- Review
- Open access
- Published:
Clinical implication of prognostic and predictive biomarkers for castration-resistant prostate cancer: a systematic review
Cancer Cell International volume 20, Article number: 409 (2020)
Abstract
Background
Diagnosis of metastatic castrate resistant prostate cancer (mCRPC) with current biomarkers is difficult and often results in unnecessary invasive procedures as well as over-diagnosis and over-treatment. There are a number of prognostic biomarkers for CRPC, but there are no validated predictive biomarkers to guide in clinical decision-making. Specific biomarkers are needed that enable to understand the natural history and complex biology of this heterogeneous malignancy, identify early response to treatment outcomes and to identify the population of men most likely to benefit from the treatment. In this systematic review, we discuss the existing literature for the role of biomarkers in CRPC and how they aid in the prognosis, treatment selection and survival outcomes.
Methods
We performed a literature search on PubMed and EMBASE databases from January 2015 through February 2020 in accordance to Preferred Reporting Items for Systematic Review and Meta-Analysis guidelines. Articles were assessed to identify relevant observational studies and randomized controlled trials regarding biomarkers which aid in identifying progression to mCRPC as well as predictive biomarkers which help in treatment selection.
Results
We identified 3640 number of hits of which 58 articles were found to be relevant. Here we addressed biomarkers in the context of prognosis, prediction and patient selection of therapy. These biomarkers were found to be effective as prognostic or predictive factors under variety of conditions. The higher levels for all these biomarkers were associated with shorter median OS and sometimes PFS. Lower amounts of biomarkers in serum or urine were associated with prolonged survival outcomes, longer time to CRPC development or CRPC progression and longer median follow-up irrespective of any therapy.
Conclusion
We observed that the biomarkers included in our study predicted clinically relevant survival outcomes and treatment exposure. Though the current biomarkers are prognostic when measured prior to initiating treatment, not all are validated as predictive markers in post treatment setting. A greater understanding of biomarkers in CRPC is need of the hour for development of more personalized approach to maximize benefit and minimize harm in men with CRPC.
Background
Prostate cancer (PCa) is the second most common cancer in men and a vital cause of cancer-related morbidity and mortality globally [1]. According to International Agency for Research on Cancer, the 5-year prevalence rates in China is 30.26% in 2018 with an estimate of 99,322 new cases of PCa [2]. Patients presenting with the advanced disease typically receive hormonal therapy using medical or surgical castration as initial treatment [3]. However, most prostate cancer patients acquire resistance to the initial hormonal therapy and develop castration-resistant prostate cancer (CRPC) within 5 years from diagnosis [4].
Initially, docetaxel and hormonal manipulation were the only available strategies to manage the patients with CRPC [5]. Recently, there has been a rapid increase in the treatment options available, including novel androgen receptor-directed therapies (abiraterone acetate and enzalutamide), radiopharmaceutical (223radium), immunotherapeutic (sipuleucel-T), and chemotherapeutic (cabazitaxel) drugs. These drugs have shown efficacy in terms of survival outcomes in phase 3 clinical trials and consequently have been recommended in the recent treatment guidelines for CRPC [6]. Therefore, it is becoming essential to understand the optimal and rational combination and sequences of these treatments in clinical practice so as to identify patients most likely to benefit from a specific treatment. Minimizing harms and costs of ineffective therapies is another equally important goal [7].
CRPC is characterized by a heterogeneous natural history and despite the availability of these treatment options, CRPC remains a lethal disease [8]. The variable response observed in the targeted therapies could be due to the biologic heterogeneity of CRPC, including both AR-mediated or AR-independent pathways [9]. Over recent decades, the development of molecular biomarker assays and genetic assays has provided an avenue for PCa biomarker development [10]. Prognosis of patients can be estimated by prognostic models and nomograms; however, response to the therapies are not predictable. Emerging biomarkers utilize serum, urinary, or tissue samples as a test substrate [10]. In clinical practice, the utility of these biomarkers is variable and may be used at different time points throughout the care of a patient with suspected or diagnosed PCa. Specifically, these biomarkers assist in diagnosis, guiding definitive treatment options, determine the risk of ongoing monitoring versus intervention, or provide risk stratification in the setting of negative initial biopsy [10].
Prostate-specific antigen (PSA) is a widely used marker of diagnosis and prognosis; however, there is evidence of disconnection between PSA level changes and survival outcomes. Sipuleucel-T treatment extends overall survival (OS) in metastatic CRPC patients; however, it has little effect on the PSA level [11]. Whereas, bevacizumab with docetaxel did not significantly improve survival but greatly reduced PSA levels [12]. Additionally, radium-223 chloride demonstrated an OS benefit in patients with metastatic CRPC but had no clear effect on PSA levels [13]. Clinicians thus need predictive biomarkers to select treatment choices for individual patients. Similarly, prognostic biomarkers provide information about a patient’s disease outcome independent of therapy [14]. New biomarkers have been discovered owing to the recent advances in the metabolomic, genomic, and transcriptomic analysis, which can be utilized in the prediction of PCa outcome and response to therapy [15]. This systematic review was conducted to evaluate the available evidence on the prognostic and the potential predictive biomarkers in CRPC and to discuss the clinical implications of these markers on the patients.
The following questions were evaluated in completing this overall objective.
-
What are the currently available prognostic biomarkers that aid in predicting clinical outcomes for progression to CRPC?
-
What is the role of the predictive biomarkers in the treatment selection for CRPC patients and are they helpful in clinical decision making?
Methods
A review protocol was developed and registered on Prospero with registration number CRD42020181860.
Evidence acquisition
Search strategy
A systematic review of the literature was conducted from January 2015 to February 2020 by searching National Center for Biotechnology Center (NCBI), PubMed and EMBASE database. The following search string was used for screening of relevant literature in PubMed and EMBASE databases with minor changes in Boolean signs to suit the database: (“prostate cancer” OR “cancer of the prostate” OR “prostatic cancer” OR “castration-resistant prostate cancer” OR “non-metastatic prostate cancer” OR “hormone sensitive prostate cancer”) AND (“tumor marker” OR “biomarker” or “biologic markers” OR “serum markers” OR “surrogate marker” OR clinical marker” OR “tumor marker” OR “urine biomarkers”) AND (“survival” OR “progression free survival” OR overall survival” OR “prognostic factor/s” OR “predictive factor/s” OR “clinical outcomes”).
