Metabolic Imaging Biomarker kio Discriminates Breast Tumor Therapy Time-Courses
Wei Huang1,2, Alina Tudorica3, Karen Y. Oh3, Stephen Y-C. Chui2,4, Nicole Roy3, Megan L. Troxell2,5, Arpana Naik2,6, Kathleen A. Kemmer4, Yiyi Chen2,7, Megan L. Holtorf2, Aneela Afzal1, Xin Li1, and Charles S. Springer, Jr.1

1Advanced Imaging Research Center, Oregon Health & Science University, Portland, OR, United States, 2Knight Cancer Institute, Oregon Health & Science University, Portland, OR, United States, 3Diagnostic Radiology, Oregon Health & Science University, Portland, OR, United States, 4Medical Oncology, Oregon Health & Science University, Portland, OR, United States, 5Pathology, Oregon Health & Science University, Portland, OR, United States, 6Surgical Oncology, Oregon Health & Science University, Portland, OR, United States, 7Public Health and Preventive Medicine, Oregon Health & Science University, Portland, OR, United States

Synopsis

The new DCE-MRI biomarker kio measures on-going vital metabolic activity. For subjects with biopsy-proven breast IDC, it monitors the course of neoadjuvant therapy. While kio decreases for most tumors, for a sub-set it increases during therapy.

Introduction

Shutter-speed [SS] [Dynamic-Contrast-Enhanced] DCE-MRI gives the unidirectional equilibrium cellular water efflux rate constant, kio, which seems to vary with cell membrane ion pump Na+,K+-ATPase homeostatic turnover.1 We determined whole tumor averaged kio 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 kio time‑courses vary.

Methods

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 finv [post-NACT, pathology-determined, tumor volume fraction of invasive cells] values: 0 %, 1 ‑ 10 %, and > 10 %.

Results

Figure 1 shows a pre-NACT axial T1-weighted DCE image slice for one subject with a kio parametric map of the right mammary gland. A lateral tumor just anterior to an implant is quite conspicuous, with kio elevated above most of the normal-appearing gland. [The serpentine high-kio gland areas correlate with hypo‑intense DCE-MR image regions: in adipose-rich loci, fat-saturation artifactually elevates kio.] There is kio 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 kio map of an individual who goes on to complete response [pCR; finv = 0 %]; a particularly cancer-rich slice. The greatest kio activity pre-NACT (2b) is mostly on the lateral anterior tumor rim. Fig. 2e shows the kio 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 kio activity pre-NACT is the most diminished after the first NACT session. Elsewhere, we report a positive correlation between in vivo tumor kio and pathology-determined finv. For each subject, we averaged the mean intracellular water lifetime, taui [from the SS analysis], over all tumor voxels in all slices showing the lesion. We calculated <kio>tum as 1/<taui>tum. [For a non-normal taui distribution, this is not strictly true:1 but the effect is small.] We determined <kio>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 <kio>tum values averaged over the n sub-group subjects, <<kio>tum>n. For the five tumors (all grade 2) that would go on to finv = 0%, the <<kio>tum>n value decreased continually from 2.1 s-1. Surprisingly, for the six tumors (five grade 3) that would go on to finv > 10%, the <<kio>tum>n value increased continually (during therapy) to eventually reach 2.4 s-1. For the finv = 1 – 10% category, kio goes through a maximum during the therapy. The time-courses are plotted in Figure 4 (red for finv = 0 %; black for finv > 10 %).

Discussion

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 kio. 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 kio > 2 s-1) for effective cytotoxicity. The results shown in Fig. 2b,e support this. Perhaps elevated kio indicates anabolic (cell proliferation) in addition to catabolic activity. For the finv = 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 finv > 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 kio can be an important monitoring imaging biomarker not only during therapy, but even before therapy.

Acknowledgements

Grant Support: NIH: UO1-CA154602; R44 CA180425.

References

1. Springer, Li, Tudorica, Oh, Roy, Chui, Naik, Holtorf, Afzal, Rooney, Huang, NMRB 27:760-773 (2014). 2. Li, Priest, Woodward, Siddiqui, Beer, Garzotto, Rooney, Springer, JMR 218:77-85 (2012). 3. Accardi, Science 349:789-790 (2015).

Figures

A pre-therapy axial T1-weighted image of a subject who went on to be a non-complete responder [non-pCR]. A kio parametric map is displayed for the right mammary gland. An invasive ductal carcinoma (proven by biopsy), just anterior to an implant, is conspicuous for its elevated kio values.

Zoomed tumor parametric maps for a pCR subject; top row before NACT, bottom after only the first NACT session (17 days). Regions with greatest kio before (2b) have the greatest reduction after (2e). The other parameters are: Ktrans [the contrast agent extravasation transfer constant] and vi [the intracellular volume fraction].

Whole tumor averaged kio values, <kio>tum, further averaged over the subjects within the finv = 0 %, 1 – 10 %, and > 10 % sub-groups, are tabulated before, during, and after a complete neoadjuvant chemotherapy [NACT] course.

The time-courses of the Fig. 3 data are plotted. <<kio>tum>n decreases during therapy for the finv = 0 % category (red) and, surprisingly, increases for the finv > 10 % category (black).



Proc. Intl. Soc. Mag. Reson. Med. 24 (2016)
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