|Year : 2017 | Volume
| Issue : 2 | Page : 143-148
Understanding prostate-specific antigen dynamics in monitoring metastatic castration-resistant prostate cancer: implications for clinical practice
Atsushi Mizokami1, Kouji Izumi1, Hiroyuki Konaka1, Yasuhide Kitagawa1, Yoshifumi Kadono1, Kazutaka Narimoto1, Takahiro Nohara1, Amit K Bahl2, Mikio Namiki1
1 Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi Kanazawa, 920-8640 Japan
2 Bristol Haematology and Oncology Centre, University Hospitals Bristol, Bristol, BS2 8ED, UK
|Date of Submission||06-Aug-2015|
|Date of Decision||11-Oct-2015|
|Date of Acceptance||01-Mar-2016|
|Date of Web Publication||03-Jun-2016|
Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1 Takaramachi Kanazawa, 920-8640 Japan
Source of Support: None, Conflict of Interest: None
Availability of novel hormonal therapies as well as docetaxel and cabazitaxel treatment for metastatic castration-resistant prostate cancer (CRPC) has changed the outlook for this group of patients with improvements in progression-free survival and overall survival. Physicians often diagnose the progression of prostate cancer using serum prostate-specific antigen (PSA). However, serum PSA is not always correlated with the clinical status in CRPC. To evaluate the PSA dynamics with greater precision, understanding of the control of PSA and of the mechanisms of development of CRPC is needed. Moreover, it is necessary to use new hormonal therapies with an appropriate timing to optimally improve the prognosis and the QOL of the patients. In the present review, we ascertain the PSA dynamics and the mechanisms of the development of CRPC to assist in optimal utilization of the new treatments for mCRPC.
Keywords: castration-resistant prostate cancer; new hormonal therapy; prostate-specific antigen
|How to cite this article:|
Mizokami A, Izumi K, Konaka H, Kitagawa Y, Kadono Y, Narimoto K, Nohara T, Bahl AK, Namiki M. Understanding prostate-specific antigen dynamics in monitoring metastatic castration-resistant prostate cancer: implications for clinical practice. Asian J Androl 2017;19:143-8
|How to cite this URL:|
Mizokami A, Izumi K, Konaka H, Kitagawa Y, Kadono Y, Narimoto K, Nohara T, Bahl AK, Namiki M. Understanding prostate-specific antigen dynamics in monitoring metastatic castration-resistant prostate cancer: implications for clinical practice. Asian J Androl [serial online] 2017 [cited 2017 Mar 1];19:143-8. Available from: http://www.ajandrology.com/text.asp?2017/19/2/143/179159 - DOI: 10.4103/1008-682X.179159
| Introduction|| |
Androgen deprivation therapy (ADT) is generally the first choice for the management of advanced prostate cancer. Unfortunately, after an initial response to ADT, prostate cancer eventually loses responsiveness to the androgen blockade and progresses into castration-resistant prostate cancer (CRPC). Physicians often use prostate-specific antigen (PSA) as a biomarker to diagnose and follow-up prostate cancer. Especially, elevation of serum PSA during ADT contributes to the early diagnosis of CRPC. The serum PSA value, however, does not always correlates with the malignant state of CRPC. In some cases, there can be worsening of symptoms though the PSA values are low and stable in that patient.
Recently, new hormonal therapy agents, abiraterone acetate and enzalutamide, which block androgen receptor (AR) axis signal pathway are available for the treatment of CRPC. These medicines eventually improve the prognosis of patients with CRPC. However, the optimal timing for use of these novel hormonal therapies is still not clearly established. Therefore, physicians need to understand the mechanisms by which progression of prostate cancer may affect the serum PSA and subsequent development of CRPC.
In this review article, we describe the implications of changes in PSA dynamics and mechanisms of development of CRPC. We also discuss on optimizing treatment strategies in the use of classical hormonal therapies and new hormonal therapies.