Study eligibility
Studies were selected for review based on the following criteria: (1) patients progressing from hormone sensitive prostate cancer (HSPC) or non-metastatic prostate cancer to CRPC or with mCRPC, (2) randomized clinical trials (RCTs), (3) observational studies, (4) English language, (5) Studies reporting outcomes based on prognostic and/or predictive biomarkers, (6) Patients on any therapy. Studies were excluded if they fell under the following criteria’s: (1) non-English language, (2) non-RCTs, (3) duplicate publications, (4) conference abstracts, (5) meta-analyses and systematic reviews, (6) not reporting appropriate outcomes. This review was performed in accordance to Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines.
Initially, titles were reviewed to assess whether they met the inclusion criteria. These studies were categorized into three categories: excluded, included and possibly relevant. Included and possibly relevant studies were rescreened to confirm eligibility.
Evidence synthesis
Only articles that clearly defined the intended study population, with or without interventions, and clinical endpoints including progression-free survival (PFS) and overall survival (OS) (biomarker-associated, clinical or radiographic), time to follow-up, significant cut-off for being a predictive or prognostic biomarker, time to CRPC progression, time to CRPC development, were included in this review.
Data extraction and quality assessment
Data from included studies regarding author, year of publication, title, study design, demographics of the study population and outcomes of interest was extracted by two independent reviewers into standardized MS Office Excel. The methodological quality of eligible RCTs was determined using the JADAD scale [16] and Newcastle–Ottawa scale [17] was used for observational studies.
Results
The literature search identified in total 3640 articles. After initial title screening and manual reduplication, 712 studies were excluded (not relevant to the topic or not original research) and 2928 references remained for abstract review. Full-text evaluation for the remaining 710 citations identified by abstract review or by a manual search of the references list was done (Fig. 1). A total of 58 articles that investigated as prognostic and predictive biomarkers in development of CRPC or its progression were finally included in the study. The summary of included studies characteristics along with quality assessment is described in Table 1.
Prognostic biomarkers
Androgen receptor (AR) splice variants in CTC
Six studies were observed for the presence of ARVs in CTC. The presence of AR-V9-positive CTCs at baseline in mCRPC was associated with poor survival outcome to cabazitaxel treatment [18], while another study reported no association of AR-V7 with OS on treatment with cabazitaxel [19]. ARV7+ was associated with shorter OS on treatment with androgen-receptor signaling inhibitors (ARSi) [20]. Further, after transurethral resection of prostate, AR-V7 expression was found to be a significant prognosticator for the development of CRPC (HR 2.627, 95% CI 1.480–4.663, p = 0.001) [21]. Similarly, ARV7+ patients had worst outcomes on OS on treatment with abiraterone acetate and enzalutamide [22, 23] (Table 2).
Number of circulating tumor cell count (CTC)
Four studies were associated with CTC as biomarker. Patients with baseline CTC counts > 5 cells/7.5 ml showed decreased OS and lower adherence to radium-223 therapy in a study [24]. Patients with < 5 CTCs prior to start of cabazitaxel therapy was prognostic indicator of better PFS and OS as compared to patients with ≥ 5 CTCs at baseline (both p < 0.001) [25]. Low CTC count was associated with longer OS than high CTC count [16.6 months (95% CI 11.7, 20.9) and 8.9 months (95% CI 6.3, 11.2)] on treatment with abiraterone or enzalutamide [26]. Similarly, CTC-positive patients were associated with shorter PFS [HR: 7.2 (95% CI 1.7–31.0; p < 0.01)]. Also, CTC-positivity (p < 0.001; HR 5.02; 95% CI 2.13–11.9) at 3 months after the start of ADT were negative prognostic markers of early progression [27] (Table 2).
Predictive biomarkers
Bone turnover markers
Most of the prostate cancer patients develop significant bone pain when progressed to CRPC [28]. Seven articles assessed the predictive role of bone biomarkers in the treatment selection for CRPC. Early changes in serum/urine biomarkers (N-telopeptide-NTx and bone alkaline phosphatase-BAP) did not predict clinical benefit in mCRPC patients with cabozantinib therapy or docetaxel with/without atrasentan [29, 30]. Patients with good bone scan index response had better performance status and achieved OS prolongation when treated with radium‐223 [31]. Further, normal total alkaline phosphatase (tALP) was associated with longer OS than with elevated tALP (p = 0.01) in patients treated with 223Ra-Dichloride [32]. Automated bone scan index (aBSI) as a predictive marker showed no significant difference in OS from baseline to 16 weeks of treatment with cabazitaxel (p = 0.72) [33]. Patients with fast alkaline phosphatase velocity (APV) values (≥ 5.42 U/l/y) and faster PSA doubling time (PSADT) (p = 0.0289) had significantly shorter median post-CRPC BAP values (p ≤ 0.0001) with androgen deprivation therapy (ADT) [34]. The combined predictive model of percent PSA change and change in automated BSI (C-index 0.77) was significantly higher than that of percent PSA change alone (C-index 0.73), p = 0.041 in enzalutamide treated patients [35] (Table 3).
Neutrophil lymphocyte ratio
Six studies were analysed for the role of NLR as biomarker. High-NLR (≥ 3.1) patients predicted worse OS and PFS in patients treated with abiraterone acetate than low NLR patients [36, 37]. Similar observations were noted in another two studies in patients with NLRlow and on docetaxel when NLR cut-off was 2.59 and 2.14 [38, 39]. Treatment of cabazitaxel over mitoxantrone was favored due to demonstration of higher median OS [15.9 vs 12.6 months, HR 1.55 (95% CI 1.3–1.84), p < 0.001], PSA progression-free survival [3 vs 3.1 months; HR 1.35 (95% CI 1.12–1.62); p = 0.002] and radiographic progression-free survival [9.3 vs 5.7 months; HR 1.42 (95% CI 1.15–1.76); p = 0.001] in patients with NLR cut-off < 3 than with NLR ≥ 3 [40]. Further another study reported that NLR ≥ 2.5 was an independent predictor of a lower risk for CSS in patients treated with docetaxel [41] (Table 3).
