Background: The NeoALTTO study demonstrated a significantly higher breast pathological complete response (pCR) rate (NSABP definition – ypT0/is) with dual HER2 blockade using lapatinib and trastuzumab compared with single HER2 blockade using either lapatinib or trastuzumab (51.3% vs. 24.7% vs. 29.5%, respectively; p< 0.01 for both) in HER2 positive primary breast cancer (BC). A similar pattern was seen for locoregional pCR (ypT0/is ypN0) (Baselga J et al. Lancet 2012). Material and Methods: From January, 2008, to December, 2009, 455 patients were randomized from 99 participating sites in 23 countries. Patients were randomized to receive either lapatinib 1500 mg/d (154 pts), or trastuzumab 4 mg/kg IV loading dose followed by 2 mg/kg IV weekly (149 pts), or lapatinib 1000 mg/d with trastuzumab for a total of 6 weeks (152 pts). After this biological window, patients continued on the same targeted therapy plus weekly paclitaxel 80 mg/m2 for a further 12 weeks, until definitive surgery (total neoadjuvant therapy duration of 18 weeks). After surgery, patients received 3 cycles of adjuvant FEC followed by the same targeted therapy as in the biological window of the neoadjuvant phase for a further 34 weeks (to complete 52 weeks of anti-HER2 therapy), with on-going follow-up planned until 10 years after last randomised patient. Secondary objectives included disease-free survival and overall survival (OS). Following current practice and draft FDA recommendations for neoadjuvant trial endpoints, an amendment was made to the protocol secondary objectives (released in May 2013). DFS (from surgery) was replaced by event-free survival (EFS) from randomisation; OS from surgery was correspondingly replaced with OS from randomisation, and examination of the association between these survival endpoints and locoregional pCR (ypT0/is ypN0) was added as a secondary objective. EFS was defined as the time from randomization to first EFS event (breast cancer relapse, second primary malignancy or death without recurrence). OS was defined as the time from randomization to death from any cause. Results: The clinical cut-off date for the first planned analysis of these secondary objectives was on 26 May 2013, three years after the date of last surgery. Data cleaning is ongoing and analysis will be completed by November 2013. Results for EFS, OS and their association with pCR will be presented at the meeting. Funding: GlaxoSmithKline is the sponsor of this trial. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S1-01.

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Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): CATCH ME Foundation Leducq BACKGROUND In cardiac myocytes, desmosomal proteins and ion channels form macromolecular complexes important for maintaining cell adhesion and electrical integrity. High serum levels of androgenic anabolic steroids (AAS) promote cardiac muscle growth, but any detrimental impact on atrial gene transcription and/or electrophysiological function is unknown. PURPOSE To investigate the effects of chronic AAS exposure on atria in a mouse model with desmosomal impairment. METHODS Young (8-10 week) male wild-type (WT) and heterozygous plakoglobin-deficient (plako+/-) mice were challenged with the AAS dihydrotestosterone (DHT) or placebo for 6 weeks by osmotic mini pumps. RNA sequencing (n = 3-6 atria/group) revealed effects of genotype and DHT on left atrial (LA) transcription. Membrane-localised cardiac sodium channels (Nav1.5) were visualised using direct STochastic Optical Reconstruction Microscopy (dSTORM, n = 5-11 LA/group, 122 cells in total) and clustering of individual molecules was quantified using persistence-based clustering. Patch clamping of LA cardiac myocytes was used to record whole cell sodium currents (n = 4-5 LA/group, 77 cells in total). LA action potentials and conduction velocity were evaluated using microelectrode and optical mapping techniques (n = 5-9 LA/group). RESULTS DHT increased expression of pro-hypertrophic transcripts, e.g. Igf1, Mtpn, fibrosis-associated transcripts, e.g. Col1a1, Col3a1, Lox and pro-inflammatory transcripts, e.g. Ccl6, C7, in both WT and plako+/- LA. Despite Scn5a transcript levels being maintained, dSTORM identified a 29% reduction (p = 0.042) in the number of Nav1.5 localisations at the membrane of plako+/- DHT LA cardiomyocytes, and 25% fewer localisations (p = 0.005) were found within Nav1.5 clusters, compared to WT DHT. Electrophysiological methods revealed a significant reduction in peak sodium current density, decreased action potential amplitude and conduction slowing in plako+/- LA after exposure to DHT. CONCLUSION This data suggests that a reduction in plakoglobin expression predisposes atrial cardiomyocytes to detrimental electrophysiological effects of high testosterone levels. This is characterised by a perturbed spatial organisation of Nav1.5, decreased sodium current density and conduction slowing. Abstract Figure. Abstract Picture