scholarly journals Improved Prognostic Stratification Using Circulating Tumor Cell Clusters in Patients with Metastatic Castration-Resistant Prostate Cancer

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 268 ◽  
Author(s):  
Chun Wang ◽  
Zhenchao Zhang ◽  
Weelic Chong ◽  
Rui Luo ◽  
Ronald E. Myers ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Progression Free Survival ◽  
Circulating Tumor Cell ◽  
Castration Resistant Prostate Cancer ◽  
Prognostic Information ◽  
Cox Models ◽  
Risk Of Death ◽  
Castration Resistant ◽  
Increased Risk ◽  
Prognostic Stratification

Liquid biopsy-based biomarkers have advantages in monitoring the dynamics of metastatic castration-resistant prostate cancer (mCRPC), a bone-predominant metastatic disease. Previous studies have demonstrated associations between circulating tumor cells (CTCs) and clinical outcomes of mCRPC patients, but little is known about the prognostic value of CTC-clusters. In 227 longitudinally collected blood samples from 64 mCRPC patients, CTCs and CTC-clusters were enumerated using the CellSearch platform. The associations of CTC and CTC-cluster counts with progression-free survival (PFS) and overall survival (OS), individually and jointly, were evaluated by Cox models. CTCs and CTC-clusters were detected in 24 (37.5%) and 8 (12.5%) of 64 baseline samples, and in 119 (52.4%) and 27 (11.9%) of 227 longitudinal samples, respectively. CTC counts were associated with both PFS and OS, but CTC-clusters were only independently associated with an increased risk of death. Among patients with unfavorable CTCs (≥5), the presence of CTC-clusters signified a worse survival (log-rank p = 0.0185). mCRPC patients with both unfavorable CTCs and CTC-clusters had the highest risk for death (adjusted hazard ratio 19.84, p = 0.0072), as compared to those with <5 CTCs. Analyses using longitudinal data yielded similar results. In conclusion, CTC-clusters provided additional prognostic information for further stratifying death risk among patients with unfavorable CTCs.

scholarly journals Integration of circulating tumor cell and neutrophil-lymphocyte ratio to identify high-risk metastatic castration-resistant prostate cancer patients

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Weelic Chong ◽  
Zhenchao Zhang ◽  
Rui Luo ◽  
Jian Gu ◽  
Jianqing Lin ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Cellsearch System ◽  
Cox Models ◽  
Neutrophil Lymphocyte Ratio ◽  
Lymphocyte Ratio ◽  
Risk Of Death ◽  
Castration Resistant ◽  
Increased Risk

Abstract Background The neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and circulating tumor cells (CTCs) have been associated with survival in castration-resistant prostate cancer (CRPC). However, no study has examined the prognostic value of NLR and PLR in the context of CTCs. Methods Baseline CTCs from mCRPC patients were enumerated using the CellSearch System. Baseline NLR and PLR values were calculated using the data from routine complete blood counts. The associations of CTC, NLR, and PLR values, individually and jointly, with progression-free survival (PFS) and overall survival (OS), were evaluated using Kaplan-Meier analysis, as well as univariate and multivariate Cox models. Results CTCs were detected in 37 (58.7%) of 63 mCRPC patients, and among them, 16 (25.4%) had ≥5 CTCs. The presence of CTCs was significantly associated with a 4.02-fold increased risk for progression and a 3.72-fold increased risk of death during a median follow-up of 17.6 months. OS was shorter among patients with high levels of NLR or PLR than those with low levels (log-rank P = 0.023 and 0.077). Neither NLR nor PLR was individually associated with PFS. Among the 37 patients with detectable CTCs, those with a high NLR had significantly shorter OS (log-rank P = 0.024); however, among the 26 patients without CTCs, the OS difference between high- and low-NLR groups was not statistically significant. Compared to the patients with CTCs and low NLR, those with CTCs and high levels of NLR had a 3.79-fold risk of death (P = 0.036). This association remained significant after adjusting for covariates (P = 0.031). Combination analyses of CTC and PLR did not yield significant results. Conclusion Among patients with detectable CTCs, the use of NLR could further classify patients into different risk groups, suggesting a complementary role for NLR in CTC-based prognostic stratification in mCRPC.