ERG
Only two articles were available for screening of ERG as biomarker. ERG positivity correlated with a lower PSA-PFS (3.2 months vs 7.4 months, p < 0.001), C/R-PFS (3.8 mos vs 9.0 mos, p < 0.001) and OS (10.8 mos vs 21.4 mos, p < 0.001), thus indicating that ERG is potential biomarker for prediction to docetaxel treatment in mCRPC patients [42]. However, another study showed that ERG expression was not associated with risk of CRPC for predicting response to primary ADT in mCRPC patients [43] (Table 3).
Predictive/prognostic biomarker
Testosterone
Role of testosterone as biomarker was assessed in four included studies. Testosterone ≥ 13 ng/dl was an independent prognostic factor of OS and PFS for patients treated with docetaxel. The high‐testosterone (TST) group had significantly shorter OS and PFS than the low‐TST group. Furthermore, a high serum TST predicted poor post‐docetaxel survival in patients who received subsequent therapy, including ARAT and/or cabazitaxel [44]. A serum testosterone level of 5 to < 50 ng/dl was a significant predictor for determining the efficacy of AR-targeted therapy [45]. PFS and OS when serum testosterone level was > 0.05 ng/ml in patients treated with ADT was significantly superior than with testosterone level below 0.05 ng/ml [46]. Testosterone levels of ≤ 25 ng dl/1 after the first month of ADT offered best overall sensitivity and specificity for prediction of a longer time to CRPC (p = 0.013) and was significantly associated with a lower risk of progression to CRPC (adjusted HR, 1.46; 95% CI 1.08–1.96; p = 0.013). The result showed that time to CRPC was related to testosterone levels (p = 0.020) [47] (Table 4).
PSA and PSA kinetics
About 23 included studies demonstrated the potency of PSA as biomarker on treatment with various therapies for prostate cancer. PSA > 100 ng/ml was found to be significant predictor for shorter OS in two studies [48,49,50] while PSA decline of > 50 or > 30% was observed to be significant in another study [49]. Higher hemoglobin level before treatment with cabazitaxel (p = 0.024) and a lower alkaline phosphatase (AP) level at the start of treatment (p = 0.034) resulted in a higher chance of PSA response in another study [50]. Time to PSA nadir (TTPN) ≥ 15 weeks was a prognostic factor associated with longer OS and PFS compared to those with a TTPN < 15 weeks (43 vs 15 months, p < 0.001; 24 vs 6 months, p < 0.001, respectively) for patients treated with docetaxel. Further, PSA nadir (nPSA) < 4.55 ng/ml were associated with longer OS and PFS (HR 4.002, 95% CI 1.890–8.856, p = 0.001) [51]. PSA response was a significant factor for longer OS and cancer-specific survival (CSS) (p = 0.014 and p = 0.05, respectively) in post-docetaxel treated patients [52].
Higher PSA nadir, higher TTN and a shorter time to PSA nadir were significant predictors of an increased risk of progression to CRPC during initial ADT and was associated with shorter PFS in ADT treated patients [53,54,55]. Correlation of testosterone to PSA levels during treatment with ADT showed median time to PSA rise was 4.5 months and especially after T > 50 ng/dl was a significant prognosticator associated with a 71% reduction in the risk of developing CRPC (p = 0.05) [56]. Similar observations were noted when nPSA cut-off was > 0.64 ng/ml in patients treated with ADT [57]. Time to CRPC (p = 0.007, HR = 4.77), regional lymph node involvement at the diagnosis of CRPC (p = 0.022, HR = 2.42), and PSA-PFS of alternative first generation androgen (FGA) therapy ≤ 6 months were identified as prognostic factors, while nPSA > 1 ng/ml during and time from starting FGA to nPSA ≤ 1 year were predictive factors for worse PSA-PFS in alternative FGA therapy [58]. CRPC-free survival was significantly shorter in the PSA ≥ 100 group than in PSA < 100 group in patients treated with ADT. However, the OS after CRPC diagnosis was significantly shorter in the PSA < 100 group indicating it might be a poor prognostic factor in CRPC patients [59]. PSA decline of > 50% proved significantly associated with better OS (20.1 months vs 10.5) and PFS (17.9 months vs 6.6 months) following treatment with 225Ac-PSMA-617 over PSA decline < 50% [60]. PSA decline ≥ 20.87% and ≥ 14% was a prognosticating indicator for longer survival, in another two studies [61, 62].
Treatment with abiraterone acetate demonstrated that PSA reduction > 30% or ≥ 50% remained predictive of better PFS and OS [63, 64]. Duration of treatment > 3 months by abiraterone acetate was significantly predictor (p = 0.00025) of treatment [65]. To determine the suitability of treatment approach, PSA response rate at > 50% and > 90% was evaluated which showed no statistically significant difference in patients treated with abiraterone acetate or enzalutamide. However, overall, nPSA (HR = 1.000, 95% CI 1.000–1.001, p = 0.010) was an independent prognostic factor for OS [66]. Time from therapy to castration resistance of ≤ 18 months was a determinant of shorter OS in another study (p = 0.007) [67]. TTPN > 19 weeks was superior to TTPN ≤ 19 weeks in abiraterone acetate group than in enzalutamide group (11.1. months vs 8.4 months) [68]. PSA response of ≥ 50% had significantly longer times to PSA progression, rPFS, and OS in patients treated with enzalutamide [69, 70] (Table 4).
Lactate dehydrogenase and alkaline phosphatase
Four studies assessed lactate dehydrogenase (LDH) and alkaline phosphatase (ALP) as biomarker. Serum LDH value was significantly prognostic marker for PFS (HR = 1.42, 95% CI 1.15–1.74; p = 0.00040) and OS (HR = 1.46, 95% CI 1.13–1.82; p = 0.0014), in addition to alkaline phosphatase levels for OS (HR = 1.04; 95% CI 1.00–1.07; p = 0.015) [71]. Pretreatment serum LDH was a strongest biomarker at the point of initiation of docetaxel therapy with LDH ≥ 450 U/l levels associated with poorer PFS (p < 0.00) and OS (p = 0.011). However, pretreatment serum LDH did not predict a positive response to docetaxel [72]. ALP was a strongest prognostic factor in discriminating patients with good or poor prognosis with median OS in patients with normal and abnormal ALP of 69.1 and 33.6 months treated with ADT with/without docetaxel [73]. Similarly, abiraterone acetate-enzalutamide group showed significantly longer total PSA PFS than enzalutamide–abiraterone acetate group (p = 0.049). Survival analysis showed that combined PFS was significantly longer among patients with LDH < 210 IU/l before the first ARAT than in those with ≥ LDH 210 IU/l [74] (Table 4).
