3511 Background: The PI3K/Akt/mTOR pathway is found dysregulated in multiple tumours, including breast cancer (BC). RAD001 is a recently developed drug which blocks mTOR. To study this compound’s anti-tumour effect and interactions with the aforementioned pathway, we set up a translational research program which integrates basic and clinical research data. Methods: The preclinal studies performed in BC cell lines and xenografts included the use of proliferation assays, western blot (WB), small interfering RNA and immunohistochemistry (IHC) analysis. The clinical studies consisted in a phase I study with escalating doses and collection of tumour biospies at different time points Results: Our first achievement was validating the antibodies used in WB and IHC and directed towards different components of the PI3K/Akt/mTOR pathway. We first reported that sensitivity to RAD001 correlated to basal levels of p-Akt. We then observed that RAD001 inhibits mTOR downstream, pS6 and eIF4G, but increases the levels of p-Akt, both in vitro and in patients’tumour biopsies. We demonstrated that knock down of the pS6 kinase mimics the effect of RAD001. Indeed, by combining the PI3K inhibitors and the genomic approch of p85 dominant negative vector, we demonstrated that RAD001 induced p-Akt is through PI3K. Besides the p-Akt induction we also found a RAD001 induction of IRS-1, the pivot mediator of the Insulin like Growth factor-1 Receptor (IGF-1R). We reported that RAD001 resulted in a prolonged activation of IRS-1 and in a sustained association with the p85 subunit of PI3K. Thus RAD001 disrupts an inhibitory mechanism impinging on the PI3K signalling, resulting in sustained activation of the IGF-1R pathway. Accordingly we demonstrated that combination of RAD001 with coumpounds directed against the IGF-1R, i.e. both IGF-1R tyrosine kinase inhibitors and monoclonal antibodies, prevented RAD001 induced p-Akt and resulted in a supradditive growth inhibitory effects both in vitro and in MCF-7 human BC derived xenografts.We are now conducting a phase I study with a monoclonal antibody directed at the IGF-1R that blocks IGF-1R signalling. Conclusions: Dual inhibition of mTOR and IGF-1R completely blocks the PI3K/Akt/mTOR pathway and provide a mechanistic-based combined approach. Clinical studies in BC patients are being planned. No significant financial relationships to disclose.

RESUMENFundamento: La prevalencia total de cáncer oscila entre un 2 y un 3% de la población. Algunos datos sugieren diferencias en función del medio urbano o rural, de otros factores geográficos, y en el entorno de las centrales nucleares. El objetivo de este trabajo es conocer dichas prevalencias y su distribución en las diferentes zonas geográficas del Area de Salud de Guadalajara.Métodos: Estudio de prevalencia de punto, en 1999, mediante revisión sistemática de casos en fuentes primarias y secundarias del Area de Salud de Guadalajara. Se incluyen tumores malignos invasivos en mayores de 14 años. Se analiza la distribución general y específica en función del lugar de residencia, comarca, y proximidad a las centrales nucleares. Se calculan prevalencias crudas y ajustadas/100.000 h y razón de prevalencia con IC al 95%.Resultados: Se detectaron 2.717 casos (prevalencia cruda: 2034,6/10 5 ), repartidos al 50% entre el medio urbano y el rural. La prevalencia ajustada (a población mundial) es de 1295,2/10 5 , mayor en el medio urbano (1479,9/10 5 ) que en el rural (1136,3/10 5 ). En relación con las comarcas geográficas únicamente el cáncer de tiroides es más prevalente en mujeres en las zonas más deprimidas y montañosas, si bien con baja casuística.Conclusiones: Las prevalencias de cáncer encontradas son similares a las publicadas y, tras ajuste por edad, son mayores en el medio urbano que en el rural. Las diferencias entre comarcas se relacionan con las características demográficas, geográficas y el carácter urbano.Palabras clave: Neoplasias. Prevalencia. Registros médicos orientados a problemas. Hábitat. Reactores Nucleares. Atención Primaria de Salud. ABSTRACT Cancer Prevalence and GeographicalDistribution in the Guadalajara Healthcare District, SpainBackground: The total cancer prevalence falls within the range of 2%-3% of the population. Some data suggests differences in terms of whether the environment is urban or rural, other geographical factors and in the area surrounding nuclear power plants. This study is aimed at ascertaining said prevalences and the distribution thereof in the different geographical areas of the Guadalajara Healthcare District.

Cancer prevalence in adults is slightly above 2%. Once adjusted for age, values are similar to other studies and as expected for our country. The most common tumours are in the digestive apparatus, breast and the genito-urinary system. The man/woman proportion is higher than that described in other studies.

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