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We developed a three-dimensional assay prepared from primary breast cancer tissue and quantified tumor response to tamoxifen therapy. Freshly harvested breast cancer biopsies obtained at the time of curative surgical resection were fragmented and embedded into collagen I cushions. Changes in proliferation, apoptosis and tumor volume in response to tamoxifen treatment were quantified using image analysis software and optical projection tomography. Individual and collective invasion of epithelial cells into the surrounding collagen I was observed over the course of the experiment using phase contrast light microscopy and histopathological methods. Addition of tamoxifen to preparations derived from ER+ tumors demonstrated a range of response as measured by proliferative and apoptotic markers. In keeping with published data, tamoxifen reduced the percentage of apoptotic cells expressing cleaved caspase-3 (p = 0.02, Poisson regression analysis). Tamoxifen also reduced residual epithelial volume in ER+ tumors (p = 0.001, Mann-Whitney test), but not in ER low/- tumors (p = 0.78). Changes in tumor volume, as measured by optical projection tomography, allowed stratification into responsive and non-responsive tumors. The model mirrors observations of breast cancer response and histopathological changes to tamoxifen in neo-adjuvant trials. This assay provides a method of screening a battery of therapeutics against individual cancers, informing subsequent design of neo-adjuvant trials., (Copyright © 2011 Elsevier Ltd. All rights reserved.)