Tyrosine phosphatase
Of the two articles included, one study reported that median time to CRPC was significantly shorter in the high tyrosine phosphatase (PTP) group (14.8 months) than that in low PTP group (86.3 months, p < 0.01). Thus, high PTP expression was a significant predictor of time to CRPC treated with ADT. [75] This was similar to another study by Ohtaka 2017, where PTP expression (high vs low; HR = 2.7, 95% CI 1.0–7.2, p = 0.04) was independent prognostic factor for OS [76] (Table 4).
Discussion
With the growing number of various therapeutic options that can extend survival in mCRPC patients, there is a need for the biomarkers to guide in simultaneous decisions for optimal treatment and predict which patients will benefit the most from the treatment. It is unlikely that a single biomarker will provide all information we need to tell how aggressive a newly diagnosed cancer is. No immunochemical, or genetic marker is currently used to differentiate between various stages of prostate cancers. PSA is the most widely used biomarker till now preferred for screening as well in follow-up after treatment [77]. However, PSA level change is variably dependent on the mechanism of action of different treatments. For example, early declines in PSA may be observed in novel hormonal therapies such as AA or enzalutamide which are highly prognostic in nature and associated with their mechanism of action [78]. A rise in PSA while a patient is receiving androgen deprivation therapy potentially signals a transition from hormone-sensitive prostate cancer to CRPC. However, castration levels of serum testosterone must be demonstrated before castration resistance is confirmed [79]. In the above included studies, it was observed that the PSA > 100 ng/ml, nPSA > 0.2 ng/ml, a velocity of PSA decline > 11 ng/ml per month were associated with shorter OS and PFS in patients with mCRPC while PSA decline > 50% or > 30% was associated with longer survival outcomes irrespective of any therapy. Similarly, TTPN > 6 weeks were a significant prognostic factor for survival. Early PSA response > 30% or > 50% after initiation of treatment is a significant predictor for longer OS. However, PSA levels have several restrictions as a biomarker in monitoring CRPC especially in the context of novel non-cytotoxic treatments that may have little effect on its levels. Further, PSA levels may not provide accurate information regarding the extent of bone metastasis or bone-specific effects of treatment, indicating the need of alternative biomarkers for this purpose. Bone is a common site of metastases affecting more than 90% of mean at autopsy. Even though the impact of these biomarkers is not known, they provide useful information related to the survival and progression of CRPC [80]. The elevated baseline level of BAP may be predictive for survival benefit with radium-223 treatments, and post treatment BAP reductions are highly associated with improvements in survival with radium-223 chloride [13]. In our studies, elevated BAP showed poorer outcomes on survival on treatment with radium-223, while faster APV and shorter PSADT were significant predictors of poorer bone metastasis free survival and OS.
It was noted that higher NLR values (> 2.14, > 2.5 or > 3.1) predicted worse OS and CSS in patients treated with novel hormonal therapies and docetaxel chemotherapy. This was in consistence to the other studies where high NLR was associated with poorer PFS in patients with metastatic CRPC across different treatments including abiraterone, docetaxel [81, 82]. Though the biology behind higher NLR to be significant predictor is unclear, it is presumed that the increased NLR may arise from altered tumor-inflammatory cell reactions, which is an indicator of progressive malignancy [83]. Testosterone as prognostic factor demonstrated that lower TST levels were associated with significant longer time to survival to treatment with docetaxel, ARAT and ADT. The mechanism of TST exhibiting benefits at lower levels may be related to acquired resistance than primary resistance, however this role is still unclear [45]. However, one study reported that high levels (> 0.05 ng/ml) was significant predictor of OS on treatment with ARAT, thus though TST is a significant prognostic factor, the role of TST in ARAT is unclear [46].
An increased LDH level after treatment may be predictive for poor treatment response [84]. This was also observed when the LDH level was > 450 U/l in patients initiated with docetaxel [72] and > 210 U/l in patients treated with ARAT and predicted poorer OS [74]. Also serum ALP is a significant biomarker for prediction to longer OS [71, 73]. ARV is an important prognostic factor in the progression from prostate cancer to mCRPC. Higher expression of ARV in CTC and not prostate tissues is poor prognostic factor [85]. Presence of ARV7+ and CTC+ in patients with mCRPC were associated with poorer outcomes on OS along with higher ARV7 values. However, one study reported no significant association with ARV7 [18]. Circulating tumor cells (CTCs) have emerged as a viable solution to the problem whereby patients with a variety of solid tumors, including PC, often do not have recent tumor tissue available for analysis [86]. CTC count < 5 has been a good prognostic factor for the PFS and OS in patients initiated with cabazitaxel and radium-223 therapy. Presence of CTC in patients after 3 months of initiation of ADT therapy was associated as a negative marker for early progression to CRPC [27]. Lesser explored biomarkers such as tyrosine phosphatase showed that higher levels predicted poorer OS and CSS in the two included studies [75, 76] while patients with ERG positive values showed poorer outcomes of OS and PFS [42, 43].
Thus, through our review, we have given an insight on how the biomarkers are significant in determining treatment selection. A meaningful observation from our included studies was that higher levels with any of the biomarkers in urine or blood were prognostic indicator for poorer survival outcomes, early development of CRPC and shorter follow-up duration to treatment. Also, the appropriate cut-off levels for biomarker was a significant predictor for exposure to treatment in the included studies. We thus highlight the need to establish the cut-off level for particular biomarker which will be helpful for the clinicians in diagnosis of CRPC and providing a suitable treatment strategy.
Conclusion
Diagnosis of CRPC and its management requires an individualized approach to both patient care and trial design. Although we have given a meaningful insight into the utility of the biomarkers for treatment responses and survival outcome, future research is needed with respect to the prediction of biomarker response in sequential therapy so as to design a series of optimal treatment in patients with CRPC. Currently all biomarkers in clinical use have prognostic implications when measure prior to initiating treatment, however not all are validated as predictive markers in post treatment setting. ARV7 splice variant and CTC also look like promising candidates in development of biomarkers and may benefit a specific group of CRPC population. More prospective studies on CRPC biomarkers are required to identify the surrogate value of these biomarkers on survival which will be helpful in clinical decision making.
