Shutter-speed [SS] [Dynamic-Contrast-Enhanced] DCE-MRI gives the unidirectional equilibrium cellular water efflux rate constant, k_io, which seems to vary with cell membrane ion pump Na⁺,K⁺-ATPase homeostatic turnover.¹ We determined whole tumor averaged k_io values for 29 grade 2-3 invasive ductal carcinomas [IDCs] before, during, and after 16-18 weeks of standard-of-care neoadjuvant chemotherapy [NACT]. For sub-groups with different post-surgery pathology outcomes, the k_io time‑courses vary. Twenty-eight consecutive subjects (in a clinical chemotherapy protocol described previously¹) consented to 3T MRI. The 3D bi-lateral DCE acquisitions yielded 96-128 image slices, and temporal resolution 14.6-20.2 s.¹ The nominal voxel dimensions were (0.94-1.1 mm)² x 1.4 mm. The SS analysis assumed a single ¹H₂O signal.^1,2 The three outcome sub-groups had f_inv [post-NACT, pathology-determined, tumor volume fraction of invasive cells] values: 0 %, 1 ‑ 10 %, and > 10 %. Figure 1 shows a pre-NACT axial T₁-weighted DCE image slice for one subject with a k_io parametric map of the right mammary gland. A lateral tumor just anterior to an implant is quite conspicuous, with k_io elevated above most of the normal-appearing gland. [The serpentine high-k_io gland areas correlate with hypo‑intense DCE-MR image regions: in adipose-rich loci, fat-saturation artifactually elevates k_io.] There is k_io heterogeneity within the Fig. 1 tumor: a small core region rises to near 4 s^-1. After therapy and surgery, this tumor was judged a non‑complete responder by the pathologist [non-pCR]. Figure 2 shows a zoomed axial right breast tumor k_io map of an individual who goes on to complete response [pCR; f_inv = 0 %]; a particularly cancer-rich slice. The greatest k_io activity pre-NACT (2b) is mostly on the lateral anterior tumor rim. Fig. 2e shows the k_io map after the first NACT session (17 days). It is not easy to find exactly the same image slice, but it is quite clear that the tumor region showing the greatest k_io activity pre-NACT is the most diminished after the first NACT session. Elsewhere, we report a positive correlation between in vivo tumor k_io and pathology-determined f_inv. For each subject, we averaged the mean intracellular water lifetime, tau_i [from the SS analysis], over all tumor voxels in all slices showing the lesion. We calculated <k_io>_tum as 1/<tau_i>_tum. [For a non-normal tau_i distribution, this is not strictly true:¹ but the effect is small.] We determined <k_io>_tum before, during, and after (but before surgery) complete NACT. Of the 29 tumors [one subject had two], 24 were judged non-pCR after NACT completion: only five were ruled pCRs. The table in Figure 3 shows the <k_io>_tum values averaged over the n sub-group subjects, <<k_io>_tum>_n. For the five tumors (all grade 2) that would go on to f_inv = 0%, the <<k_io>_tum>_n value decreased continually from 2.1 s^-1. Surprisingly, for the six tumors (five grade 3) that would go on to f_inv > 10%, the <<k_io>_tum>_n value increased continually (during therapy) to eventually reach 2.4 s^-1. For the f_inv = 1 – 10% category, k_io goes through a maximum during the therapy. The time-courses are plotted in Figure 4 (red for f_inv = 0 %; black for f_inv > 10 %). Cancer cells exhibit overexpression of ion channels and reduced membrane potential.³ It is sensible this increases Na⁺,K⁺-ATPase turnover (a futile re‑polarization attempt) and elevates k_io. Cytotoxic drugs are intended to disproportionately kill more rapidly metabolizing cells. The Fig. 3,4 results suggest a possible metabolic activity threshold (say, manifest as k_io > 2 s^-1) for effective cytotoxicity. The results shown in Fig. 2b,e support this. Perhaps elevated k_io indicates anabolic (cell proliferation) in addition to catabolic activity. For the f_inv = 1 – 10 % subjects, Fig. 4 may show therapy “taking effect” after 2-3 sessions. However, the behavior of the tumors that would go on to f_inv > 10% was unexpected. If our hypothesis is correct, metabolic activity actually increases during the therapy. If this is true, one should know it as early as possible. It seems that k_io can be an important monitoring imaging biomarker not only during therapy, but even before therapy.