| What is the Mechanism of Serum PSA Changes?|| |
PSA was first purified from prostate and seminal plasma. Wang et al. examined the serum PSA in patients with prostate cancer, since PSA was localized within prostatic ductal epithelial cells and was secreted into the medium where prostate cancer-derived cell lines were cultured., They found that serum PSA value decreased in respond to the treatment and increased on recurrence of prostate cancer. Now, PSA has been widely used for the diagnosis of prostate cancer and for monitoring patients with prostate cancer. PSA is especially available as a good tool to diagnose the progression of prostate cancer after androgen deprivation therapy (ADT) or chemotherapy. PSA (KLK3), one of the kallikrein-related peptidases (KLKs) belonging to a family of proteases, is associated with sperm motility by changing semen liquefaction.,, In cancer, PSA may induce the adhesion of prostate cancer cells to bone marrow cells and proliferation of osteoblasts.,
The expression of PSA mRNA is usually stimulated by androgens. This regulation is mainly mediated through the PSA promoter that contains at least three androgen-response elements (AREs), ([Figure 1]). Especially, the 4.1 kb upstream region of the transcription initiation site of PSA mRNA is extremely important for the androgens to induce PSA promoter activity., When androgen receptor (AR) with DHT binds to AREs of the PSA promoter, the expression of PSA mRNA is up-regulated. Conversely, the PSA mRNA expression in the prostate is down-regulated by ADT, and the serum PSA protein level is also decreased. PSA itself, however, is not a growth factor that stimulates the proliferation of prostate cancer directly. The proliferation of LNCaP-SF cells in charcoal-stripped fetal calf serum instead of fetal calf serum from androgen-sensitive LNCaP cells was repressed by DHT, although the expression of PSA mRNA was simultaneously induced by DHT in a dose-dependent manner, suggesting that the proliferation of prostate cancer cells is not always correlated with the expression of PSA.
|Figure 1: Primary structure of the PSA promoter. PSA mRNA is transcribed from the transcription initiation site (TIS) (+1). E: EcoRI, C: ClaI, X: XbaI, and H: Hind III restriction enzyme site. The consensus sequence of androgen response element (ARE) is AGAACAnnnTGTTCT.|
Click here to view
Postulated mechanisms that explain why serum PSA is elevated in prostate cancer before ADT are (1) Because basal cells disappear in prostate cancer, and the ductal structure is destroyed, PSA can leak easily into the blood stream from a duct, (2) AR activity can also be elevated by some mechanisms, such as AR amplification, increased AR protein, or involvement of various AR coactivators,, (3) On a tumor volume effect with an increased number of prostate cancer cells, serum PSA is elevated as cells secrete a slight dose of PSA. For example, if patients with prostate cancer have many bone metastases, the serum PSA level should increase. However, the serum PSA levels are considerably different among patients even when the levels of bone metastases and local prostate volume are practically similar.
| Mechanisms of PSA Decrease and Increase during Hormonal Therapy|| |
As described above, PSA expression from one prostate cancer cell is basically regulated by the androgens' axis, and the serum PSA level is regulated not only by androgen, but also by tumor volume. [Figure 2] shows one typical clinical case in which prostate cancer with bone metastasis was treated with ADT.
|Figure 2: Change of bone metastasis volume and PSA levels by ADT. (a) Bone scan index (BSI) was measured by EXINI bone (BONENAVI). (b) Changes in PSA, bone metabolic markers (BAP and I-CTP), and BSI by hormonal therapy. Flu: flutamide and EMP: estramustine phosphate. (c) Change of PSA and mechanism of PSA rising during ADT.|
Click here to view
This case illustrates the mechanism of PSA decrease and increase during ADT. The initial serum PSA was 2163 ng ml−1 , Gleason score was 4 + 4 = 8, and Stage was T4, N1, and M1b. When the bone metastasis extent was measured using the EXINI bone (BONENAVI) computer-assisted diagnosis (CAD) system,, the bone scan index (BSI) was 3.9% ([Figure 2]a). After the patient had been treated with LH-RH agonist and bicalutamide as initial ADT, the serum PSA level decreased to 12.1 ng ml−1 rapidly in 3 months. The half-life of serum PSA in this period was approximately 12 days ([Figure 2]b). Most likely, the initial rapid decrease of serum PSA was a result from the inactivation of PSA promoter by ADT (PSA-androgen response phase in [Figure 2]c). Then, the serum PSA gradually decreased to a nadir 3.1 ng ml−1 in the next 6 months. The half-life of serum PSA in this period was approximately 90 days ([Figure 2]b). The slow decrease of the serum PSA could be resulted from a decrease of the prostate cancer cell number by apoptosis through several signal pathways induced by ADT (tumor