Abbreviations
- aBSI:
-
Automated bone scan index
- ADT:
-
Androgen deprivation therapy
- ALP:
-
Alkaline phosphatase
- APV:
-
Alkaline phosphatase velocity
- BAP:
-
Bone alkaline phosphatase
- CRPC:
-
Castration-resistant prostate cancer
- CTC:
-
Circulating tumor cell count
- HSPC:
-
Hormone sensitive prostate cancer
- LDH:
-
Lactate dehydrogenase
- mCRPC:
-
Metastatic castrate resistant prostate cancer
- NCBI:
-
National Center for Biotechnology Center
- OS:
-
Overall survival
- PCa:
-
Prostate cancer
- PFS:
-
Progression-free survival
- PSA:
-
Prostate-specific antigen
- PSADT:
-
PSA doubling time
- PTP:
-
Tyrosine phosphatase
- RCTs:
-
Randomized clinical trials
- tALP:
-
Total alkaline phosphatase
- TST:
-
Testosterone
References
Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67:7–30.
Cancer Today. https://gco.iarc.fr/today/. Accessed 24 Apr 2020.
Terada N, Akamatsu S, Kobayashi T, Inoue T, Ogawa O, Antonarakis ES. Prognostic and predictive biomarkers in prostate cancer: latest evidence and clinical implications. Ther Adv Med Oncol. 2017;9:565–73.
Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol. 2017;71:630–42.
Graham J, Baker M, Macbeth F, Titshall V. Diagnosis and treatment of prostate cancer: summary of NICE guidance. BMJ. 2008;336:610–2.
Komura K, Sweeney CJ, Inamoto T, Ibuki N, Azuma H, Kantoff PW. Current treatment strategies for advanced prostate cancer. Int J Urol. 2018;25:220–31.
Li J, Armstrong AJ. Prognostic and predictive biomarkers for castration resistant prostate cancer. In: Preedy VR, Patel VB, editors. Biomarkers in cancer. Dordrecht: Springer Netherlands; 2015. p. 447–80. https://doi.org/10.1007/978-94-007-7681-4_13.
Huang JG, Campbell N, Goldenberg SL. PSA and beyond: biomarkers in prostate cancer. 8.
Aggarwal R, Ryan CJ. Castration-resistant prostate cancer: targeted therapies and individualized treatment. Oncologist. 2011;16:264–75.
McGrath S, Christidis D, Perera M, Hong SK, Manning T, Vela I, et al. Prostate cancer biomarkers: are we hitting the mark? Prostate Int. 2016;4:130–5.
Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T Immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411–22.
Kelly WK, Halabi S, Carducci M, George D, Mahoney JF, Stadler WM, et al. Randomized, double-blind, placebo-controlled phase III trial comparing docetaxel and prednisone with or without bevacizumab in men with metastatic castration-resistant prostate cancer: CALGB 90401. JCO. 2012;30:1534–40.
Parker C, Heinrich D, O’Sullivan JM, Fossa S, Chodacki A, Demkow T, et al. Overall survival benefit of radium-223 chloride (Alpharadin™) in the treatment of patients with symptomatic bone metastases in castration-resistant prostate cancer (CRPC): a phase III randomized trial (ALSYMPCA). Eur J Cancer. 2011;47:3.
Dancey JE, Dobbin KK, Groshen S, Jessup JM, Hruszkewycz AH, Koehler M, Biomarkers Task Force of the NCI Investigational Drug Steering Committee, et al. Guidelines for the development and incorporation of biomarker studies in early clinical trials of novel agents. Clin Cancer Res. 2010;16:1745–55.
Barbieri CE, Bangma CH, Bjartell A, Catto JWF, Culig Z, Grönberg H, et al. The mutational landscape of prostate cancer. Eur Urol. 2013;64:567–76.
Appendix: Jadad Scale for Reporting Randomized Controlled Trials. Evidence-based obstetric anesthesia. Wiley. 2007. p. 237–8. https://onlinelibrary.wiley.com/doi/abs/10.1002/9780470988343.app1. Accessed 24 Apr 2020.
Ottawa Hospital Research Institute. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed 22 Apr 2020.
Sieuwerts AM, Onstenk W, Kraan J, Beaufort CM, Van M, De Laere B, et al. AR splice variants in circulating tumor cells of patients with castration-resistant prostate cancer: relation with outcome to cabazitaxel. Mol Oncol. 2019;13:1795–807.
Belderbos BPS, Sieuwerts AM, Hoop EO, Mostert B, Kraan J, Hamberg P, et al. Associations between AR-V7 status in circulating tumour cells, circulating tumour cell count and survival in men with metastatic castration-resistant prostate cancer. Eur J Cancer. 2019;121:48–54.
Cattrini C, Rubagotti A, Zinoli L, Cerbone L, Zanardi E, Capaia M, et al. Role of circulating tumor cells (CTC), Androgen receptor full length (AR-FL) and Androgen Receptor Splice Variant 7 (AR-V7) in a prospective cohort of castration-resistant metastatic prostate cancer patients. Cancers. 2019;11:1365.
Qu Y, Dai B, Ye D, Kong Y, Chang K, Jia Z, et al. Constitutively active AR-V7 plays an essential role in the development and progression of castration-resistant prostate cancer. Sci Rep. 2015;5:7654.
Antonarakis ES, Lu C, Luber B, Wang H, Chen Y, Zhu Y, et al. Clinical significance of androgen receptor splice variant-7 mRNA detection in circulating tumor cells of men with metastatic castration-resistant prostate cancer treated with first- and second-line abiraterone and enzalutamide. J Clin Oncol. 2017;35:2149–56.
Qu F, Xie W, Nakabayashi M, Zhang H, Jeong SH, Wang X, et al. Association of AR-V7 and prostate-specific antigen RNA levels in blood with efficacy of abiraterone acetate and enzalutamide treatment in men with prostate cancer. Clin Cancer Res. 2017;23:726–34.
