A novel PARP inhibitor PET tracer for breast cancer Breast cancer is the most common cancer in women, and 1 in 8 women will develop invasive breast cancer in her lifetime. Approximately 5-10% of those patients have BRCA mutations (BReast CAncer susceptibility gene). Current therapeutic strategies take advantage of the DNA repair defect in patients with BRCA mutations (BRCAMUT). By selectively targeting cancer cells rather than healthy cells, molecularly targeted agents have the potential to improve cancer outcomes and reduce toxicity compared to standard therapy. Patients who have BRCA mutations are more sensitive to PARPi. Currently, PARPi are approved for patients with metastatic germline BRCA -mutated (BRCAMUT) breast cancer. Patients with other defects in the DNA repair pathway may also benefit. Under current methods, however, which require invasive tumor biopsies, it is difficult to identify which patients may benefit as the biopsies may provide only limited information about a patient?s sensitivity to PARPi, given tumor heterogeneity and under-sampling. Furthermore, not all patients with DNA repair defects in BRCA are responsive to PARPi. Current therapeutic strategies often fail to identify the patients who are most likely to benefit. Through positron emission tomography (PET) of PARP-1 using a novel PET tracer [18F] Fluorthanatrace (FTT) that binds to activated PARP1, we can non-invasively measure PARP1 protein levels in the tumor and direct therapy to patients who are most likely to benefit from PARPi, thereby sparing those who would not benefit the unnecessary toxicities. Additionally, this novel imaging technology is low risk and can be repeated throughout treatment. Patients with locally advanced or metastatic BRCA1/2 mutated breast cancer who are enrolled on a phase II clinical trial at MD Anderson Cancer Center in which they receive PARP inhibitors will be co-enrolled on our companion imaging clinical trial of repeat [18F] FTT PET/CT imaging. [18F] FTT PET/CT will occur pretreatment and soon after PARPi initiation or twice prior to treatment initiation. Our first goal is to validate our technology for measuring PARP1 protein levels in breast cancer patients. The next goal is to demonstrate the reproducibility of our measurements in patients by having a small group undergo two scans prior to treatment. Finally, we will image a larger group of patients before treatment and then soon after treatment initiation to evaluate if PARPi reached the target. Our ultimate goal is to validate this novel imaging technology, as an early, non-invasive method to measure target engagement of PARPi in patients with metastatic germline BRCAMUT breast cancer, and thus predict responsiveness to PARPi. At the completion of this study, we will be able to confirm that this imaging technology measures PARP1 protein expression in patients and demonstrate the value of this novel imaging technology in measuring target engagement in patients receiving PARPi.
A novel PARPi PET tracer for breast cancer Current therapeutic strategies are often hindered by the inability to identify the patients who are most likely to benefit. Patients who have mutations in BRCA (BReast CAncer Susceptibility gene) have greater sensitivity to PARPi (inhibitors of the poly-ADP ribose polymerase (PARP) protein 1), which we hypothesize is due to higher levels of PARP1. However, patients who have other defects in DNA strand break repair may also be sensitive to PARPi. Through medical imaging (whole body positron emission tomography (PET)) of PARP-1 using a novel PET tracer [18F] Fluorthanatrace (FTT) that binds to activated PARP1, we can non-invasively measure PARP1 protein levels in the tumor and direct therapy to patients who are most likely to benefit from PARPi, thereby sparing those who derive no benefit from PARPi the unnecessary toxicities of therapy.
