Abstract P5-01-01: Personalized neoadjuvant treatment planning using optical metabolic imaging
Authors: Sharick JT , Walsh AJ , Sanders ME , Kelley MC , Meszoely IM , Hooks MA , Burkard ME , Esbona K , Choudhary A , Skala MC 
Published: February 2018

Currently, there are no reliable methods to optimize treatment regimens for individual breast cancer patients. Oncologists choose drug treatments based on expression levels of tumor cell signaling receptors (i.e. HER2, ER, PR) and other factors, and assess whether the treatment is effective after significant time has passed. Unfortunately, over one third of patients exhibit resistance to their initial treatment, increasing their risk of future metastasis and death. Morbidities from sub-optimal drug regimens could be reduced with a personalized drug screen for breast cancer at the time of diagnosis. With the vast number of therapeutic options available to patients (&gt;50 drugs approved with more on the way), a high-throughput screening technology is needed to accurately evaluate how a patient will respond to these options.

Here we present Optical Metabolic Imaging (OMI) of tumor-derived organoids as a predictive drug screening platform for individual breast cancer patients. Changes in cell metabolism precede changes in tumor volume and thus present an earlier marker of treatment response. OMI is sensitive to these early changes by exploiting the intrinsic fluorescent properties of NAD(P)H and FAD, coenzymes of metabolic reactions. OMI endpoints include the optical redox ratio (the fluorescence intensity of NAD(P)H divided by the fluorescence intensity of FAD), as well as the fluorescence lifetimes of NAD(P)H and FAD. The redox ratio reflects the cellular redox balance, and the fluorescence lifetimes report on the binding activity of these coenzymes. OMI has the unique ability to non-invasively monitor metabolism in living, intact samples on the single-cell level, and can thus quantify heterogeneity in drug response. Changes were quantified at the single-cell level using the OMI Index, a linear combination of the optical redox ratio and the mean NAD(P)H and FAD fluorescence lifetimes. This index was derived using a multivariate analysis of variance and has been shown previously to correlate with treatment response in human cancer cells. OMI also allows for high-throughput screening of potential cancer drugs and drug combinations on patient biopsy samples cultured ex vivo. These samples are grown as organoids in a 3D matrix that mimics the natural tumor environment.

Organoids were successfully generated from core needle biopsies of untreated breast tumors. These organoids were treated with the patient's prescribed neoadjuvant therapy, and early metabolic changes were quantified using OMI. Organoids grew from a variety of untreated breast tumor subtypes, and early metabolic changes could be resolved at the single-cell level after only 24 hours of treatment in vitro. In parallel, each patient's Residual Cancer Burden (RCB) score was quantified by a surgical pathologist after neoadjuvant treatment and served as gold standard validation of tumor drug response. Results from an early cohort of patients suggest that OMI could be used to predict patient clinical response to therapy. A linear combination of OMI variables measured in vitro in only 48 hours correlated strongly with patient RCB score (Pearson correlation coefficient=0.97, n=5). This methodology could allow oncologists to determine the ideal treatment regimen for their patients at the time of diagnosis.

Citation Format: Sharick JT, Walsh AJ, Sanders ME, Kelley MC, Meszoely IM, Hooks MA, Burkard ME, Esbona K, Choudhary A, Skala MC. Personalized neoadjuvant treatment planning using optical metabolic imaging [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-01-01.