Carles J, Castellano D, Méndez-Vidal M-J, Mellado B, Saez M-I, González Del Alba A, et al. Circulating tumor cells as a biomarker of survival and response to radium-223 therapy: experience in a cohort of patients with metastatic castration-resistant prostate cancer. Clin Genitourin Cancer. 2018;16:e1133–9.
De Kruijff IE, Sieuwerts AM, Onstenk W, Kraan J, Smid M, Van MN, et al. Circulating tumor cell enumeration and characterization in metastatic castration-resistant prostate cancer patients treated with cabazitaxel. Cancers. 2019;11:1212.
Bitting RL, Healy P, Halabi S, George DJ, Goodin M, Armstrong AJ. Clinical phenotypes associated with circulating tumor cell enumeration in metastatic castration-resistant prostate cancer. Urol Oncol. 2015;33(110):e1–9.
Josefsson A, Linder A, Flondell Site D, Canesin G, Stiehm A, Anand A, et al. Circulating tumor cells as a marker for progression-free survival in metastatic castration-naïve prostate cancer. Prostate. 2017;77:849–58.
Nguyen NC, Shah M, Appleman LJ, Parikh R, Mountz JM. Radium-223 therapy for patients with metastatic castrate-resistant prostate cancer: an update on literature with case presentation. Int J Mol Imaging. 2016. https://www.hindawi.com/journals/ijmi/2016/2568031/. Accessed 22 Jun 2020.
Vaishampayan UN, Podgorski I, Heilbrun LK, Lawhorn-Crews JM, Dobson KC, Boerner J, et al. Biomarkers and bone imaging dynamics associated with clinical outcomes of oral cabozantinib therapy in metastatic castrate-resistant prostate cancer. Clin Cancer Res. 2019;25:652–62.
Lara PN, Plets M, Tangen C, Gertz E, Vogelzang NJ, Hussain M, et al. Bone turnover biomarkers identify unique prognostic risk groups in men with castration resistant prostate cancer and skeletal metastases: results from SWOG S0421. Cancer Treat Res Commun. 2018;16:18–23.
Naito M, Ukai R, Hashimoto K. Bone scan index can be a useful biomarker of survival outcomes in patients with metastatic castration-resistant prostate cancer treated with radium-223. Cancer Rep. 2019;2:e1203.
Dizdarevic S, Jessop M, Begley P, Main S, Robinson A. 223Ra-Dichloride in castration-resistant metastatic prostate cancer: improving outcomes and identifying predictors of survival in clinical practice. Eur J Nucl Med Mol Imaging. 2018;45:2264–73.
Miyoshi Y, Sakamoto S, Kawahara T, Uemura K, Yokomizo Y, Uemura H. Correlation between automated bone scan index change after cabazitaxel and survival among men with castration-resistant prostate cancer. Urol Int. 2019;103:279–84.
Hammerich K, Donahue T, Rosner I, Cullen J, Kuo H-C, Hurwitz L, et al. Alkaline phosphatase velocity predicts overall survival and bone metastasis in patients with castration-resistant prostate cancer. Urol Oncol Semin Orig Invest. 2017;35:460.e21–8.
Anand A, Morris MJ, Larson SM, Minarik D, Josefsson A, Helgstrand JT, et al. Automated Bone Scan Index as a quantitative imaging biomarker in metastatic castration-resistant prostate cancer patients being treated with enzalutamide. EJNMMI Res. 2016;6:23.
Onal C, Sedef AM, Kose F, Oymak E, Guler OC, Sumbul AT, et al. The hematologic parameters in metastatic castration-resistant prostate cancer patients treated with abiraterone acetate. Future Oncol. 2019;15:1469–79.
Loubersac T, Nguile-Makao M, Pouliot F, Fradet V, Toren P. Neutrophil-to-lymphocyte ratio as a predictive marker of response to abiraterone acetate: a retrospective analysis of the COU302 study. Eur Urol Oncol. 2019;3:298–305.
Tatenuma T, Kawahara T, Hayashi N, Hasumi H, Makiyama K, Nakaigawa N, et al. The pretherapeutic neutrophil-to-lymphocyte ratio for docetaxel-based chemotherapy is useful for predicting the prognosis of japanese patients with castration-resistant prostate cancer. Biomed Res Int. 2019;2019:2535270.
Kumano Y, Hasegawa Y, Kawahara T, Yasui M, Miyoshi Y, Matsubara N, et al. Pretreatment neutrophil to lymphocyte ratio (NLR) predicts prognosis for castration resistant prostate cancer patients underwent enzalutamide. BioMed Res Int. 2019. https://www.hindawi.com/journals/bmri/2019/9450838/. Accessed 6 Apr 2020.
Lorente D, Mateo J, Templeton AJ, Zafeiriou Z, Bianchini D, Ferraldeschi R, et al. Baseline neutrophil-lymphocyte ratio (NLR) is associated with survival and response to treatment with second-line chemotherapy for advanced prostate cancer independent of baseline steroid use. Ann Oncol. 2015;26:750–5.
Koo KC, Lee JS, Ha JS, Han KS, Lee KS, Hah YS, et al. Optimal sequencing strategy using docetaxel and androgen receptor axis-targeted agents in patients with castration-resistant prostate cancer: utilization of neutrophil-to-lymphocyte ratio. World J Urol. 2019;37:2375–84.
Song W, Kwon GY, Kim JH, Lim JE, Jeon HG, Il Seo S, et al. Immunohistochemical staining of ERG and SOX9 as potential biomarkers of docetaxel response in patients with metastatic castration-resistant prostate cancer. Oncotarget. 2016;7:83735–43.
Berg KD, Røder MA, Thomsen FB, Vainer B, Gerds TA, Brasso K, et al. The predictive value of ERG protein expression for development of castration-resistant prostate cancer in hormone-naïve advanced prostate cancer treated with primary androgen deprivation therapy. Prostate. 2015;75:1499–509.
Ando K, Sakamoto S, Takeshita N, Fujimoto A, Maimaiti M, Saito S, et al. Higher serum testosterone levels predict poor prognosis in castration-resistant prostate cancer patients treated with docetaxel. Prostate. 2020;80:247–55.
Hashimoto K, Tabata H, Shindo T, Tanaka T, Hashimoto J, Inoue R, Sapporo Medical University Urologic Oncology Consortium (SUOC), et al. Serum testosterone level is a useful biomarker for determining the optimal treatment for castration-resistant prostate cancer. Urol Oncol. 2019;37:485–91.
