64Cu-SAR-Bombesin PET-CT Imaging in the Staging of Estrogen/Progesterone Receptor Positive, HER2 Negative Metastatic Breast Cancer Patients: Safety, Dosimetry and Feasibility in a Phase I Trial.

Breast cancers are most frequently oestrogen receptor (ER) and progesterone receptor (PR) positive and [18F]Fluorodeoxyglucose PET-CT (FDG) has lower sensitivity for these subtypes. The gastrin-releasing peptide receptor (GRPR) is overexpressed in ER+/PR+ breast cancers. This study assessed the safety and potential of [64Cu]Cu-Sarcophagine (SAR)-Bombesin PET/CT (BBN) in re-staging metastatic ER+/PR+/human epidermal growth-factor-2-negative (HER2-) breast cancer. Seven patients with metastatic ER+/PR+/HER2- breast cancer undergoing staging underwent [64Cu]Cu-SAR-BBN PET-CT. Bloods, vital signs and electrocardiogram, blood tracer-clearance and dosimetry were undertaken. GRPR status was assessed in available metastatic biopsy samples. Staging with conventional imaging ([18F]FDG, bone scan and diagnostic CT) was within 3 weeks of [64Cu]Cu-SAR-BBN PET/CT. PET scans were assessed visually and quantitatively. Seven patients underwent imaging. One of the seven had de-novo metastatic breast cancer and six of the seven recurrent metastatic disease. Two of the seven had lobular subtype. No adverse events were reported. All seven patients were positive on conventional imaging (six of seven on FDG). [64Cu]Cu-SAR-BBN imaging was positive in five of the seven. Both [64Cu]Cu-SAR-BBN-negative patients had disease identified on [18F]FDG. One patient was [64Cu]Cu-SAR-BBN positive/[18F]FDG negative. Four of seven patients were [64Cu]Cu-SAR-BBN positive/[18F]FDG positive. In these four, mean SUVmax was higher for [64Cu]Cu-SAR-BBN than [18F]FDG (SUVmax 15 vs. 12). In the classical lobular subtype (two of seven), [64Cu]Cu-SAR-BBN was more avid compared to [18F]FDG (SUVmax 20 vs. 11, and 20 vs. <3). Dosimetry calculations estimated whole-body effective dose for 200 MBq of [64Cu]Cu-SAR-BBN to be 1.9 mSv. [64Cu]Cu-SAR-BBN PET/CT appears safe and may have diagnostic value in metastatic ER+/PR+/HER2- breast cancer, particularly the lobular subtype. Further evaluation is warranted.

Diagnostic value of 68 Ga-DOTATATE PET-CT imaging for staging of ER+ /PR+ HER2- breast cancer patients with metastatic disease: Comparison with conventional imaging with bone scan, diagnostic CT and 18 F-FDG PET-CT in a prospective pilot trial.

INTRODUCTION: 18 F-Fludeoxyglucose PET-CT (FDG) is increasingly used to stage breast cancer. Most breast cancers express the Oestrogen Receptor (ER) and Progesterone Receptor (PR), and this subtype demonstrates lower activity on FDG imaging. Somatostatin receptors (SSTR) offer a potentially improved radiotracer target for ER+ /PR+ breast cancer. We present the first in vivo clinical study comparing 68 Ga-DOTATATE PET-CT (DOTA) to FDG and conventional imaging (bone scan and diagnostic CT), in metastatic ER+ /PR+ human epidermal growth factor receptor 2 (HER2) negative breast cancer. METHODS: Patients with clinically progressive metastatic ER+ /PR+ HER2- breast cancer underwent restaging with DOTA, FDG and conventional imaging. Scans were analysed visually, and semi-quantitatively. Wilcoxon-Rank Scoring was used to assess significance. RESULTS: Ten women (mean age 57 years) underwent imaging. 8/10 demonstrated disease on both DOTA and FDG. 2/10 positive on conventional imaging, but DOTA- /FDG- , and had no disease progression at 1-year follow-up. Heterogeneity of uptake was seen between DOTA and FDG with 5 bone lesions DOTA+ /FDG- and 1 bone lesion FDG+ /DOTA- . Twenty-one visceral lesions were FDG+ /DOTA- (2 patients), with 10/21 identified on conventional imaging. Maximum standard uptake values (SUV max) of DOTA were greater than FDG (10.9 vs. 6.6, P = ns). Four sites were biopsied (3 patients). 3/4 had high ER/PR expression (mean DOTA SUV max 9.4) and 1/4 low ER/PR expression (DOTA SUV max 3.1). CONCLUSION: Whilst we have not demonstrated DOTA to be superior to FDG in staging of ER+ /PR+ breast cancers, DOTA may have a role in assessing HR status and treatment decisions; further evaluation of this is warranted.

Phase I/II Trial of the Combination of 177Lutetium Prostate specific Membrane Antigen 617 and Idronoxil (NOX66) in Men with End-stage Metastatic Castration-resistant Prostate Cancer (LuPIN).