regression phase in [Figure 2]c). After this phase, the decrease in the serum PSA stopped and reached nadir (3.1 ng ml−1 ). BSI also decreased to 0.12% ([Figure 2]b). In this situation, the ratio of proliferating cells and dying cells is potentially balanced (proliferation quiescent phase in [Figure 2]c). Finally, prostate cancer cell proliferation that was regulated by ADT relapsed became castration-resistant prostate cancer (CRPC). As a follow-up, serum PSA increased to 41.8 ng ml−1 after 8 months of the PSA nadir. BSI was also elevated to 4.3% after 10 months of PSA nadir. Although serum PSA was still low (approximately 2% compared with the initial serum PSA value), BSI in this situation was almost at the same value as at initial diagnosis. What does this mean? Several mechanisms of progression into CRPC have been proposed, such as AR mutation, adaptation to low androgen environment, and clonal selection.,,,,, A great deal of interest has been paid to the clonal selection of androgen-independent prostate cancer cells in these mechanisms. When AR expression in prostate cancer tissue is investigated by immunohistochemistry, AR expression is often heterogeneous in cancer patients. AR expression was significantly correlated with the endocrine response, time to progression, and survival (P = 0.02)., AR content in prostate tumor cells also became more variable with an increasing Gleason score. As described above, tumor volume effect caused by AR-negative prostate cancer cells (androgen-independent prostate cancer cells) at the bone metastasis site might raise serum PSA in this CRPC case ([Figure 2]c). Therefore, the severity in bone metastases in CRPC can be the same as pretreatment even if the serum PSA on CRPC is at a low value, since growth factors in bone can replace androgens as stimulators of cancer cell proliferation.
As described in this case, sometimes, the degree of bone metastases does not coincide with an absolute value of serum PSA. Clinicians, therefore, need to examine not only serum PSA level, but also bone scintigraphy regularly when they follow-up CRPC patients with bone metastasis.
| Level of PSA Nadir and Prognosis|| |
It is generally accepted that the scenario of a patient having high Gleason score in spite of low serum PSA level at initial diagnosis is often associated with a poor prognosis compared with a low Gleason score. In such cases, the level of AR expression might be low or the ratio of AR-positive cells might be low in the prostate cancer tissue. In this situation, the serum PSA level can be low because PSA is mainly regulated by androgen as described above.
Clinicians also recognize that the prognosis of patients with a high PSA nadir after ADT is generally poor., There is no clear evidence to explain the mechanisms of this observation. We hypothesize that the presence of androgen-independent prostate cancer cells before ADT could explain this observation ([Figure 3]). When the majority of prostate cancer cells are androgen-sensitive, and androgen-independent cells hardly exist before ADT, decline of serum PSA is dependent on ADT and on apoptosis by ADT ([Figure 3]a). Moreover, the cases that take long time until a serum PSA level reaches a nadir and a serum PSA is elevated again during ADT have better prognosis. This reason is that a ratio of androgen-independent cells is low before ADT, and it takes long time for androgen-sensitive prostate cancer cells to adapt themselves to low androgen environment. In contrast, when a lot of androgen-independent cells exist and the ratio of these cells is high before ADT, ADT cannot diminish serum PSA level dramatically and PSA nadir is high because the serum PSA level is dependent on the total number of androgen-independent prostate cancer cells as described above ([Figure 3]b). In such cases, the effectiveness of second-line anti-androgen may not be so promising due to the preponderance of androgen-independent prostate cancer cells.
|Figure 3: Potential explanation for the prognosis of a patient where the PSA nadir is high and time to PSA nadir is short is generally poor. (a) Situation with few androgen-independent cells before ADT. (b) Situation with many androgen-independent cells before ADT. (c) Docetaxel decreases the number of androgen-independent prostate cancer cells.|
Click here to view
CHAARTED trial (Androgen ablation therapy with or without chemotherapy in treating patients with metastatic prostate cancer) and STAMPEDE trial (Docetaxel and/or zoledronic acid for hormone-naive prostate cancer: first overall survival results from STAMPEDE) showed that addition of six courses of docetaxel chemotherapy to initial hormonal therapy improved overall survival in patients with hormone-naive metastatic prostate cancer., These results indicate that androgen-independent prostate cancer cells present in high volume metastatic prostate cancer before ADT may be potentially killed by initial docetaxel treatment ([Figure 3]c).
