, who had received neo-adjuvant trastuzumab and/or lapatinib for 6 weeks and then together with 12 cycles of weekly paclitaxel were included in this analysis. The HER2/CEP17 ratio in the primary tumor samples was correlated with pCR and survival outcome. Results: The Median HER2/CEP17 ratio in NeoALTTO was 5.1 (range: 1.1 – 100.0), and ratios were not associated with age, hormone receptor status, or any of the other clinicopathological variables analyzed. The log HER2/CEP17 ratio significantly predicted for pCR in both uni-variate (OR: 1.83; 95% CI: 1.11 - 3.01, p = 0.0176) and multivariate analysis (OR: 1.79; 95% CI: 1.07 - 2.99, p = 0.0257). Higher HER2/CEP17 ratios were, however, not associated with improved EFS (adjusted HR = 0.79; p = 0.3537). A pCR prediction model which included HER2/CEP17 ratio, treatment arm, and hormone receptor status improved the predictive strength of treatment arm alone from a ROC AUC value of 0.60 to 0.69. Conclusions: In patients treated with HER2-based neoadjuvant therapy, quantitative analysis of the readily available pre-treatment HER2/CEP17 ratio by FISH is predictive of pCR but not EFS.