Abstract 5293: Redox imaging biomarkers for breast cancer diagnosis/prognosis: a pilot study
Authors: Xu He N. , Tchou Julia , Feng Min , Zhao Huaqing , Sun Nannan , Zhang Sophia , Moon Lily , Li Lin Z. 
Published: August 2015

Metastasis accounts for 90% of cancer death and there are no reliable clinical biomarkers predicting metastatic risk. Our studies using preclinical models have shown that tumors with higher propensity for metastasis have distinct metabolic profiles. We aim to evaluate the prognostic value of several optical metabolic imaging biomarkers as previously demonstrated by our group to have diagnostic/prognostic potential in mouse tumor models. As a pilot study, we have successfully employed the 3D cryogenic NADH/oxidized flavoproteins (Fp) fluorescence imager (the Chance redox scanner) to imaging the breast tissue core biopsies of 16 breast cancer patients. We found that the redox indices (including Fp, NADH, Fp/(NADH+Fp), NADH/Fp, and their standard deviations) could readily differentiate cancer from non-cancer and the cancerous tissues were more oxidized and more heterogeneous. To test the prognostic power of this technique, we acquired the frozen breast tumor tissue collected at the time of the patient's primary breast cancer surgery (n = 29) selected from a fully annotated breast tumor tissue bank. The clinical breast cancer subtypes in our cohort (65% ER+/PR+ (luminal A), 20% TNBC, 15% Her2+ (including both luminal B and Her2+)) follow the expected distribution. Of the 29 patients, six of them have developed metastatic disease (MET) while the remaining patients have no evidence of disease (NED) at the time of study. Three to four tissue sections (spacing 100-200 μm) of each specimen were scanned with the Chance redox scanner. Comparison of redox indices between MET and NED, calculated by averaging indices globally, demonstrated no significant differences. However, as the redox state was heterogeneous within the tumor tissue, we developed heterogeneity-associated mitochondrial redox indices (HAMRI) based on the observed intra-specimen redox heterogeneity. By fitting the histogram of the Fp redox ratio, Fp/(NADH+Fp) for each of the image sections with 2-4 Gaussian functions, whereby each Gaussian curve represented a subpopulation of image pixels with a unique averaged redox ratio, we identified the most reduced (the smallest Fp redox ratio - br) and the most oxidized (the largest Fp redox ratio - bo) redox ratios for each patient (br&lt; bo). HAMRI indices were then derived for each patient's tumor sample and were statistically tested for their prognostic power. Our results from this pilot study showed that HAMRI is a strong predictor of MET (sensitivity 83%, specificity 88%, AUC = 0.93, p = 0.01), more robust than conventional prognostic factors (e.g. tumor grade, size, molecular types, nodal status). HAMRI indices also predicted the nodal status in our cohort. Our findings suggest that our quantitative redox scanning technique has prognostic value and warrants further investigation.

Citation Format: He N. Xu, Julia Tchou, Min Feng, Huaqing Zhao, Nannan Sun, Sophia Zhang, Lily Moon, Lin Z. Li. Redox imaging biomarkers for breast cancer diagnosis/prognosis: a pilot study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5293. doi:10.1158/1538-7445.AM2015-5293