| New Hormonal Therapies|| |
Recently, new hormonal agents have been available for CRPC treatment, one being enzalutamide, a second-generation anti-androgen while the other one is abiraterone acetate, an adrenal androgen synthesis inhibitor. When we look at the effectiveness of these new agents, we notice a difference in responsiveness for these new agents between overseas and Japan. In the AFFIRM trial (phase 3, double-blind, placebo-controlled trial, 1199 men with CRPC after chemotherapy), the major clinical efficacy end points, overall survival (OS), and time to PSA progression (TTPP) were evaluated. Enzalutamide consistently improved OS and TTPP compared with placebo. The median OS was 18.4 months (95% confidence interval [95% CI], 17.3 to not yet reached) in the enzalutamide group versus 13.6 months (95% CI, 11.3-15.8) in the placebo group, and TTPP was 8.3 in the enzalutamide group versus 2.9 months in the placebo group (hazard ratio, 0.40; P < 0.001). In Japan, a single arm phase 1/2 study was conducted. The median OS and TTPP were 10.6 months (95% CI, 6.9 to not yet reached) and 4.1 months (95% CI, 2.9-6.6) after chemotherapy in the enzalutamide group, respectively. In Japan, enzalutamide did not improved OS and TTPP like in the AFFIRM trial. A phenomenon similar to the clinical studies with enzalutamide was observed in clinical studies with abiraterone acetate. The COU-AA-301 randomized, double-blind, placebo-controlled phase 3 study showed that median OS for the abiraterone group was longer than in the placebo group (15.8 months [95% CI, 14.8-17.0] vs 11.2 months [10.4-13.1]; 95% CI, 0.64-0.86; P < 0.0001). Median TTPP was also improved in the abiraterone group (8.5 months, 95% CI, 8.3-11.1, vs 6.6 months, 5.6-8.3, in the placebo group). In a similar study conducted in Japan (JNJ-212082-JPN-202), median TTPP in JNJ-212082-JPN-202 study in the abiraterone acetate group was shorter than overseas (3.6 months [2.8-3.8]).
We speculate that the reason why the overseas results were better than the Japanese ones in both the enzalutamide and abiraterone acetate studies is mainly due to a difference of the number of anti-androgens used before chemotherapy ([Figure 4]). In the AFFIRM study, 338/392 (86.2%) of patients were treated only with 0, first-line, or second-line hormonal therapy before enrollment. In contrast, all patients were treated with second-, third- or fourth-line hormonal therapy before enrollment in Japan. In the COU-AA-301 study, 18%, 65%, and 15% of registered patients were treated with 0, 1, and 2 anti-androgens, respectively. In contrast, 0%, 12.8%, 48.9%, 23.4%, 10.6%, and 4.3% of enrolled patients were treated with 0, 1, 2, 3, 4, and 5 anti-androgens in Japan, respectively. The AFFIRM and COU-AA-301 studies revealed that docetaxel is eventually not sufficient to attack androgen-hypersensitive prostate cancer cells. However, sequential classical hormonal therapies including anti-androgens (bicalutamide, flutamide, chlormadinone acetate, and estrogens) in Japan might regulate androgen-hypersensitive prostate cancer cells ([Figure 5]).
|Figure 4: Number of anti-androgens before docetaxel treatment. (a) Clinical trial of abiraterone acetate after docetaxel. (b) Clinical trial of enzalutamide after docetaxel.|
Click here to view
|Figure 5: Difference of cell population between overseas patients and Japanese patients when new hormonal therapies were used after docetaxel treatment for metastatic disease. The situation of the cell population at the time of the clinical study (abiraterone and enzalutamide) performed abroad (a) and Japan (b).|
Click here to view
Another reason for the enzalutamide and abiraterone studies in Japan showing inferior results to the pivotal registration trials overseas could be due to difference of the use of docetaxel in Japan. Although docetaxel can be used only up to ten courses irrespective of the effectiveness in overseas, in Japan, it is used for as many courses as required without limitation as long as docetaxel is effective and is being tolerated. Use of docetaxel for a long time (more than ten courses) may inhibit the growth of androgen-hypersensitive prostate cancer cells. It is possible that the patients who were registered in the trials were treated with docetaxel for a long time. When CRPC relapses again after docetaxel treatment in Japan, it is very likely that CRPC has already lost androgen sensitivity. As a result of these reasons, enzalutamide and abiraterone acetate may not be so effective after long-term docetaxel treatment any more in Japan.