Shiota M, Kashiwagi E, Murakami T, Takeuchi A, Imada K, Inokuchi J, et al. Serum testosterone level as possible predictive marker in androgen receptor axis-targeting agents and taxane chemotherapies for castration-resistant prostate cancer. Urol Oncol. 2019;37:180.e19–24.
Wang Y, Dai B, Ye D-W. Serum testosterone level predicts the effective time of androgen deprivation therapy in metastatic prostate cancer patients. Asian J Androl. 2017;19:178–83.
Yasuoka S, Yuasa T, Ogawa M, Komai Y, Numao N, Yamamoto S, et al. Risk factors for poor survival in metastatic castration-resistant prostate cancer treated with cabazitaxel in Japan. Anticancer Res. 2019;39:5803–9.
Kosaka T, Hongo H, Mizuno R, Oya M. Risk stratification of castration-resistant prostate cancer patients treated with cabazitaxel. Mol Clin Oncol. 2018;9:683–8.
Belderbos BPS, de Wit R, Hoop EO, Nieuweboer A, Hamberg P, van Alphen RJ, et al. Prognostic factors in men with metastatic castration-resistant prostate cancer treated with cabazitaxel. Oncotarget. 2017;8:106468–74.
Pei X, Wu K, Sun Y, Gao X, Gou X, Xu J, Chinese Prostate Cancer Consortium, et al. PSA time to nadir as a prognostic factor of first-line docetaxel treatment in castration-resistant prostate cancer: multicenter validation in patients from the Chinese Prostate Cancer Consortium. Urol Oncol. 2020;38:2.e11–7.
Yang K-F, Lee H-Y, Wu W-J, Huang C-H, Chou Y-H, Huang C-N, et al. Prediction for survival following docetaxel-based chemotherapy in Taiwanese men with castration-resistant metastatic prostate cancer. Urol Sci. 2015;26:271–6.
Lin T-T, Chen Y-H, Wu Y-P, Chen S-Z, Li X-D, Lin Y-Z, et al. Risk factors for progression to castration-resistant prostate cancer in metastatic prostate cancer patients. J Cancer. 2019;10:5608–13.
Ji G, Song G. Rapidly decreasing level of prostate-specific antigen during initial androgen deprivation therapy is a risk factor for early progression to castration-resistant prostate cancer. Ann Oncol. 2017;28:x77.
He M, Liu H, Cao J, Wang Q, Xu H, Wang Y. Predicting castration-resistant prostate cancer after combined androgen blockade. Oncotarget. 2017;8:105458–62.
Kuo KF, Hunter-Merrill R, Gulati R, Hall SP, Gambol TE, Higano CS, et al. Relationships between times to testosterone and prostate-specific antigen rises during the first off-treatment interval of intermittent androgen deprivation are prognostic for castration resistance in men with nonmetastatic prostate cancer. Clin Genitourin Cancer. 2015;13:10–6.
Hamano I, Hatakeyama S, Narita S, Takahashi M, Sakurai T, Kawamura S, et al. Impact of nadir PSA level and time to nadir during initial androgen deprivation therapy on prognosis in patients with metastatic castration-resistant prostate cancer. World J Urol. 2019;37:2365–73.
Fukuoka K, Teishima J, Nagamatsu H, Inoue S, Hayashi T, Mita K, et al. Predictors of poor response to first-generation anti-androgens as criteria for alternate treatments for patients with non-metastatic castration-resistant prostate cancer. Int Urol Nephrol. 2020;52:77–85.
Kodama H, Hatakeyama S, Narita S, Takahashi M, Sakurai T, Kawamura S, et al. Clinical characterization of low prostate-specific antigen on prognosis in patients with metastatic castration-naive prostate cancer. Clin Genitourin Cancer. 2019;17:e1091–8.
Sathekge M, Bruchertseifer F, Vorster M, Lawal IO, Knoesen O, Mahapane J, et al. Predictors of overall and disease-free survival in metastatic castration-resistant prostate cancer patients receiving 225Ac-PSMA-617 radioligand therapy. J Nucl Med. 2020;61:62–9.
Rahbar K, Boegemann M, Yordanova A, Eveslage M, Schäfers M, Essler M, et al. PSMA targeted radioligandtherapy in metastatic castration resistant prostate cancer after chemotherapy, abiraterone and/or enzalutamide. A retrospective analysis of overall survival. Eur J Nucl Med Mol Imaging. 2018;45:12–9.
Ahmadzadehfar H, Schlolaut S, Fimmers R, Yordanova A, Hirzebruch S, Schlenkhoff C, et al. Predictors of overall survival in metastatic castration-resistant prostate cancer patients receiving [177Lu]Lu-PSMA-617 radioligand therapy. Oncotarget. 2017;8:103108–16.
Alvim CM, Mansinho A, Paiva RS, Brás R, Semedo PM, Lobo-Martins S, et al. Prognostic factors for patients treated with abiraterone. Future Sci OA. 2019;6:FSO436.
Schiff JP, Cotogno P, Feibus A, Steinwald P, Ledet E, Lewis B, et al. Early prostate-specific antigen response post-abiraterone as predictor of overall survival in metastatic castrate-resistant prostate cancer. BMC Cancer. 2019;19:524.
Houédé N, Beuzeboc P, Gourgou S, Tosi D, Moise L, Gravis G, et al. Abiraterone acetate in patients with metastatic castration-resistant prostate cancer: long term outcome of the Temporary Authorization for Use programme in France. BMC Cancer. 2015;15:222.
Chang L-W, Hung S-C, Wang S-S, Li J-R, Yang C-K, Chen C-S, et al. Abiraterone acetate and enzalutamide: similar efficacy in treating post docetaxel metastatic castration-resistant prostate cancer: single center experience. Anticancer Res. 2019;39:3901–8.
Fan L, Dong B, Chi C, Wang Y, Gong Y, Sha J, et al. Abiraterone acetate for chemotherapy-naive metastatic castration-resistant prostate cancer: a single-centre prospective study of efficacy, safety, and prognostic factors. BMC Urol. 2018;18:110.
