Recurrence rate after radical prostatectomy following primary staging of high-risk prostate cancer with 68Ga-PSMA PET/CT.

BACKGROUND: Accurate primary staging is one of the most important issues for initial management of prostate cancer (PCa) patients to perform an optimal selection of patients for curative intended treatment. 68Ga-Prostate-Specific-Membrane-Antigen (PSMA) PET/CT was found superior to conventional imaging both for detection of recurrence after curative intended treatment and for primary staging. We studied the recurrence rate after radical prostatectomy in high-risk PCa patients primary staged with 68Ga-PSMA PET/CT compared with conventional imaging. MATERIAL AND METHODS: The study included 247 D'Amico high-risk PCa patients treated with radical prostatectomy (RP) after primary staging with 68Ga-PSMA PET/CT and a reference group of 137 high-risk patients with RP after conventional imaging (99mTc bone scintigraphy and CT). Recurrence rates were assessed by Cox regression and Kaplan-Meier analysis. RESULTS: The 5-year recurrence-free survival rate was 71.1% in the 68Ga-PSMA PET/CT cohort compared with 56.4% in the conventional imaging cohort. Primary staging by 68Ga-PSMA PET/CT reduced biochemical recurrence (BCR) risk by 42% (HR = 0.58 (0.41-0.83), p = .004). CONCLUSION: The present data could indicate a lower recurrence rate after RP following primary staging with 68Ga-PSMA PET/CT compared to conventional imaging, likely due to improved selection of patients for surgery.

A genome-wide CRISPR-Cas9 knockout screen identifies novel PARP inhibitor resistance genes in prostate cancer.

DNA repair gene mutations are frequent in castration-resistant prostate cancer (CRPC), suggesting eligibility for poly(ADP-ribose) polymerase inhibitor (PARPi) treatment. However, therapy resistance is a major clinical challenge and genes contributing to PARPi resistance are poorly understood. Using a genome-wide CRISPR-Cas9 knockout screen, this study aimed at identifying genes involved in PARPi resistance in CRPC. Based on the screen, we identified PARP1, and six novel candidates associated with olaparib resistance upon knockout. For validation, we generated multiple knockout populations/clones per gene in C4 and/or LNCaP CRPC cells, which confirmed that loss of PARP1, ARH3, YWHAE, or UBR5 caused olaparib resistance. PARP1 or ARH3 knockout caused cross-resistance to other PARPis (veliparib and niraparib). Furthermore, PARP1 or ARH3 knockout led to reduced autophagy, while pharmacological induction of autophagy partially reverted their PARPi resistant phenotype. Tumor RNA sequencing of 126 prostate cancer patients identified low ARH3 expression as an independent predictor of recurrence. Our results advance the understanding of PARPi response by identifying four novel genes that contribute to PARPi sensitivity in CRPC and suggest a new model of PARPi resistance through decreased autophagy.

Evaluation of Predictors of Biochemical Recurrence in Prostate Cancer Patients, as Detected by 68Ga-PSMA PET/CT.

OBJECTIVES: To explore the existence of new predictors of the 68Ga-Prostate-Specific Membrane Antigen (PSMA) PET/CT detection rate at biochemical recurrence (BCR) and to determine the detection rate of 68Ga-PSMA PET/CT dependent of prostate-specific antigen (PSA) levels. MATERIALS AND METHODS: In total, 189 PCa patients scanned with 68Ga-PSMA PET/CT for detection of BCR after curatively intended treatment with either radical prostatectomy (n = 153) or radiotherapy (n = 36) were included. Clinicopathological information at the time of diagnosis (PSA, clinical tumor-stage, International Society of Urological Pathology Grade Group and whether 68Ga-PSMA PET/CT was used for primary staging), treatment (RT/RP and histopathology of the prostatectomies), and pre-PET PSA were collected from medical records. RESULTS: Of the 189 68Ga-PSMA PET/CT scans, 103 (54.5%) were positive for BCR of PCa. No significant coherency was observed between detection rate and any clinicopathological variables at diagnosis. Detection rates significantly increased with rising PSA: <0.5 ng/mL = 28%, 0.5 ≤ 1 ng/mL = 39%, 1 ≤ 2 ng/mL = 64%, 2 ≤ 5 ng/mL = 87.5% and ≥5 ng/mL = 97%. CONCLUSIONS: The detection rate of PCa recurrence was strongly dependent of pre-PET PSA levels. None of the additional clinical variables acquired during primary staging, prostatectomy pathology reports, nor primary staging imaging modality affected the detection rate.

The transcriptional landscape and biomarker potential of circular RNAs in prostate cancer.

BACKGROUND: Circular RNAs (circRNAs) constitute a largely unexplored source for biomarker discovery in prostate cancer (PC). Here, we characterize the biomarker potential of circRNAs in PC, where the need for novel diagnostic and prognostic tools to facilitate more personalized management is pressing. METHODS: We profiled the transcriptomic landscape of circRNAs in PC by total RNA sequencing of 31 adjacent-normal and 143 tumor samples from localized (radical prostatectomy (RP)) and metastatic PC patients (cohort 1, training). Diagnostic and prognostic potential was evaluated in cohort 1, and 39 top circRNA candidates were selected for validation in two additional PC cohorts (cohort 2, n = 111; RP cohort 3, n = 191) by NanoString-based expression analysis. Biochemical recurrence (BCR)-free survival was assessed using Kaplan-Meier, univariate, and multivariate Cox regression analyses. The circRNA candidates were further detected in extracellular vesicle (EV)-enriched plasma samples from PC patients and controls (cohort 4, n = 54). RESULTS: Expression of circABCC4, circFAT3, circATRNL1, and circITGA7 was highly cancer-specific (area under the curve 0.71-0.86), while low circITGA7 expression was significantly (P < 0.05) associated with BCR in univariate analysis in two RP cohorts. Moreover, we successfully trained and validated a novel 5-circRNA prognostic signature (circKMD1A/circTULP4/circZNF532/circSUMF1/circMKLN1) significantly associated with BCR beyond routine clinicopathological variables (RP cohort 1: P = 0.02, hazard ratio = 2.1; RP cohort 3: P < 0.001, hazard ratio = 2.1). Lastly, we provide proof-of-principle for detection of candidate circRNAs in EV-enriched plasma samples from PC patients. CONCLUSIONS: circRNAs hold great biomarker potential in PC and display both high cancer specificity and association to disease progression.