These causes may reflect the relative inefficacy of novel hormonal therapies after docetaxel treatment in Japan. Therefore, clinicians need to consider the total duration of docetaxel treatment and prior hormonal therapies to optimize the use of novel hormonal therapies.
| Future Treatment Strategy for CRPC|| |
Clinicians should confirm the PSA nadir level and time to PSA nadir following primary ADT. These surrogate markers would predict the prognosis of CRPC. The previous duration of response to ADT may also become a predictor of sensitivity to next generation AR axis-targeted drugs in patients with mCRPC. However, there is no clear evidence about the optimal sequencing strategy to achieve the best prognosis, namely the new hormonal therapies (enzalutamide or abiraterone acetate) or docetaxel treatment.
Based on the mechanism of PSA elevation described above, clinicians can postulate which cell population contributes to the progression of prostate cancer after classical hormonal therapy. To help distinguish the predominant cell population in CRPC after classical hormonal therapy, the use of classical second-line anti-androgen therapy may be one alternative. When classical second-line anti-androgen therapy is not effective, it can be considered that an androgen-independent cell population has become predominant and the AR axis plays a minor role in the progression of disease. In this case, docetaxel could be used first before using new hormonal therapy. In contrast, it can be hypothesized that the AR axis is clearly involved in recurrence when anti-androgen reduces serum PSA level., The prognosis of such patients is expected to be better. Considerably, an androgen-sensitive cell population is predominant in such a case. Then, the way can be opened to conduct other third-line or fourth-line hormonal therapy.
New hormonal therapies using enzalutamide and/or abiraterone acetate can significantly decrease the risk of radiographic progression and death and delay the initiation of chemotherapy in men with metastatic prostate cancer., However, it does not mean that classical hormonal therapies used until recently are not useful following the availability of enzalutamide and abiraterone acetate. Not only anti-androgen, but also estrogen agents (ethinyl estradiol and diethylstilbestrol) have been effective for CRPC., Omlin et al. reported that abiraterone acetate had antitumor activity in men with CRPC even after diethylstilbestrol. If this retrospective observation is reproducible, abiraterone acetate could be used after estrogen agents, since an additional PSA response by diethylstilboestrol could be expected before abiraterone acetate treatment. Moreover, the early use of the new hormonal medicines could also induce resistance to these medicines early.
Several groups have already described the potential mechanisms of resistance for enzalutamide and abiraterone acetate. Cells expressing the AR F876L mutation confer an antagonist-to-agonist switch that drives phenotypic resistance to enzalutamide. Rodriguez-Vida et al. reported that an enzalutamide withdrawal effect was observed in 10% (3/30) of patients with metastatic CRPC after docetaxel chemotherapy. Moreover, although the CYP17A1 inhibitor abiraterone acetate markedly reduces androgen precursors and is thereby effective in CRPC, abiraterone increases progesterone, which may be selected for progesterone-responsive mutant AR, such as T877A. This selection may activate androgen-responsive genes.
Furthermore, AR splice variants may also confer resistance to enzalutamide and abiraterone. AR splice variant (AR3 or AR-V7) is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth.,,, Liu et al. have described a molecular mechanism of AR splicing. Under ADT conditions, recruitment of several RNA splicing factors to the 3'-splicing site for AR-V7 (U2AF65 and ASF/SF2) was increased. Activation of U2AF65 and ASF/SF2 expression by strong ADT using enzalutamide and abiraterone might further induce AR splicing. AR-V7 induced by ADT modulates not only canonical androgen-responsive genes, such as PSA, TMPRSS2, NKX3.1, but also AR-V7-specific genes, such as UBE2C, ACOX1, MAP2K4, IGFBP3, NRP1, and multiple tumor-promoting autocrine/paracrine factors.,, Especially, ACOX1 and MAP2K4, and a high expression of IGFBP3 and NRP1 were significantly associated with shorter time to PSA failure. AR-V7 overexpression may also cause docetaxel-resistance. Therefore, attention should be paid to the possibility that maximizing ADT in the early phase of CRPC might cause resistance to other treatments.
