Abstract P2-01-01: Evaluating the order of treatments to enhance efficacy in a murine model of triple negative breast cancer with quantitative imaging
Authors: Lu Yun , Massicano Adriana , David Rachel , Sorace Anna 
Published: March 2020

Introduction: The purpose of this study is to determine if order of dosing of combination chemotherapies (paclitaxel, doxorubicin) alters response in triple negative breast cancers (TNBCs). TNBC has limited treatment options and primarily relies on chemotherapy in both primary and metastatic disease. There are a number of clinically utilized regimens of combination chemotherapies and the optimal treatment strategy is still unknown. Thus, there is a need to explore how the order of regimens effects tumor response and optimize treatment efficacy in breast cancer population. Currently, one of the most commonly used regimens for locally advanced TNBCs is administration of doxorubicin (DRB) followed by paclitaxel (PTX). DRB, as a topoisomerase inhibitor, targets both cell cycle stage G1 and S, while PTX only targets cell cycle stage S. Our goal is to evaluate and compare tumor response of the order of dosing of PTX and DRB with quantitative molecular imaging. Advanced molecular imaging provides a noninvasive and highly sensitive approach to identify changes in quantify the early signal of drug response prior tumor size changes.

Experimental Design: MDA-MB-231-FUCCI (Green fluorescence during S, G2, M phase; Red fluorescence during G1 phase) TNBC cells (2 × 106) were subcutaneously injected into nude mice (n = 12) and randomly assigned into three treatment groups: PTX (10 mg/kg)→DRB (10 mg/kg), DRB→PTX (same drug dosage), and saline control. 3’-Deoxy-3’-[18F]fluorothymidine ([18F]-FLT) positron emission tomography (PET)/computed tomography (CT) (SOFIE preclinical PET/CT) was performed before treatment (day 0), and on days 3 and 6. Treatment occurred on days 0 and 3 post imaging. GFP and RFP fluorescence were measured through in vivo imaging system (IVIS) on baseline and on day 6. In vivo cell proliferation was quantifying the percent change from baseline of normalized [18F]-FLT standard uptake value (SUV) (tumor mean/muscle mean) and normalized GFP signal (tumor/muscle). In vivo cell viability was determined by RFP signal percentage change. Statistical significance was evaluated with a t-test.

Results: Cell proliferation and viability assessed through [18F]-FLT PET and fluorescence imaging showed that PTX prior to DRB treatment significantly decreased cancer cell proliferation and viability. From day 0 to 6, overall RFP signal of control increased 14%, while DRB → PTX decreased 36%, and PTX→DRB decreased 50% (p=0.060). Fluorescence imaging showed DRB→PTX treatment GFP signal increase by 3-fold (p=0.029) compared to control, while PTX→DRB treatment is similar to control (p&gt;0.05). 18F-FLT PET SUV revealed from day 0 to 6, control had a 110% increase, DRB→PTX showed 60% increase, while PTX→DRB showed about 10% increase (p=0.010).

Conclusion: PTX prior to DRB significantly improved tumor response to chemotherapy in this TNBC model by decreasing tumor cell viability and proliferation. Molecular imaging allows us to visualize and quantitate these cellular changes prior tumor size changes and may help guide clinical decision making for the treatment for TNBC patients.

We acknowledge the support of ACS RSG-18-006-01-CCE

Citation Format: Yun Lu, Adriana Massicano, Rachel David, Anna Sorace. Evaluating the order of treatments to enhance efficacy in a murine model of triple negative breast cancer with quantitative imaging [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-01-01.