Abstract PD4-07: PET imaging of PARP-1 expression in breast cancer
Authors: ES McDonald, S Carlin, KN Maxwell, A Nayak, RK Doot, AR Pantel, MD Farwell, DA Pryma, AS Clark, P Shah, AM DeMichele, A Ziober, EK Schubert, K Palmer, HS Lee, J Matro, L de la Cruz, J Tchou, DN Anderson, MD Feldman, RE Sheffer, H Knollman, MD Schnall, M Makvandi, S Domchek, RA Hubbard, RH Mach, DA Mankoff
Journal: Cancer Research (2019)

Abstract 18F-FluorThanatrace ([18F]-FTT) is a novel radiotracer shown to quantify Poly [ADP-ribose] polymerase 1 (PARP-1) expression in vitro and in vivo through a receptor-ligand interaction. A recent study at the University of Pennsylvania in women with ovarian cancer demonstrated in vivo visualization of PARP-1 expression in tumors using this radiotracer that closely correlated with an in vitro assay of PARP-1 in tumor tissue (Makvandi, M. J. Clin. Invest. 128:2116, 2018). A radioligand with PARP-1 specificity, [125I]-KX1, was also developed as a companion tool for ex vivo evaluation of PARP-1 expression and PARP inhibitor (PARPi) drug occupancy by radioligand binding assay (Makvandi, M. Cancer Res. 76:4516, 2016). As the first step in validating this biomarker in breast cancer, we performed a prospective clinical trial comparing in vivo [18F]-FTTuptake and ex vivo PARP-1 expression in women with primary breast cancer. Methods: 24 patients with Stage I-IV primary breast cancer were imaged with [18F]-FTT prior to any therapy including surgery. We correlated in vivo uptake with ex vivo immunohistochemistry (IHC) for PARP-1 and [125I]-KX1 autoradiography in untreated surgical specimens. Tumors were analyzed for alterations in DNA repair genes, copy number-based as well as mutational signatures indicative of homologous recombination deficiency (HRD) and mutational burden, using our established protocol (Maxwell, KN, Nature Commun. 8:319, 2017). Results: [18F]-FTT uptake was visualized above background in all primary breast tumors and known metastases. Two areas of unexpected uptake revealed an unknown contralateral breast cancer and an ovarian carcinoid, respectively. We expected that uptake might be highest in triple negative breast cancer (TNBC), where PARPi have been most heavily studied. However, a range of tracer uptake was observed in tumors independent of breast cancer subtype (hormone receptor positive/HER2 negative, TNBC, HER2+) and BRCA status. Uptake ratios (SUVmax tumor/SUV max opposite breast) ranged from 1.2-10.5 with a median 4.0. Ex vivo[125I]-KX1 autoradiography was performed on a subset of untreated primary tumors (n=5) and compared with IHC staining for PARP-1 on sequential sections. This revealed a close spatial correspondence between elevated PARP-1 expression by IHC and regions of elevated [125I]-KX1 binding radiographically. There was also a strong positive correlation between in vivo [18F]-FTT uptake and ex vivo quantitative [125I]-KX1 autoradiography (r=0.78). Genomic analysis of HRD in all tumors is pending and will be reported. Conclusion: Initial analyses support the ability of [18F]-FTT to visualize and measure PARP-1 expression in breast cancer. This is the first step toward developing an imaging companion diagnostic to help guide PARP inhibitor treatment in breast cancer. Ongoing studies are expanding upon these results, testing the extent to which expression of PARP-1 by [18F]-FTT can predict response to PARP inhibitors and measure target engagement during therapy. Citation Format: McDonald ES, Carlin S, Maxwell KN, Nayak A, Doot RK, Pantel AR, Farwell MD, Pryma DA, Clark AS, Shah P, DeMichele AM, Ziober A, Schubert EK, Palmer K, Lee HS, Matro J, de la Cruz L, Tchou J, Anderson DN, Feldman MD, Sheffer RE, Knollman H, Schnall MD, Makvandi M, Domchek S, Hubbard RA, Mach RH, Mankoff DA. PET imaging of PARP-1 expression in breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD4-07.