| Conclusion|| |
Monitoring for metastatic CRPC with PSA measurements alone is not adequate. Therefore, we need to evaluate bone metastasis by bone scintigraphy and quantification of bone metastasis as well as other imaging studies. Moreover, from the results of CHAARTED trial and STAMPEDE trial, positioning of chemotherapy for the prostate cancer with high risk and high volume metastasis is changing now., As clinicians are likely to use docetaxel upfront with ADT in metastatic prostate cancer, this may have an impact on the timing and nature of metastatic CRPC (mCRPC). Despite the trial results of enzalutamide and abiraterone in the predocetaxel setting in mCRPC, the robustness of an overall survival benefit in relation to these drugs given in the postdocetaxel setting remains uncertain, especially as there has been no Phase 3 RCT to address this question. Sequential therapy using these medicines after classical anti-androgens and other proven therapies may further prolong the life of patients better than single therapy. Clinicians should evaluate various factors including prognosis, QOL, and cost-effectiveness along with patient preference when considering which treatments will be most beneficial for the patients. However, the optimal sequencing strategy needs to be robustly evaluated in clinical trials.
| Author Contribution|| |
AM is the corresponding author and managed everything. KI, HK, YK, YK, KN, TN, and MN contributed to the discussion about CRPC and drafted the manuscript. AKB contributed to the discussion about CRPC and corrected English grammar.
| Competing Interests|| |
All authors declare no competing interests.
| Acknowledgments|| |
We appreciate Prof. Fernand Labrie for his valuable discussion.
| References|| |
Wang MC, Valenzuela LA, Murphy GP, Chu TM. Purification of a human prostate specific antigen. Invest Urol
1979; 17: 159-63.
Wang MC, Papsidero LD, Kuriyama M, Valenzuela LA, Murphy GP, et al.
Prostate antigen: a new potential marker for prostatic cancer. Prostate
1981; 2: 89-96.
Kuriyama M, Wang MC, Lee CI, Papsidero LD, Killian CS, et al.
Use of human prostate-specific antigen in monitoring prostate cancer. Cancer Res
1981; 41: 3874-6.
Watt KW, Lee PJ, M′Timkulu T, Chan WP, Loor R. Human prostate-specific antigen: structural and functional similarity with serine proteases. Proc Natl Acad Sci U S A
1986; 83: 3166-70.
Elzanaty S, Richthoff J, Malm J, Giwercman A. The impact of epididymal and accessory sex gland function on sperm motility. Hum Reprod
2002; 17: 2904-11.
Emami N, Scorilas A, Soosaipillai A, Earle T, Mullen B, et al.
Association between kallikrein-related peptidases (KLKs) and macroscopic indicators of semen analysis: their relation to sperm motility. Biol Chem
2009; 390: 921-9.
Romanov VI, Whyard T, Adler HL, Waltzer WC, Zucker S. Prostate cancer cell adhesion to bone marrow endothelium: the role of prostate-specific antigen. Cancer Res
2004; 64: 2083-9.
Yonou H, Aoyagi Y, Kanomata N, Kamijo T, Oda T, et al.
Prostate-specific antigen induces osteoplastic changes by an autonomous mechanism. Biochem Biophys Res Commun
2001; 289: 1082-7.
Young CY, Montgomery BT, Andrews PE, Qui SD, Bilhartz DL, et al.
Hormonal regulation of prostate-specific antigen messenger RNA in human prostatic adenocarcinoma cell line LNCaP. Cancer Res
1991; 51: 3748-52.
Cleutjens KB, van Eekelen CC, van der Korput HA, Brinkmann AO, Trapman J. Two androgen response regions cooperate in steroid hormone regulated activity of the prostate-specific antigen promoter. J Biol Chem
1996; 271: 6379-88.
Schuur ER, Henderson GA, Kmetec LA, Miller JD, Lamparski HG, et al.
Prostate-specific antigen expression is regulated by an upstream enhancer. J Biol Chem
1996; 271: 7043-51.
Mizokami A, Gotoh A, Yamada H, Keller ET, Matsumoto T. Tumor necrosis factor-alpha represses androgen sensitivity in the LNCaP prostate cancer cell line. J Urol
2000; 164: 800-5.
Iwasa Y, Mizokami A, Miwa S, Koshida K, Namiki M. Establishment and characterization of androgen-independent human prostate cancer cell lines, LN-REC4 and LNCaP-SF, from LNCaP. Int J Urol
2007; 14: 233-9.
Kastendieck H, Altenahr E. Cyto- and histomorphogenesis of the prostate carcinoma. A comparative light- and electron-microscopic study. Virchows Arch A
1976; 370: 207-24.
Kuwahara T, Nagayama T. Distribution of keratin protein in normal prostate and prostatic tumors. An immunohistochemical study. Acta Pathol Jpn
1987; 37: 339-42.
Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinanen R, et al. In vivo
amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet
1995; 9: 401-6.
Takeda H, Akakura K, Masai M, Akimoto S, Yatani R, et al.
