Very small nuclear circulating tumor cell (vsnCTC) as a putative biomarker for visceral metastasis in metastatic castration-resistant prostate cancer (mCRPC).

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 64-64
Author(s):  
Jie-Fu Chen ◽  
Hao Ho ◽  
Elisabeth Hodara ◽  
Ann Go ◽  
Alexander Ureno ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Circulating Tumor Cell ◽  
Castration Resistant Prostate Cancer ◽  
Visceral Metastasis ◽  
Eligibility Criteria ◽  
Castration Resistant ◽  
Potential Biomarker ◽  
Anticancer Treatment ◽  
Blood Specimens

64 Background: Patients with metastatic castration-resistant prostate cancer (mCRPC) who develop visceral metastasis (VM) have a poorer clinical outcome in comparison to those without VM. Their clinical course is aggressive and culminates in organ failure as this process is often discovered late in the disease course. There are no existing tests that identify men at risk for VM. Our team has identified an association between the presence of very small nuclear circulating tumor cells (vsnCTCs) and VM. We hypothesized that vsnCTC that can predict the development of VM and monitor the response to anticancer treatment. Methods: In our database we identified mCRPC patients who had progressed through next generation hormonal maneuvers such as abiraterone, enzalutamide, or an equivalent drug. Serial blood specimens were used for vsnCTC enumeration using published methods. The vsnCTC counts were related to the presence and development of VM as well as the response to anticancer treatment. Results: Blood specimens were identified from 28 patients who met the eligibility criteria; 16/28 patients presented with VM and 12/28 had bone-only disease at their first CTC enumeration. Five out of 12 non-VM patients developed VM during follow-up, and vsnCTCs were detected 86-196 days prior to radiographic detection of VM (true positive); 3/12 had vsnCTCs detected but no VM was found by the time of analysis (false positive). None of the vsnCTC(-) patients developed VM. vsnCTCs were detected in 21/21 VM patients compared to 3/12 non-VM patients. Reduction of vsnCTC count occurred at initiation of anticancer treatment; transition from vsnCTC(-) to vsnCTC(+) was seen prior to progression under the treatment. Conclusions: vsnCTC is associated with the presence of VM and is a potential biomarker for predicting the development of VM and monitoring the treatment response in mCRPC. Transition from vsnCTC(-) to vsnCTC(+) was associated with the development of VM and progression under the treatment.

Evaluating biomarkers in metastatic castration-resistant prostate cancer patients treated with enzalutamide: PSA, circulating tumor cell counts, AR-V7 status and radiographic progression.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17569-e17569
Author(s):  
Shruti U. Gandhy ◽  
Fatima Karzai ◽  
Jennifer L. Marte ◽  
Marijo Bilusic ◽  
Sheri McMahon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Tumor Cell ◽  
Disease Progression ◽  
Median Time ◽  
Circulating Tumor Cell ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Castration Resistant ◽  
Cell Counts