YB-1 variant and androgen receptor axis-targeted agents in metastatic castration-resistant prostate cancer patients

2020 ◽  
Vol 21 (13) ◽  
pp. 919-928
Author(s):  
Ana Afonso ◽  
Jani Silva ◽  
Ana Rita Lopes ◽  
Sara Coelho ◽  
Ana Sofia Patrão ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Patients ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Castration Resistant Prostate Cancer ◽  
Allelic Discrimination ◽  
Cox Regression Analysis ◽  
Castration Resistant ◽  
Increased Risk

Aim: To evaluate the influence of YB-1 rs10493112 variant as a genetic marker for response to second-generation androgen receptor axis-target agents. Methods: A hospital-based cohort study of 78 patients with metastatic castration-resistant prostate cancer was conducted. Genotyping was performed by TaqMan® allelic discrimination technology. Main results: In abiraterone-treated and high-risk patients, YB-1 rs10493112 AA genotype carriers showed lower progression-free survival than C allele genotype patients (4 vs 17 months; p = 0.009). For carriers of AA genotype, multivariate Cox regression analysis revealed a fivefold increased risk of progression (p = 0.035). Conclusion: The study findings suggest that, for metastatic and castration-resistant prostate cancer patients, this polymorphism might be a putative marker for the clinical outcome.

Incidence of skeletal-related events in men with castration-resistant prostate cancer.

2018 ◽  
Vol 36 (34_suppl) ◽  
pp. 188-188
Author(s):  
Alison Tse Kawai ◽  
David Martinez ◽  
Catherine W. Saltus ◽  
Zdravko Vassilev ◽  
Montse Soriano-Gabarro ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Real World ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistance ◽  
Cohort Entry ◽  
Risk Of Death ◽  
Castration Resistant ◽  
Increased Risk ◽  
Before And After ◽  
Skeletal Related Events

188 Background: Skeletal-related events (SREs) are common in men with bone metastases and have negative consequences for patients with castration-resistant prostate cancer (CRPC), including pain, reduced quality of life, and increased risk of death. Published data on background rates of SREs in men with CPRC in real-world practice are sparse. Methods: We included men aged ≥ 65 years in the SEER-Medicare database with a prostate cancer diagnosis in 2000-2011 if they had no prior malignancy, had surgical or medical castration, and met protocol-defined criteria for castration resistance. Castration resistance was inferred from subsequent treatment with any of these systemic therapies: abiraterone, cabazitaxel, docetaxel, enzalutamide, mitoxantrone, or sipuleucel-T. The first occurrence of an SRE was identified in Medicare claims using diagnosis or procedure codes for fracture, bone surgery, radiation therapy, or spinal cord compression. We estimated incidence rates (IRs) of SREs in all eligible person-time and stratified by person-time before and after any use of the following bone-targeted agents (BTAs): alendronate, denosumab, ibandronate, pamidronate, risedronate, or zoledronic acid. Results: Of 2,234 men with CRPC (84% white, mean age 76.6 years), 896 (40%) had an SRE during follow-up, with 74% occurring within a year after cohort entry. Overall, the IR of SREs was 3.78 (95% CI, 3.53-4.03) per 100 person-months. The IR of SREs before any BTA use was 4.16 (95% CI, 3.71-4.65) per 100 person-months, and after any use was 3.60 (95% CI, 3.32-3.91) per 100 person-months. Conclusions: In this large cohort of elderly men with CRPC in a real-world setting in the U.S., SREs were common, with most occurring within a year after cohort entry. Although a direct causal interpretation of the difference in rates before and after BTA use is not possible (since confounding by indication and other factors cannot be excluded), further analysis may address at least some potential confounders.