Androgen receptor content of prostate carcinoma cells estimated by immunohistochemistry is related to prognosis of patients with stage D2 prostate carcinoma. Cancer
1996; 77: 934-40.
Chmelar R, Buchanan G, Need EF, Tilley W, Greenberg NM. Androgen receptor coregulators and their involvement in the development and progression of prostate cancer. Int J Cancer
2007; 120: 719-33.
Imbriaco M, Larson SM, Yeung HW, Mawlawi OR, Erdi Y, et al
. A new parameter for measuring metastatic bone involvement by prostate cancer: the bone scan index. Clin Cancer Res
1998; 4: 1765-72.
Wakabayashi H, Nakajima K, Mizokami A, Namiki M, Inaki A, et al.
Bone scintigraphy as a new imaging biomarker: the relationship between bone scan index and bone metabolic markers in prostate cancer patients with bone metastases. Ann Nucl Med
2013; 27: 802-7.
Schroder FH. Progress in understanding androgen-independent prostate cancer (AIPC): a review of potential endocrine-mediated mechanisms. Eur Urol
2008; 53: 1129-37.
Lamont KR, Tindall DJ. Minireview: alternative activation pathways for the androgen receptor in prostate cancer. Mol Endocrinol
2011; 25: 897-907.
Tombal B. What is the pathophysiology of a hormone-resistant prostate tumour? Eur J Cancer
2011; 47 Suppl 3: S179-88.
Egan A, Dong Y, Zhang H, Qi Y, Balk SP, et al.
Castration-resistant prostate cancer: adaptive responses in the androgen axis. Cancer Treat Rev
2014; 40: 426-33.
Mizokami A, Namiki M. Reconsideration of progression to CRPC during androgen deprivation therapy. J Steroid Biochem
2015; 145C: 164-71.
Craft N, Chhor C, Tran C, Belldegrun A, DeKernion J, et al.
Evidence for clonal outgrowth of androgen-independent prostate cancer cells from androgen-dependent tumors through a two-step process. Cancer Res
1999; 59: 5030-6.
Miyamoto KK, McSherry SA, Dent GA, Sar M, Wilson EM, et al.
Immunohistochemistry of the androgen receptor in human benign and malignant prostate tissue. J Urol
1993; 149: 1015-9.
Pertschuk LP, Macchia RJ, Feldman JG, Brady KA, Levine M, et al.
Immunocytochemical assay for androgen receptors in prostate cancer: a prospective study of 63 cases with long-term follow-up. Ann Surg Oncol
1994; 1: 495-503.
Magi-Galluzzi C, Xu X, Hlatky L, Hahnfeldt P, Kaplan I, et al.
Heterogeneity of androgen receptor content in advanced prostate cancer. Mod Pathol
1997; 10: 839-45.
Fowler JE Jr., Pandey P, Seaver LE, Feliz TP, Braswell NT. Prostate specific antigen regression and progression after androgen deprivation for localized and metastatic prostate cancer. J Urol
1995; 153: 1860-5.
Kitagawa Y, Ueno S, Izumi K, Mizokami A, Hinotsu S, et al.
Nadir prostate-specific antigen (PSA) level and time to PSA nadir following primary androgen deprivation therapy as independent prognostic factors in a Japanese large-scale prospective cohort study (J-CaP). J Cancer Res Clin
2014; 140: 673-9.
Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, et al.
Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med
2015; 373: 737-46.
James N, Sydes M, Clarke N, Mason M, Dearnaley D, et al.
Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet
2015; 387: 1163-77.
[Epub ahead of print].
Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, et al.
Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med
2012; 367: 1187-97.
Fizazi K, Scher HI, Molina A, Logothetis CJ, Chi KN, et al.
Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol
2012; 13: 983-92.
Satoh T, Uemura H, Tanabe K, Nishiyama T, Terai A, et al
. A phase 2 study of abiraterone acetate in Japanese men with metastatic castration-resistant prostate cancer who had received docetaxel-based chemotherapy. Jpn J Clin Oncol
2014; 44: 1206-15.
Bellmunt J, Kheoh T, Yu MK, Smith MR, Small EJ, et al
. Prior endocrine therapy impact on Abiraterone acetate clinical efficacy in metastatic castration-resistant prostate cancer: post-hoc analysis of randomised phase 3 studies. Eur Urol
2015. pii: S0302-2838(15)01002-7. Doi: 10.1016/j.eururo.2015.10.021. [Epub ahead of print].
