Imaging plays a central role in the evaluation of breast tumor response to neoadjuvant chemotherapy. Image-based assessment of tumor change via deformable registration is a powerful, quantitative method potentially to explore novel information of tumor heterogeneity, structure, function, and treatment response. In this study, we continued a previous pilot study to further validate the feasibility of an open source deformable registration algorithm DRAMMS developed within our group as a means to analyze spatiooral tumor changes for a set of 14 patients with DCE-MR imaging. Two experienced breast imaging radiologists marked landmarks according to their anatomical meaning on image sets acquired before and during chemotherapy. Yet, chemotherapy remarkably changed the anatomical structure of both tumor and normal breast tissue, leading to significant discrepancies between both raters for landmarks in certain areas. Therefore, we proposed a novel method to grade the manually denoted landmarks into different challenge levels based on the inter-rater agreement, where a high level indicates significant discrepancies and considerable amounts of anatomical structure changes, which would indeed impose giant problem for the following registration algorithm. It is interesting to observe that DRAMMS performed in a similar manner as the human raters: landmark errors increased as inter-rater differences rose. Among all selected six deformable registration algorithms, DRAMMS achieves the highest overall accuracy, which is around 5.5 mm, while the average difference between human raters is 3 mm. Moreover, DRAMMS performed consistently well within both tumor and normal tissue regions. Lastly, we comprehensively tuned the fundamental parameters of DRAMMS to better understand DRAMMS to guide similar works in the future. Overall, we further validated that DRAMMS is a powerful registration tool to accurately quantify tumor changes and potentially predict early tumor response to chemotherapy. Therefore, future studies that aim at examining if DRAMMS can generate valuable biomarkers for tumor response prediction during chemotherapy become feasible.