Bone metabolism biomarkers (BMB) and progression-free survival (PFS) in men with metastatic hormone-sensitive prostate cancer (HSPC): SWOG S1216, a phase III trial of androgen deprivation therapy (ADT) with or without orteronel.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5523-5523
Author(s):  
Primo Lara ◽  
Edward Mayerson ◽  
Erik Gertz ◽  
Catherine Tangen ◽  
Amir Goldkorn ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Progression Free Survival ◽  
Bone Alkaline Phosphatase ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Disease Extent ◽  
Phase Iii Trial ◽  
Correlative Analysis ◽  
Castration Resistant ◽  
Increased Risk

5523 Background: We previously reported that baseline BMB are independently prognostic for overall survival (OS) in men with castration resistant prostate cancer. We correlated BMB with outcomes in mHSPC as part of S1216, a phase III trial of ADT +/- the novel CYP17 inhibitor orteronel. Methods: Blood was obtained at study entry for bone resorption [C-telopeptide(CTx) & Pyridinoline(PYD)] & formation markers [C-terminal collagen propeptide(CICP) & bone alkaline phosphatase(BAP)]. With prior DSMC approval, patients were sampled to mask potential treatment effect. Logistic regression was used to assess if BMB elevation above median was prognostic for a PFS event w/in 2 years across pooled study treatment arms, adjusting for baseline variables (including disease extent, PSA, age, pre-randomization ADT, & presence of bone mets). An additional interaction term between BMB elevation & presence of bone mets was included; if significant, separate models were developed for men +/- bone mets. Results: Of 1,313 men, 656 were included in this analysis. All 4 BMB levels were higher in men with a PFS event w/in 2 years vs. those with no PFS event. The odds ratio (OR) for a PFS event was significantly higher in men w/ elevated baseline BMB (see table). For BAP, a significant interaction between marker elevation and bone mets was seen (p = 0.003); men w/ bone mets and BAP elevation had an OR of 1.83 for a PFS event in 2 years. Conclusions: In men with newly diagnosed HSPC, elevated baseline levels of BMB were significantly associated with PFS, with about a two-fold increased risk of a progression event w/in 2 years. For CICP, CTx, & PYD, this association was independent of the presence of bone metastases. Baseline BMB levels have strong prognostic value in the mHSPC context. Correlative analysis of BMB & OS is planned. Clinical trial information: NCT01809691 . [Table: see text]

scholarly journals Randomized, Noncomparative, Phase II Trial of Early Switch From Docetaxel to Cabazitaxel or Vice Versa, With Integrated Biomarker Analysis, in Men With Chemotherapy-Naïve, Metastatic, Castration-Resistant Prostate Cancer

2017 ◽  
Vol 35 (28) ◽  
pp. 3181-3188 ◽  
Author(s):  
Emmanuel S. Antonarakis ◽  
Scott T. Tagawa ◽  
Giuseppe Galletti ◽  
Daniel Worroll ◽  
Karla Ballman ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Clinical Benefit ◽  
Specific Antigen ◽  
Progression Free Survival ◽  
Circulating Tumor Cell ◽  
Historical Control ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Biomarker Analysis