Loriot Y, Eymard JC, Patrikidou A, Ileana E, Massard C, et al.
Prior long response to androgen deprivation predicts response to next-generation androgen receptor axis targeted drugs in castration resistant prostate cancer. Eur J Cancer
2015; 51: 1946-52.
Tombal B. Hormone therapy for prostate cancer: what have we done with Charles Huggins′ legacy? Eur Urol
2012; 61: 26-8.
Suzuki H, Okihara K, Miyake H, Fujisawa M, Miyoshi S, et al.
Alternative nonsteroidal antiandrogen therapy for advanced prostate cancer that relapsed after initial maximum androgen blockade. J Urol
2008; 180: 921-7.
Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, et al.
Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med
2014; 371: 424-33.
Rathkopf DE, Smith MR, de Bono JS, Logothetis CJ, Shore ND, et al.
Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Eur Urol
2014; 66: 815-25.
Izumi K, Kadono Y, Shima T, Konaka H, Mizokami A, et al.
Ethinylestradiol improves prostate-specific antigen levels in pretreated castration-resistant prostate cancer patients. Anticancer Res
2010; 30: 5201-5.
Grenader T, Plotkin Y, Gips M, Cherny N, Gabizon A. Diethylstilbestrol for the treatment of patients with castration-resistant prostate cancer: retrospective analysis of a single institution experience. Oncol Rep
2014; 31: 428-34.
Omlin A, Pezaro CJ, Zaidi S, Lorente D, Mukherji D, et al.
Antitumour activity of abiraterone and diethylstilboestrol when administered sequentially to men with castration-resistant prostate cancer. Br J Cancer
2013; 109: 1079-84.
Korpal M, Korn JM, Gao X, Rakiec DP, Ruddy DA, et al.
An F876L mutation in androgen receptor confers genetic and phenotypic resistance to MDV3100 (enzalutamide). Cancer Discov
2013; 3: 1030-43.
Rodriguez-Vida A, Bianchini D, Van Hemelrijck M, Hughes S, Malik Z, et al.
Is there an antiandrogen withdrawal syndrome with enzalutamide? Br J Urol Int
2014; 115: 373-80.
Chen EJ, Sowalsky AG, Gao S, Cai C, Voznesensky O, et al.
Abiraterone treatment in castration-resistant prostate cancer selects for progesterone responsive mutant androgen receptors. Clin Cancer Res
2015; 21: 1273-80.
Antonarakis ES, Lu C, Wang H, Luber B, Nakazawa M, et al.
AR-V7 and resistance to enzalutamide and abiraterone in prostate cancer. N Engl J Med
2014; 371: 1028-38.
Hu R, Dunn TA, Wei S, Isharwal S, Veltri RW, et al.
Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res
2009; 69: 16-22.
Guo Z, Yang X, Sun F, Jiang R, Linn DE, et al
. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res
2009; 69: 2305-13.
Chan SC, Li Y, Dehm SM. Androgen receptor splice variants activate androgen receptor target genes and support aberrant prostate cancer cell growth independent of canonical androgen receptor nuclear localization signal. J Biol Chem
2012; 287: 19736-49.
Li Y, Chan SC, Brand LJ, Hwang TH, Silverstein KA, et al.
Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res
2013; 73: 483-9.
Liu LL, Xie N, Sun S, Plymate S, Mostaghel E, et al.
Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene
2014; 33: 3140-50.
Hu R, Lu C, Mostaghel EA, Yegnasubramanian S, Gurel M, et al.
Distinct transcriptional programs mediated by the ligand-dependent full-length androgen receptor and its splice variants in castration-resistant prostate cancer. Cancer Res
2012; 72: 3457-62.
Sun F, Chen HG, Li W, Yang X, Wang X, et al.
Androgen receptor splice variant AR3 promotes prostate cancer via modulating expression of autocrine/paracrine factors. J Biol Chem
2014; 289: 1529-39.
Lu J, Lonergan PE, Nacusi LP, Wang L, Schmidt LJ, et al.
The cistrome and gene signature of androgen receptor splice variants in castration resistant prostate cancer cells. J Urol
2015; 193: 690-8.
Thadani-Mulero M, Portella L, Sun S, Sung M, Matov A, et al.
Androgen receptor splice variants determine taxane sensitivity in prostate cancer. Cancer Res
2014; 74: 2270-82.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]