BACKGROUND: Trials of lutetium prostate specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC) have demonstrated good safety and efficacy, but combination strategies may improve outcomes. Idronoxil is a synthetic flavonoid derivative with radiosensitising properties. OBJECTIVE: To evaluate the safety and activity of 177Lu PSMA 617 (LuPSMA-617) in combination with idronoxil suppositories (NOX66) in patients with end-stage mCRPC. DESIGN, SETTING, AND PARTICIPANTS: Thirty-two men with progressive mCRPC previously treated with taxane-based chemotherapy (91% treated with both docetaxel and cabazitaxel) and abiraterone and/or enzalutamide were enrolled in this phase I dose escalation study with phase II dose expansion. INTERVENTION: Screening with 68Ga PSMA and 18F-fludeoxyglucose positron emission tomography (PET)/computed tomography (CT) was performed. Men received up to six cycles of LuPSMA-617 (7.5 GBq) on day 1, with escalating doses of NOX66 on days 1-10 of a 6-wk cycle. Cohort 1 (n = 8) received 400 mg and cohort 2 (n = 24) 800 mg of NOX66. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Adverse events (AEs), pain inventory scores, prostate-specific antigen (PSA) response, progression-free survival, and overall survival were evaluated. RESULTS AND LIMITATIONS: Fifty-six men were screened and 32 (57%) were enrolled with a screen failure rate of 21% for PET imaging criteria. Dosing was as follows: 97% (31/32) received two or more doses and 47% (15/32) completed six doses. Common AEs included xerostomia, fatigue, and anaemia. Anal irritation attributable to NOX66 occurred in 28%. PSA responses were as follows: 91% (29/32) had any PSA response (median -74%; 95% confidence interval [CI] 76-97) and 62.5% (20/32) had a PSA fall of >50% (95% CI 45-77). The median PSA progression-free survival was 6.1 mo (95% CI 2.8-9.2) and median overall survival was 17.1 mo (95% CI 6.5-27.1). CONCLUSIONS: NOX66 with LuPSMA-617 is a safe and feasible therapeutic strategy in men treated with third-line therapy and beyond for mCRPC. PATIENT SUMMARY: Addition of NOX66 to 177Lu prostate-specific membrane antigen 617 is safe, and further studies are needed to assess its potential to augment the anticancer effects of LuPSMA-617.

The Additive Diagnostic Value of Prostate-specific Membrane Antigen Positron Emission Tomography Computed Tomography to Multiparametric Magnetic Resonance Imaging Triage in the Diagnosis of Prostate Cancer (PRIMARY): A Prospective Multicentre Study.

BACKGROUND: Multiparametric magnetic resonance imaging (MRI) is validated for the detection of clinically significant prostate cancer (csPCa), although patients with negative/equivocal MRI undergo biopsy for false negative concerns. In addition, 68Ga-PSMA-11 positron emission tomography/computed tomography (prostate-specific membrane antigen [PSMA]) may also identify csPCa accurately. OBJECTIVE: This trial aimed to determine whether the combination of PSMA + MRI was superior to MRI in diagnostic performance for detecting csPCa. DESIGN, SETTING, AND PARTICIPANTS: A prospective multicentre phase II imaging trial was conducted. A total of 296 men were enrolled with suspected prostate cancer, with no prior biopsy or MRI, recent MRI (6 mo), and planned transperineal biopsy based on clinical risk and MRI. In all, 291 men underwent MRI, pelvic-only PSMA, and systematic ± targeted biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Sensitivity, specificity, and predictive values (negative predictive value [NPV] and positive predictive value) for csPCa were determined for MRI, PSMA, and PSMA + MRI. PSMA + MRI was defined as negative for PSMA negative Prostate Imaging Reporting and Data System (PI-RADS) 2/3 and positive for either MRI PI-RADS 4/5 or PSMA positive PI-RADS 2/3; csPCa was any International Society of Urological Pathology (ISUP) grade group ≥2 malignancy. RESULTS AND LIMITATIONS: Of the patients, 56% (n = 162) had csPCa; 67% had PI-RADS 3-5, 73% were PSMA positive, and 81% were combined PSMA + MRI positive. Combined PSMA + MRI improved NPV compared with MRI alone (91% vs 72%, test ratio = 1.27 [1.11-1.39], p < 0.001). Sensitivity also improved (97% vs 83%, p < 0.001); however, specificity was reduced (40% vs 53%, p = 0.011). Five csPCa cases were missed with PSMA + MRI (four ISUP 2 and one ISUP 3). Of all men, 19% (56/291) were PSMA + MRI negative (38% of PI-RADS 2/3) and could potentially have avoided biopsy, risking delayed csPCa detection in 3.1% men with csPCa (5/162) or 1.7% (5/291) overall. CONCLUSIONS: PSMA + MRI improved NPV and sensitivity for csPCa in an MRI triaged population. Further randomised studies will determine whether biopsy can safely be omitted in men with a high clinical suspicion of csPCa but negative combined imaging. PATIENT SUMMARY: The combination of magnetic resonance imaging (MRI) + prostate-specific membrane antigen positron emission tomography reduces false negatives for clinically significant prostate cancer (csPCa) compared with MRI, potentially allowing a reduction in the number of prostate biopsies required to diagnose csPCa.