Purpose The TAXYNERGY trial ( ClinicalTrials.gov identifier: NCT01718353) evaluated clinical benefit from early taxane switch and circulating tumor cell (CTC) biomarkers to interrogate mechanisms of sensitivity or resistance to taxanes in men with chemotherapy-naïve, metastatic, castration-resistant prostate cancer. Patients and Methods Patients were randomly assigned 2:1 to docetaxel or cabazitaxel. Men who did not achieve ≥ 30% prostate-specific antigen (PSA) decline by cycle 4 (C4) switched taxane. The primary clinical endpoint was confirmed ≥ 50% PSA decline versus historical control (TAX327). The primary biomarker endpoint was analysis of post-treatment CTCs to confirm the hypothesis that clinical response was associated with taxane drug-target engagement, evidenced by decreased percent androgen receptor nuclear localization (%ARNL) and increased microtubule bundling. Results Sixty-three patients were randomly assigned to docetaxel (n = 41) or cabazitaxel (n = 22); 44.4% received prior potent androgen receptor–targeted therapy. Overall, 35 patients (55.6%) had confirmed ≥ 50% PSA responses, exceeding the historical control rate of 45.4% (TAX327). Of 61 treated patients, 33 (54.1%) had ≥ 30% PSA declines by C4 and did not switch taxane, 15 patients (24.6%) who did not achieve ≥ 30% PSA declines by C4 switched taxane, and 13 patients (21.3%) discontinued therapy before or at C4. Of patients switching taxane, 46.7% subsequently achieved ≥ 50% PSA decrease. In 26 CTC-evaluable patients, taxane-induced decrease in %ARNL (cycle 1 day 1 v cycle 1 day 8) was associated with a higher rate of ≥ 50% PSA decrease at C4 ( P = .009). Median composite progression-free survival was 9.1 months (95% CI, 4.9 to 11.7 months); median overall survival was not reached at 14 months. Common grade 3 or 4 adverse events included fatigue (13.1%) and febrile neutropenia (11.5%). Conclusion The early taxane switch strategy was associated with improved PSA response rates versus TAX327. Taxane-induced shifts in %ARNL may serve as an early biomarker of clinical benefit in patients treated with taxanes.

Metabolic syndrome in castration-resistant prostate cancer patients treated with abiraterone.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 213-213
Author(s):  
Vincenza Conteduca ◽  
Orazio Caffo ◽  
Lisa Derosa ◽  
Antonello Veccia ◽  
Elisabetta Petracci ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Metabolic Syndrome ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Consecutive Series ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Increased Risk ◽  
Hormonal Therapies ◽  
The Impact

213 Background: The presence and the impact of metabolic syndrome (MS) in castration-resistant prostate cancer (CRPC) men treated with novel hormonal therapies, as abiraterone, has not still been studied. The study aims to assess the impact of MS on progression free survival (PFS) and overall survival (OS) from time starting abiraterone. Methods: We retrospectively evaluated a consecutive series of metastatic CRPC patients treated with abiraterone after docetaxel failure. MS, as defined by modified Adult Treatment Panel (ATP) III criteria, was assessed at the time of initiation of abiraterone, during treatment and follow-up. Cox regression model was used to evaluate the role of MS on the two end-points. Results: One hundred seventy eight patients had sufficient data to assess the presence of MS. Mean age (± SD) at start of abiraterone was 74.0 ± 7.7 years. Seventy out of 178 patients (39.5%) met MS criteria at baseline, before abiraterone initiation, whereas for eleven patients this occurred during treatment. Median PFS was equal to 5 months for patients with MS versus 9 months for those without MS. Patients with MS had a 2-fold increased risk of progression or death for all causes than patients without MS (HR=1.9, 95% CI [1.3-2.7], P<0.001). Median OS was 16 months and 22 months in patients with and without MS, respectively. After adjusting for covariates, MS resulted not significantly associated to OS (HR=1.2, 95% CI [0.8-1.9], P=0.340). Conclusions: MS may represent a complication of patients treated with abiraterone. The presence of MS appears to be a risk factor for shorter PFS in patients with CRPC treated with abiraterone, even if it does not show any impact on OS, so it needs a further prospective evaluation.

