Methods, systems, and related computer program products for computer-aided detection (CAD) of anatomical abnormalities in a breast volume based on a plurality of two-dimensional x-ray tomosynthesis projection images thereof is described. Each projection image is processed according to at least one predetermined feature extraction algorithm to generate at least one projection feature array corresponding thereto. For each of the at least one predetermined features extracted, the plurality of corresponding projection feature arrays is backprojected according to a predetermined tomosynthesis reconstruction algorithm to form a plurality of two-dimensional tomosynthesis reconstructed feature arrays. Each pixel in the three-dimensional breast geometry is then individually classified as being either a pixel of interest, or not a pixel of interest, based upon the at least one tomosynthesis reconstructed feature array value corresponding to that pixel. CAD detections for the breast volume are then generated based on the identified pixels of interest.