e17569 Background: Enzalutamideis ahighly effective treatment in metastatic castration resistant prostate cancer (mCRPC). Although Prostate Cancer Working Group (PCWG) guidelines recommend continuing treatment until radiographic/clinical progression (rPD/cPD), many patients discontinue therapy for rising PSA alone. Methods: We conducted an open label, randomized phase 2 trial in mCRPC patients untreated with docetaxel, abiraterone, or enzalutamide, comparing enzalutamide alone or in combination with PROSTVAC, a therapeutic cancer vaccine designed to induce an anti-tumor immune response. The study discontinued accrual after planned interim analysis indicated no difference in progression between the two arms. Patients were followed beyond 1st of 3 confirmed PSA rises until rPD. 49 patients were analyzed for Circulating Tumor Cell (CTC) count and AR-V7 status at 1st PSA rise and at rPD/cPD or last follow up. Results: 57 patients were enrolled with median follow up time of 55.4 mo. 49/57 (86%) patients had rising PSA; median time to 1st PSA rise for all patients was 6.4 mo (95% CI: 3.7-11.0 mo) after starting enzalutamide. 38/57 (67%) patients had progressive disease (majority with rPD; 1/38 (3%) with cPD); median time to progression for all patients was 23.3 mo (95% CI: 16.1-27.8 mo). 5 patients tested positive for AR-V7 within 30 days of rPD. In patients who experienced rPD/cPD, CTCs were detected in 11/24 (46%) samples taken at rPD vs. in only 3/24 (13%) samples taken at rising PSA. CTC counts were higher at rPD compared to samples taken at rising PSA (P = 0.004, Wilcoxon unpaired test). Of the 7 patients still being treated (median time on drug = 4.2 yrs), 2 experienced rising PSA; however none of the patients had detectable CTCs at a median of 30 days from last follow up. Conclusions: These data suggest that a rising PSA may not be a warning of near-term clinically significant disease progression in mCRPC patients treated with enzalutamide, given the 17-month difference between the first rise in PSA and ultimate rPD/cPD seen in this analysis. Further, CTCs and AR-V7 status associate strongly with rPD but not with rising PSA, adding biological rationale to the hypothesis that CTC counts and AR-V7 status are associated with disease progression. Collectively, these data highlight the need to continue to educate patients and providers on PCWG criteria for progression and appropriately-timed utilization of both therapies and diagnostic tests to maximize drug efficacy in mCRPC. Clinical trial information: NCT01867333 .

Development of a circulating tumor cell-based RNA classifier for patients with castration-resistant prostate cancer: CTC-PCS/PAM50.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17509-e17509
Author(s):  
Pai-Chi Teng ◽  
Yu Jen Jan ◽  
Minhyung Kim ◽  
Jie-Fu Chen ◽  
Junhee Yoon ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Progression Free Survival ◽  
Circulating Tumor Cell ◽  
Clinical Test ◽  
Castration Resistant Prostate Cancer ◽  
Luminal A ◽  
Luminal B ◽  
Castration Resistant ◽  
Therapeutic Decisions ◽  
Blood Specimens

e17509 Background: Genomic profiling has strongly impacted the contemporary understanding of prostate cancer (PCa). Clinical trials are now testing the utility of genomic classifiers such as the PCS (You, Ca Res 2016) and PAM50 (Zhao, JAMA Onc 2017) systems to optimize therapy selection. As contemporary tissue is not always readily available, especially in metastatic, castration-resistant PCa (mCRPC), a blood-based test would be better suited for assessing patients and predicting treatment response. Methods: The CTC-RNA assay combines the Thermoresponsive (TR)-NanoVelcro system with the NanoString nCounter platform. This allows for CTC purification and RNA analysis. Using a novel bioinformatics approach that accounts for differences in background signals between tissue and blood, we reconstructed the PCS and PAM50 panels to recapitulate both classifiers in this blood-based assay. A weighted Z-score and nearest centroid classifier were used to calculate gene expression and to assign PCS and PAM50 subtypes. Performance of the revised signatures and CTC-RNA assay was benchmarked on simulated spiked-blood specimens. An initial clinical test was performed using clinically annotated, banked blood specimens within the Translational Oncology Program Blood and Biospecimen Bank. Results: CTC-RNA profiles of C4-2B AR signaling inhibitor (ARSI)-resistant sublines were compared to parental C4-2B. C4-2B ARSI-resistant cells had significantly higher PCS1 Z scores, PCS1 probability, and basal probability compared to the parental C4-2B cells. Blood samples from 34 mCRPC patients prior to initiation of therapy with ARSIs (abiraterone, enzalutamide, or apalutamide) were then analyzed. Samples were classified as PCS1 (n = 3), PCS2 (n = 20), and PCS3 (n = 11); luminal A (n = 12), luminal B (n = 11), and basal (n = 11). The biochemical progression-free survival (bPFS) on ARSI and overall survival (OS) for PCS1/Basal vs. other are shown in the table. Conclusions: The CTC-RNA assay is capable of generating luminal-basal classifications such as those in the PCS and PAM50 systems. Given early data of these classifiers and their potential to guide therapeutic decisions, this approach may be useful as an alternative to biopsy to facilitate such decisions. Larger prospective studies will be needed to confirm and validate its clinical utility. [Table: see text]

