Michael D. Farwell

Background Poly (ADP-ribose) polymerase inhibitors (PARPi) are approved for Breast Cancer gene (BRCA)-mutant HER2- breast cancer, and there is clinical interest in expanding indications to include homologous recombination deficient (HRD) breast cancers. Yet, response in these populations remains variable, suggesting clinical utility in developing a better biomarker to select patients for PARPi and predict response. Here, we evaluate a radiolabeled PARPi, [¹⁸F]FluorThanatrace ([¹⁸F]FTT), as a functional biomarker of PARPi response in breast cancer. Methods A single-arm prospective observational trial was conducted at the University of Pennsylvania. [¹⁸F]FTT-PET uptake was measured in 24 women with untreated primary breast cancer and correlated with tumor HRD score. In a separate cohort of ten subjects with metastatic HER- breast cancer, [¹⁸F]FTT-PET uptake was measured at baseline and after a short interval on a PARPi (a measure of drug-target engagement) and correlated to progression free survival (PFS). Results Here we show that baseline [¹⁸F]FTT-PET uptake does not correlate to HRD tissue score, supporting that [¹⁸F]FTT provides distinct information from genetic features. Baseline [¹⁸F]FTT-PET uptake and the change in uptake from baseline to after PARPi initiation significantly correlates to PFS in woman with breast cancer who received a PARPi (ρ = 0.74, P = 0.023 and ρ = −0.86, P = 0.012, respectively). Conclusions These early results suggest the potential of [¹⁸F]FTT-PET to select patients for PARPi treatment and monitor in vivo pharmacodynamics after therapy start. Absence of association with HRD scores supports [¹⁸F]FTT uptake as a novel measure that may be leveraged as a biomarker. Further studies are warranted.

BACKGROUND: Fluorine-18 fluorodeoxyglucose (FDG) with positron emission tomography (PET) is the standard for detecting myocardial inflammation in cardiac sarcoidosis, requiring preparation with the ketogenic diet (KD) to achieve myocardial glucose suppression. Despite this, incomplete myocardial glucose suppression remains a significant issue, and strategies to reduce myocardial glucose uptake (MGU) and identify incomplete myocardial glucose suppression are required. This study sought to understand the relationship between point-of-care beta-hydroxybutyrate (BHB) and different patterns of MGU and between KD and fasting duration with MGU in patients undergoing evaluation for cardiac sarcoidosis. METHODS: We prospectively included 471 outpatients who underwent FDG-PET for cardiac sarcoidosis evaluation, followed the KD for 1 (n=100), 2 (n=29), and ≥3 days (n=342), fasted for at least 12 hours, and had BHB levels measured immediately before FDG injection. Images were classified as (1) no MGU (negative), (2) focal/multifocal (positive), (3) diffuse (nondiagnostic), or (4) nonspecific uptake (NS-MGU). RESULTS: Cardiac FDG-PET scans were interpreted as the following: 376 (79.83%) negative; 61 (12.95%) positive; 14 (2.97%) diffuse; and 20 (4.25%) NS-MGU. There was a strong negative relationship between BHB levels and MGU ( P P P =0.0067). The combined rate of diffuse, NS-MGU, and positive scans (34%, 28%, 16%) decreased inversely with KD duration (1, 2, and ≥3 days, respectively). However, MGU was not different across different fasting times ( P =0.6). Blood glucose levels were not associated with MGU ( P =0.17) and only weakly associated with BHB levels (R ² =0.03; P <0.001). CONCLUSIONS: We observed a strong inverse relationship between ketosis and patterns of MGU. Longer KD and fasting durations are associated with higher ketosis. However, only KD duration was associated with lower rates of MGU. Measurement of BHB levels before FDG-PET using point-of-care testing is feasible and may facilitate the management of patients referred for myocardial inflammation.

Supplementary Table S1. Baseline patient and disease characteristics.

Supplementary Table S2. Representativeness of Study Participants.

Supplementary Figure S3. CD8 T cells from patient 5 display an exhausted phenotype.

Purpose:Immunologic response to anti–programmed cell death protein 1 (PD-1) therapy can occur rapidly with T-cell responses detectable in as little as one week. Given that activated immune cells are FDG avid, we hypothesized that an early FDG PET/CT obtained approximately 1 week after starting pembrolizumab could be used to visualize a metabolic flare (MF), with increased tumor FDG activity due to infiltration by activated immune cells, or a metabolic response (MR), due to tumor cell death, that would predict response.Patients and Methods:Nineteen patients with advanced melanoma scheduled to receive pembrolizumab were prospectively enrolled. FDG PET/CT imaging was performed at baseline and approximately 1 week after starting treatment. FDG PET/CT scans were evaluated for changes in maximum standardized uptake value (SUVmax) and thresholds were identified by ROC analysis; MF was defined as >70% increase in tumor SUVmax, and MR as >30% decrease in tumor SUVmax.Results:An MF or MR was identified in 6 of 11 (55%) responders and 0 of 8 (0%) nonresponders, with an objective response rate (ORR) of 100% in the MF-MR group and an ORR of 38% in the stable metabolism (SM) group. An MF or MR was associated with T-cell reinvigoration in the peripheral blood and immune infiltration in the tumor. Overall survival at 3 years was 83% in the MF-MR group and 62% in the SM group. Median progression-free survival (PFS) was >38 months (median not reached) in the MF-MR group and 2.8 months (95% confidence interval, 0.3–5.2) in the SM group (P = 0.017).Conclusions:Early FDG PET/CT can identify metabolic changes in melanoma metastases that are potentially predictive of response to pembrolizumab and significantly correlated with PFS.

Supplementary Table S1. Baseline patient and disease characteristics.

Supplementary Figure S1. Analysis of Ki67+ CD8 T cells in peripheral blood.

Supplementary Figure S1. Analysis of Ki67+ CD8 T cells in peripheral blood.

Supplementary Figure S2. Change in SUVmax versus percentage of Ki67+ CD8 T cells.