Abstract
386
Objectives: Epithelial ovarian carcinoma has the highest mortality rate amongst gynecologic malignancies due to its insidious onset, lack of efficient screening methods, and late presentation. Numerous treatment options exist, including targeted therapy directed at the poly(ADP-ribose) polymerase (PARP) enzymes involved in DNA repair. Clinically, several PARP inhibitors are now approved for the treatment of relapsed ovarian cancer with BRCA mutations, as these DNA-repair deficient tumors rely on PARP for survival. However, an unmet clinical challenge is identifying patients that may best respond to such therapy, suggesting the need for a predictive biomarker of response to DNA-damaging therapy including radiation therapy, chemotherapy, and PARP inhibitors. [18F]FluorThanatrace (FTT) is a novel positron-emitting PARP-1 inhibitor with animal studies demonstrating FTT as a marker of PARP expression. We report initial results on a pilot study of FTT in women with ovarian, fallopian tube, or primary peritoneal cancer.
Methods: As of this interim analysis, 17 patients with newly diagnosed or recurrent ovarian, fallopian tube, or primary peritoneal cancer and measurable disease underwent both FDG-PET/CT and FTT-PET/CT in close proximity. FTT-PET/CT scans (10 mCi injection) performed over four hours were obtained to evaluate the biodistribution and dosimetry in four patients with disease not accessible for biopsy. Dynamic FTT-PET/CT scans performed over one hour at an imaging field-of-view selected using FDG PET/CT to identify active disease were obtained in patients who were scheduled for surgery or with disease amenable to biopsy. This was followed by two static scans from the skull base to thigh at approximately 1.5 and 3 hours. FDG-PET/CT was performed with a routine clinical protocol. In image analysis, lesions were first identified on FDG-PET/CT and correlated to FTT-PET/CT. Maximum SUV values were recorded for each lesion on each scan (~1.5 hour static scan for patients scanned with the dynamic protocol and ~2 hour static scan for dosimetry patients). Ex vivo autoradiography was performed on ten tissue samples from seven patients using with [125I]-KX, a novel radio-iodinated PARP radiotracer that can quantitatively assess PARP-1 enzyme expression in vitro. Immunofluorescent microscopy for PARP-1 was also performed on ten tissue samples from seven patients.
Results: Of the 17 enrolled patients with imaging, increased radiotracer uptake was seen in 15 of 17 patients on FDG-PET/CT. FTT-PET demonstrated notable physiologic uptake in the liver, spleen, and bowel. FTT uptake had a wide dynamic range with maximum SUV of lesions ranging from background to greater than 10. Maximum SUV on FTT correlated with average and maximum counts/area on [125I]-KX autoradiography and PARP-1 immunohistochemistry on tissue samples (both with r>0.7). No correlation was seen with SUV maximum on FDG and autoradiography or immunohistochemistry, and only a weak correlation was seen between maximum SUV of FTT and FDG (r≍0.3). There was close correlation between immunohistochemistry and autoradiography data (r>0.8).
Conclusion: Preliminary results of this phase I pilot study demonstrate FTT localizes to areas of known ovarian cancer with a wide dynamic range of uptake FTT measures correlated well with in vitro markers of PARP-1, while uptake of FDG did not. These data suggest that FTT holds promise as a non-invasive measure of PARP-1 expression and warrants further study as a predictive biomarker for response to DNA-damaging agents. Research Support: Supported by Marsha Rivkin Ovarian Cancer Foundation, Kaleidoscope of Hope, Department of Energy (DE-SE0012476), NIH training grant (T32-EB004311).