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]

Safety and tolerance of androgen receptor antagonists in nonmetastatic, castration-resistant prostate cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17607-e17607
Author(s):  
Sariya Wongsaengsak ◽  
Nusrat Jahan ◽  
Fred L. Hardwicke
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Final Analysis ◽  
Treatment Discontinuation ◽  
Castration Resistant Prostate Cancer ◽  
Phase 3 ◽  
Risk Of Death ◽  
Castration Resistant ◽  
Increased Risk ◽  
Grade 3

e17607 Background: Metastatic castration resistant prostate cancer (mCRPC) is a fatal disease. Nonmetastatic, castration-resistant prostate cancer (nmCRPC) often predates mCRPC. Recently, three androgen receptor (AR) antagonists i.e. apalutamide, enzalutamide, and darolutamide have been approved for nmCRPC. Nonetheless, any new therapeutic approach poses new safety concerns. We conducted a systematic review and meta-analysis of the published phase 3 randomized controlled trials (RCTs) to determine the safety and tolerance of AR-antagonists in nmCRPC patients. Methods: We conducted a systematic search at PUBMED, MEDLINE, EMBASE, and meeting abstracts as per PRISMA guidelines from inception until November 2019. Published phase 3 RCTs using AR-antagonists in the study arm for nmCRPC were included in the analyses. We used Mantel-Haenszel (MH) method and random effects model to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI). Heterogeneity was tested with I2 value and Cochran’s Q-test. Results: Three phase 3 RCTs (ARAMIS, PROSPER, and SPARTAN) comprising 2687 patients in the AR-antagonist arm and 1417 patients in the control arm were included in the final analysis. AR-antagonists used in the study arms were following— ARAMIS: darolutamide, PROSPER: enzalutamide, and SPARTAN: apalutamide. Placebo was used in the control arms. All patients continued androgen deprivation therapy (ADT). Randomization was 2:1 in all studies. No publication bias was appreciated all three studies. The pooled RR of any-grade adverse events (AEs) is 1.08 (95% CI: 1.02 – 1.14, p = 0.01, I2 = 79%) which was statistically significant. The pooled RR of grade ≥ 3 AEs was also significant at 1.32 (95% CI: 1.19 – 1.46, p < 0.00001, I2 = 0%). The pooled RR of grade 5 event is 2.67 (95% CI: 0.79 – 9.02, p = 0.11, I2 = 70%) which was not statistically significant. The pooled RR for discontinuation of treatment regimen was also statistically significant at 1.31 (95% CI: 1.00 – 1.72, p = 0.05, I2 = 35%). Conclusions: In nmCRPC patients, AR-antagonists in combination with ADT is associated with a mild increase risk of any-grade AEs, grade ≥3 AEs, and treatment discontinuation secondary AEs. However, AR-antagonists were not associated with a significantly increased risk of death due to AEs. Careful clinical vigilance and timely intervention with appropriate supportive care are critical to prevent AEs related morbidities and prevent treatment discontinuation.

scholarly journals Comparative Survival of Asian and White Metastatic Castration-Resistant Prostate Cancer Men Treated With Docetaxel

2020 ◽  
Vol 4 (2) ◽  
Author(s):  
Susan Halabi ◽  
Sandipan Dutta ◽  
Catherine M Tangen ◽  
Mark Rosenthal ◽  
Daniel P Petrylak ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
White Men ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Risk Of Death ◽  
Castration Resistant ◽  
Increased Risk ◽  
Asian Men ◽  
Few Data

Abstract There are few data regarding disparities in overall survival (OS) between Asian and white men with metastatic castration-resistant prostate cancer (mCRPC). We compared OS of Asian and white mCRPC men treated in phase III clinical trials with docetaxel and prednisone (DP) or a DP-containing regimen. Individual participant data from 8820 men with mCRPC randomly assigned on nine phase III trials to receive DP or a DP-containing regimen were combined. Men enrolled in these trials had a diagnosis of prostate adenocarcinoma. The median overall survival was 18.8 months (95% confidence interval [CI] = 17.4 to 22.1 months) and 21.2 months (95% CI = 20.8 to 21.7 months) for Asian and white men, respectively. The pooled hazard ratio for death for Asian men compared with white men, adjusted for baseline prognostic factors, was 0.95 (95% CI = 0.84 to 1.09), indicating that Asian men were not at increased risk of death. This large analysis showed that Asian men did not have shorter OS duration than white men treated with docetaxel.

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