Patient set-up optimization is required in breast-cancer radiotherapy to fill the accuracy gap between personalized treatment planning and uncertainties in the irradiation set-up. Opto-electronic systems allow implementing automatic procedures to minimize the positional mismatches of light-reflecting markers located on the patient surface with respect to a corresponding reference configuration. The same systems are used to detect the position of the irradiated body surface by means of laser spots; patient set-up is then corrected by matching the control points onto a CT based reference model through surface registration algorithms. In this paper, a non-deterministic approach based on Artificial Neural Networks is proposed for the automatic, real-time verification of geometrical set-up of breast irradiation. Unlike iterative surface registration methods, no passive fiducials are used and true real-time performance is obtained. Moreover, the non-deterministic modeling performed by the neural algorithm minimizes sensitivity to intra-fractional and inter-fractional non-rigid motion of the breast. The technique was validated through simulated activities by using reference CT data acquired on four subjects. Results show that the procedure is able to detect and reduce simulated set-up errors and revealed high reliability in patient position correction, even when the surface deformation is included in testing conditions.