68Ga-PSMA PET/CT for Primary Lymph Node and Distant Metastasis NM Staging of High-Risk Prostate Cancer.

With the largest high-risk prostate cancer (PCa) cohort to date undergoing 68Ga-prostate-specific membrane antigen (PSMA) PET/CT primary staging, we aimed to, first, characterize the metastatic spread of PCa in relation to tumor 68Ga-PSMA uptake and the D'Amico classification and, second, compare 68Ga-PSMA PET/CT findings with radical prostatectomy and pelvic lymph node dissection (PLND) histopathology findings. Methods: The study included 691 consecutive newly diagnosed, biopsy-proven, treatment-naïve, D'Amico high-risk PCa patients primary-staged by 68Ga-PSMA PET/CT. PSMA SUVmax and metastatic findings were compared with prostate-specific antigen level, International Society of Urological Pathology (ISUP) grade, and clinical stage as traditional risk stratification parameters. Moreover, 68Ga-PSMA PET/CT findings were compared with histology findings in radical prostatectomy patients undergoing PLND. Undetected lymph node metastases (LNMs) underwent immunohistochemical PSMA staining. Results: Advanced disease (N1/M1) was observed in 35.3% of patients (244/691) and was associated with increasing prostate-specific antigen level, ISUP grade, and clinical stage. LNMs (N1/M1a) were detected in 31.4% (217/691) and bone metastases (M1b) in 16.8% (116/691). Advanced disease frequencies in patients with ISUP grades 2 and 3 were 10.8% (11/102) and 37.1% (33/89), respectively. Risk of advanced disease for cT2a, cT2b, and cT2c tumors was almost equal (24.2%, 27.9%, and 22.4%, respectively). We observed a weak correlation between SUVmax and biopsy ISUP grade (ρ = 0.21; P < 0.001) and a modest correlation between SUVmax and postprostatectomy ISUP grade (ρ = 0.38; P < 0.001). Sensitivity, specificity, positive and negative predictive value, and accuracy for LNM detection on 68Ga-PSMA PET/CT in the PLND cohort were 30.6%, 96.5%, 68.8%, 84.5%, and 83.1%, respectively. Undetected LNMs either were micrometastases located in the lymph node border or were without PSMA expression. Conclusion: In this high-risk PCa cohort, we identified advanced disease in about one third at diagnosis. ISUP grade was the superior predictor for advanced disease at diagnosis. We found a significant difference in frequency of advanced disease between ISUP grades 2 and 3, as supports the Gleason score 7 subdivision. Interestingly, we observed no significant differences in risk of advanced disease when comparing the different cT2 stages. The undetected LNMs were either PSMA-negative or micrometastases.

Avid 68Ga-PSMA Uptake in Periappendicular Abscess.

Ga-prostate-specific membrane antigen (PSMA) PET/CT for primary staging of high-risk prostate cancer revealed increased Ga-PSMA uptake in a known periappendicular abscess in a patient, who had undergone surgical drainage of the abscess 1 month earlier. The case presents another example of Ga-PSMA uptake in a benign infectious and inflammatory condition.

68Ga-PSMA Uptake in Escherichia coli Spondylodiscitis.

In a patient with recently diagnosed intermediate-risk prostate cancer, Ga-prostate-specific-membrane-antigen (PSMA) PET/CT for primary staging discovered increased Ga-PSMA uptake in spondylodiscitis in the thoracic spine. The bacteria Escherichia coli was found both in blood cultures and bone biopsies from the thoracic lesion. This case presents spondylodiscitis as a potential benign pitfall to be aware of when interpreting PSMA PET/CT in prostate cancer patients.

68Ga-PSMA Uptake in Anal Fistula on PET/CT Scan.

Ga-prostate-specific membrane antigen (PSMA) PET/CT scan for primary staging discovered increased Ga-PSMA uptake in a known anal fistula in a recently diagnosed high-risk prostate cancer patient. The patient had an ongoing history of surgical revisions of complex fistulas in the perianal region, contributing to active inflammation and infection. Recently, reports have demonstrated increased Ga-PSMA uptake in different benign inflammatory conditions. This case demonstrates another case of a benign condition associated with increased Ga-PSMA uptake.

Benign Esophageal Findings on 68Ga-Prostate-Specific Membrane Antigen PET/CT Scan.

In 2 high-risk prostate cancer patients, PET scans revealed focally increased Ga-prostate-specific membrane antigen uptake in the distal esophagus. Both patients had hiatus herniation on gastroscopy, and esophageal biopsies revealed acute and chronic inflammation in both patients and a benign hyperplastic polyp in one of the patients. Recently, reports have demonstrated that inflammation can cause false-positive findings on Ga-prostate-specific membrane antigen PET/CT, and these cases present this phenomenon in the esophagus as well.