Miyake H, Hara T, Tamura K, Sugiyama T, Furuse H, Ozono S, et al. Independent association between time to prostate-specific antigen (PSA) nadir and PSA progression-free survival in patients with docetaxel-naïve, metastatic castration-resistant prostate cancer receiving abiraterone acetate, but not enzalutamide. Urol Oncol. 2017;35:432–7.
Papazoglou D, Wannesson L, Berthold D, Cathomas R, Gillessen S, Rothermundt C, et al. Enzalutamide in patients with castration-resistant prostate cancer progressing after docetaxel: retrospective analysis of the swiss enzalutamide named patient program. Clin Genitourin Cancer. 2017;15:e315–23.
Armstrong AJ, Lin P, Higano CS, Iversen P, Sternberg CN, Tombal B, et al. Prognostic association of prostate-specific antigen decline with clinical outcomes in men with metastatic castration-resistant prostate cancer treated with enzalutamide in a randomized clinical trial. Eur Urol Oncol. 2019;2:677–84.
Kobayashi T, Namitome R, Hirata YU, Shiota M, Imada K, Kashiwagi E, et al. Serum prognostic factors of androgen-deprivation therapy among Japanese men with de novo metastatic prostate cancer. Anticancer Res. 2019;39:3191–5.
Hiew K, Hart CA, Ali A, Elliott T, Ramani V, Sangar V, et al. Primary mutational landscape linked with pre-docetaxel lactate dehydrogenase levels predicts docetaxel response in metastatic castrate-resistant prostate cancer. Eur Urol Focus. 2019;5:831–41.
Gravis G, Boher J-M, Fizazi K, Joly F, Priou F, Marino P, et al. Prognostic factors for survival in noncastrate metastatic prostate cancer: validation of the glass model and development of a novel simplified prognostic model. Eur Urol. 2015;68:196–204.
Mori K, Kimura T, Onuma H, Kimura S, Yamamoto T, Sasaki H, et al. Lactate dehydrogenase predicts combined progression-free survival after sequential therapy with abiraterone and enzalutamide for patients with castration-resistant prostate cancer. Prostate. 2017;77:1144–50.
Miyoshi Y, Ohtaka M, Kawahara T, Ohtake S, Yasui M, Uemura K, et al. Prediction of time to castration-resistant prostate cancer using low-molecular-weight protein tyrosine phosphatase expression for men with metastatic hormone-naïve prostate cancer. Urol Int. 2019;102:37–42.
Ohtaka M, Miyoshi Y, Kawahara T, Ohtake S, Yasui M, Uemura K, et al. Low-molecular-weight protein tyrosine phosphatase expression as a prognostic factor for men with metastatic hormone-naïve prostate cancer. Urol Oncol. 2017;35:607.e9–14.
Cary KC, Cooperberg MR. Biomarkers in prostate cancer surveillance and screening: past, present, and future. Ther Adv Urol. 2013;5:318–29.
Fuerea A, Baciarello G, Patrikidou A, Albigès L, Massard C, Di Palma M, et al. Early PSA response is an independent prognostic factor in patients with metastatic castration-resistant prostate cancer treated with next-generation androgen pathway inhibitors. Eur J Cancer. 2016;61:44–51.
Van Gils MPMQ, Stenman UH, Schalken JA, Schröder FH, Luider TM, Lilja H, et al. Innovations in serum and urine markers in prostate cancer current European research in the P-Mark project. Eur Urol. 2005;48:1031–41.
Saylor PJ, Armstrong AJ, Fizazi K, Freedland S, Saad F, Smith MR, et al. New and emerging therapies for bone metastases in genitourinary cancers. Eur Urol. 2013;63:309–20.
Van Soest RJ, Templeton AJ, Vera-Badillo FE, Mercier F, Sonpavde G, Amir E, et al. Neutrophil-to-lymphocyte ratio as a prognostic biomarker for men with metastatic castration-resistant prostate cancer receiving first-line chemotherapy: data from two randomized phase III trials. Ann Oncol. 2015;26:743–9.
Leibowitz-Amit R, Templeton AJ, Omlin A, Pezaro C, Atenafu EG, Keizman D, et al. Clinical variables associated with PSA response to abiraterone acetate in patients with metastatic castration-resistant prostate cancer. Ann Oncol. 2014;25:657–62.
Templeton AJ, Pezaro C, Omlin A, McNamara MG, Leibowitz-Amit R, Vera-Badillo FE, et al. Simple prognostic score for metastatic castration-resistant prostate cancer with incorporation of neutrophil-to-lymphocyte ratio. Cancer. 2014;120:3346–52.
Scher HI, Morris MJ, Larson S, Heller G. Validation and clinical utility of prostate cancer biomarkers. Nat Rev Clin Oncol. 2013;10:225–34.
Park S-W, Kim JH, Lee HJ, Shin DH, Lee SD, Yoon S. The expression of androgen receptor and its variants in human prostate cancer tissue according to disease status, and its prognostic significance. World J Mens Health. 2019;37:68–77.
Galletti G, Portella L, Tagawa ST, Kirby BJ, Giannakakou P, Nanus DM. Circulating tumor cells in prostate cancer diagnosis and monitoring: an appraisal of clinical potential. Mol Diagn Ther. 2014;18:389–402.
Kodama K, Tojjar D, Yamada S, Toda K, Patel CJ, Butte AJ. Ethnic differences in the relationship between insulin sensitivity and insulin response: a systematic review and meta-analysis. Diabetes Care. 2013;36:1789–96.
Acknowledgements
The author would like to acknowledge Anwesha Mandal and Dr. Anuradha Nalli (Indegene Pvt Ltd, India), for their medical writing support.
Funding
The work was supported by Natural Science Research Foundation of Jilin Province for Sciences and Technology (20200201575JC).
Author information
Authors and Affiliations
Contributions
Conceptualization: ST and MP. Data curation: ST and ZS. Investigation: MP. Methodology: ST, ZL and MP. Writing-original draft: ST, ZL, ZG. Writing-review and editing: ST, DX, and MP. All authors read and approved the final manuscript.
Corresponding authors
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Tian, S., Lei, Z., Gong, Z. et al. Clinical implication of prognostic and predictive biomarkers for castration-resistant prostate cancer: a systematic review. Cancer Cell Int 20, 409 (2020). https://doi.org/10.1186/s12935-020-01508-0
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s12935-020-01508-0