Decreased fracture rate by mandating bone protecting agents in the EORTC 1333/PEACEIII trial combining Ra223 with enzalutamide versus enzalutamide alone: An updated safety analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5002-5002
Author(s):  
Silke Gillessen ◽  
Ananya Choudhury ◽  
Alejo Rodriguez-Vida ◽  
Franco Nole ◽  
Enrique Gallardo Diaz ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Safety Analysis ◽  
Phase Iii ◽  
Fracture Rate ◽  
Castration Resistant Prostate Cancer ◽  
Continuous Administration ◽  
Castration Resistant ◽  
Radium 223 ◽  
Safety Population

5002 Background: The randomized phase III EORTC-1333-GUCG (NCT02194842) trial compares enzalutamide vs. a combination of Radium 223 and enzalutamide in asymptomatic or mildly symptomatic metastatic castration resistant prostate cancer (mCRPC) patients. The premature unblinding of ERA223 (NCT02043678) in Nov 2017 due to a significant increase in the rate of fractures in the combination of abiraterone and Ra223 arm led to the implementation of the mandatory use of bone protecting agents (BPA) in the EORTC-1333-GUCG trial. Skeletal fractures, pathological or not, are a frequent and underestimated adverse event of systemic treatment of advanced prostate cancer. Whether this mandated use of BPA (zoledronic acid or denosumab) would mitigate the risk of fractures in this patient population was unclear. An early safety analysis (Tombal, ASCO, 2019) suggested that the risk of fractures was well controlled in both arms when patients receive BPA. We present here an updated analysis of fracture incidence with longer follow-up. Methods: As of 28/01/2021, a total of 253 patients (134 after making BPA mandatory) were randomized between enzalutamide/Ra223 and enzalutamide. The fracture rate was estimated with the cumulative incidence method in the safety population of 237 (122 after making BPA mandatory) treated patients. Death in absence of fracture was analyzed as competing risk and censoring was applied at last follow-up. Results: Overall, 69.5% of enzalutamide/Ra223 patients (95.2% after making BPA mandatory) and 73.1% of enzalutamide patients (95% after making BPA mandatory) received BPA on treatment: 13.6% in the enzalutamide/Ra223 arm and 21.8% in the enzalutamide arm did not use BPA at registration, but started during protocol treatment and 55.9% and 51.3% respectively, received BPA since entry. At 36.7 months median follow-up in patients without BPA and 23.1 months median follow-up in patients receiving BPA, a total of 39 patients reported a fracture. Among them, 30 patients (20 in enzalutamide/Ra223 arm) did not receive BPA and 9 (4 in the enzalutamide/Ra223 arm) received BPA (see table). Conclusions: The updated safety analysis confirms the early fracture rate results. In the absence of BPA, the risk of fracture is increased when RA223 is added to enzalutamide. Strikingly, in both arms, the risk remains almost abolished by a preventive continuous administration of BPA, thus stressing the importance of complying to international recommendations in terms of giving BPA to mCRPC patients. This study is sponsored by EORTC and supported by Bayer and Astellas. Clinical trial information: NCT02194842. [Table: see text]

scholarly journals Re‐treatment with radium‐223: 2‐year follow‐up from an international, open‐label, phase 1/2 study in patients with castration‐resistant prostate cancer and bone metastases

The Prostate ◽  
2019 ◽  
Vol 79 (14) ◽  
pp. 1683-1691 ◽  
Author(s):  
Oliver Sartor ◽  
Daniel Heinrich ◽  
Neil Mariados ◽  
Maria José Méndez Vidal ◽  
Daniel Keizman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Bone Metastases ◽  
Phase 1 ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Castration Resistant ◽  
Radium 223 ◽  
Open Label Phase
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