[18F]FDG and [18F]FLT PET for the evaluation of response to neo-adjuvant chemotherapy in a model of triple negative breast cancer

RESEARCH ARTICLE [18F]FDG and [18F]FLT PET for the evaluation of response to neo-adjuvant chemotherapy in a model of triple negative breast cancer Isabella Raccagni1,2,3☯, Sara Belloli1,3☯, Silvia Valtorta1,3,4, Alessandro Stefano1, Luca Presotto5, Claudio Pascali6, Anna Bogni6, Monica Tortoreto7, Nadia Zaffaroni7, Maria Grazia Daidone8, Giorgio Russo1, Emilio Bombardieri9‡, Rosa Maria Moresco1,2,3,4‡* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Institute of Molecular Bioimaging and Physiology (IBFM), CNR, Segrate, Italy, 2 Tecnomed, Foundation of the University of Milano-Bicocca, Monza, Italy, 3 Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Milan, Italy, 4 Medicine and Surgery Department, University of Milano-Bicocca, Monza, Italy, 5 Nuclear Medicine Unit, IRCCS San Raffaele Scientific Institute, Milano, Italy, 6 Nuclear Medicine Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 7 Molecular Pharmacology Unit, Experimental Oncology and Molecular Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 8 Biomarkers Unit, Experimental Oncology and Molecular Medicine Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, 9 Nuclear Medicine Department, Humanitas Gavazzeni, Bergamo, Italy ☯ These authors contributed equally to this work. ‡ Joint senior authors. * OPEN ACCESS Citation: Raccagni I, Belloli S, Valtorta S, Stefano A, Presotto L, Pascali C, et al. (2018) [18F]FDG and [18F]FLT PET for the evaluation of response to neoadjuvant chemotherapy in a model of triple negative breast cancer. PLoS ONE 13(5): e0197754. https://doi.org/10.1371/journal. pone.0197754 Editor: Juri G. Gelovani, Wayne State University, UNITED STATES Received: May 30, 2017 Accepted: May 8, 2018 Published: May 23, 2018 Copyright: © 2018 Raccagni et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by AIRC (Associazione Italiana per la Ricerca sul Cancro) Project Molecular and Cellular Imaging of Cancer and by grant 2006 PIO (Programma Integrato Oncologia) under grant agreement N˚: R04/07 from the Italian Ministry of Health. This work was partially supported by the project grant Abstract Rationale Pathological response to neo-adjuvant chemotherapy (NAC) represents a commonly used predictor of survival in triple negative breast cancer (TNBC) and the need to identify markers that predict response to NAC is constantly increasing. Aim of this study was to evaluate the potential usefulness of PET imaging with [18F]FDG and [18F]FLT for the discrimination of TNBC responders to Paclitaxel (PTX) therapy compared to the response assessed by an adapted Response Evaluation Criteria In Solid Tumors (RECIST) criteria based on tumor volume (Tumor Volume Response). Methods Nu/nu mice bearing TNBC lesions of different size were evaluated with [18F]FDG and [18F] FLT PET before and after PTX treatment. SUVmax, Metabolic Tumor Volume (MTV) and Total Lesion Glycolysis (TLG) and Proliferation (TLP) were assessed using a graph-based random walk algorithm. Results We found that in our TNBC model the variation of [18F]FDG and [18F]FLT SUVmax similarly defined tumor response to therapy and that SUVmax variation represented the most accurate parameter. Response evaluation using Tumor Volume Response (TVR) showed that the effectiveness of NAC with PTX was completely independent from lesions size at baseline. PLOS ONE | https://doi.org/10.1371/journal.pone.0197754 May 23, 2018 1 / 14 [18F]FDG and [18F]FLT PET in TNBC “SysBioNet”, a MIUR initiative for the Italian Roadmap of European Strategy Forum on Research Infrastructures (ESFRI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Conclusions Our study provided interesting results in terms of sensitivity and specificity of PET in TNBC, revealing the similar performances of [18F]FDG and [18F]FLT in the identification of responders to Paclitaxel. Competing interests: The authors have declared that no competing interests exist. Introduction Breast cancer (BC) is a heterogeneous disease composed of several biological subtypes having different clinical course, response to therapy and molecular profile. The lack of expression of Estrogen Receptor (ER), Progesterone Receptor (PR), Epidermal Growth Factor Receptor 2 (HER2) and the absence of HER2 amplification define the TNBC [1]. TNBC represents approximately 15–20% of all invasive breast cancers and is characterized by ductal histology, high mitotic rates and earlier lymph node involvement when compared to other BC subtypes [2]. TNBC is frequently associated to high expression of proliferation markers as Ki67 and cyclins and activation of the beta-catenin pathway [3]. High aggressiveness, as well as non-susceptibility to hormone and targeted therapies, limits the number of therapeutic opportunities and makes the prognosis of TNBC patients poor. NAC with anthracyclines and the mitotic inhibitors taxanes used in sequential or combined treatment, represents the standard pharmaceutical approach for TNBC [4,5,6] and describes therapeutic interventions prior to surgery to reduce size of unresectable tumors and test therapies efficacy. Despite its intrinsic aggressiveness, TNBC is highly responsive to NAC, a phenomenon called “triple negative paradox” [4,6]. Unfortunately, those patients who do not achieve pathological complete response (pCR) present a high rate of relapse. Therefore, much research is focused on the development of biomarkers predictive of clinical response, avoiding the use of ineffective protocols and customizing the optimal strategy. Traditionally, treatment response has been assessed through the application of RECIST, which classifies effectiveness on the basis of tumor shrinkage, using anatomical measurements. However, this parameter represents a later event compared to other changes which may be triggered by treatments [7]. PET allows the non-invasive monitoring of biological aspects related to tumor growth and aggressiveness, like glucose metabolism, cell proliferation and hypoxia [8]. In different types of cancer, the radioligand 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) has been reported as useful tool for early prediction of response or resistance to pharmacological treatment [9]. Considering TNBC, a reduction of [18F]FDG uptake after two cycles of neo-adjuvant chemotherapy has been recently proposed as a powerful marker of patients’ outcome [10,11,12], but preclinical as well as clinical studies identified other tracers of potential interest. Among these, the thymidine analogue 3’-[18F]fluoro-3 (...truncated)