3-Year Freedom from Progression After 68Ga-PSMA PET/CT-Triaged Management in Men with Biochemical Recurrence After Radical Prostatectomy: Results of a Prospective Multicenter Trial.

68Ga-labeled prostate-specific membrane antigen (PSMA) PET/CT is increasingly used in men with biochemical recurrence (BCR) after radical prostatectomy (RP), but its longer-term prognostic or predictive potential in these men is unknown. The aim of this study was to evaluate the predictive value of PSMA PET for a 3-y freedom from progression (FFP) in men with BCR after RP undergoing salvage radiotherapy (sRT). Methods: This prospective multicenter study enrolled 260 men between 2015 and 2017. Eligible patients were referred for PSMA PET with a rising level of prostate-specific antigen (PSA) after RP. Management after PSMA PET was recorded but not mandated. PSMA PET protocols were standardized across sites and reported prospectively. Clinical, pathologic, and surgical information; sRT; timing and duration of androgen deprivation; 3-y PSA results; and clinical events were documented. FFP was defined as a PSA rise of no more than 0.2 ng/mL above nadir after sRT, with no additional treatment. Results: The median PSA was 0.26 ng/mL (interquartile range, 0.15-0.59 ng/mL), and follow-up was 38 mo (interquartile range, 31-43 mo). PSMA PET had negative results in 34.6% (90/260), showed disease confined to the prostatic fossa in 21.5% (56/260), showed disease in the pelvic nodes in 26.2% (68/260), and showed distant disease in 17.7% (46/260). Of the patients, 71.5% (186/260) received sRT: 38.2% (71/186) to the fossa only, 49.4% (92/186) to the fossa plus the pelvic nodes, and 12.4% (23/186) to the nodes alone or stereotactic body radiation therapy. PSMA PET was highly predictive of FFP at 3 y after sRT. Overall, FFP was achieved in 64.5% (120/186) of those who received sRT, 81% (81/100) with negative results or fossa-confined findings versus 45% (39/86) with extrafossa disease (P < 0.0001). On logistic regression, PSMA PET was more independently predictive of FFP than established clinical predictors, including PSA, T stage, surgical margin status, or Gleason score (P < 0.002). Thirty-two percent of men with a negative PSMA PET result did not receive treatment. Of these, 66% (19/29) progressed, with a mean rise in PSA of 1.59 ng/mL over the 3 y. Conclusion: PSMA PET results are highly predictive of FFP at 3 y in men undergoing sRT for BCR after RP. In particular, men with negative PSMA PET results or disease identified as still confined to the prostatic fossa demonstrate high FFP, despite receiving less extensive radiotherapy and lower rates of additional androgen deprivation therapy than those with extrafossa disease.

Asymptomatic Prostate Cancer Brain Metastases on 68Ga-PSMA PET/CT.

Brain metastases from prostate cancer are rare and occur at a late stage in the natural history of the disease. Men usually present with neurological manifestations. We present a 66-year-old asymptomatic man who had incidental brain metastases detected on Ga-PSMA PET/CT, which was later confirmed on biopsy to be prostate adenocarcinoma. With newer androgen deprivation agents and improved imaging capabilities increasing the mean survival and thus the incidence of brain metastases from prostate cancer, it is important to consider this important differential not only in men who display neurological symptoms but also in men who are asymptomatic.

Centromere RNA is a key component for the assembly of nucleoproteins at the nucleolus and centromere.

The centromere is a complex structure, the components and assembly pathway of which remain inadequately defined. Here, we demonstrate that centromeric alpha-satellite RNA and proteins CENPC1 and INCENP accumulate in the human interphase nucleolus in an RNA polymerase I-dependent manner. The nucleolar targeting of CENPC1 and INCENP requires alpha-satellite RNA, as evident from the delocalization of both proteins from the nucleolus in RNase-treated cells, and the nucleolar relocalization of these proteins following alpha-satellite RNA replenishment in these cells. Using protein truncation and in vitro mutagenesis, we have identified the nucleolar localization sequences on CENPC1 and INCENP. We present evidence that CENPC1 is an RNA-associating protein that binds alpha-satellite RNA by an in vitro binding assay. Using chromatin immunoprecipitation, RNase treatment, and "RNA replenishment" experiments, we show that alpha-satellite RNA is a key component in the assembly of CENPC1, INCENP, and survivin (an INCENP-interacting protein) at the metaphase centromere. Our data suggest that centromere satellite RNA directly facilitates the accumulation and assembly of centromere-specific nucleoprotein components at the nucleolus and mitotic centromere, and that the sequestration of these components in the interphase nucleolus provides a regulatory mechanism for their timely release into the nucleoplasm for kinetochore assembly at the onset of mitosis.