Prostate cancer is the most common noncutaneous cancer in men and the second most common cause of cancer-related death.1 Normal prostate cells and prostate cancer cells require the presence of androgen for growth and survival. In advanced prostate cancer, androgen deprivation therapy (ADT), medically or surgically, has been the mainstay. Initially, androgen-sensitive prostate cancer cells stop dividing and undergo apoptosis. Eventually, some cells evolve to become castration-resistant prostate cancer (CRPC).2 Once CRPC develops, treatment options are limited along with shortened overall survival (OS). To date, despite extensive research, there is no clinically meaningful predictive biomarker available for selecting treatment for prostate cancer. Here we conduct a review of existing markers that can potentially predict response to ADT.
The Gleason score (GS) grading system is a dominant prognostic factor for both localized and metastatic prostate cancer, both hormone-sensitive and castration-resistant disease, and an independent predictor of duration of hormone sensitivity.3-10 Traditionally, GS is classified homogenously into low/intermediate risk (GS ≤7) and high risk (GS ≥8). Rusthoven et al collected data through the Surveillance, Epidemiology, and End Results database to assess outcomes of prostate cancer based on GS. ADT was utilized in a majority of patients. At 4 years of follow-up, there were highly significant differences between GS 7 versus 8, 8 versus 9, and 9 versus 10 (all P<.001) in multivariate analysis for both OS and prostate cancer–specific survival. Gleason pattern of 5 in GS of 6 to 10 was an independent poor prognostic factor.11 Benaim et al conducted a retrospective study in 150 patients with advanced prostate cancer treated with ADT. A GS of 8 to 10 was also associated with shorter response to ADT in metastatic hormone-sensitive prostate cancer.9
Minor Histologic Subtypes
Adenocarcinoma comprises more than 95% of prostate cancer. Most prostate cancer treatment studies are based on adenocarcinoma histologic subtype. Minor histologic subtypes include neuroendocrine (small cell) carcinoma, transitional cell carcinoma, ductal prostate cancer, basal cell carcinoma, carcinosarcoma, and stromal sarcoma. These usually do not respond to ADT and are characterized by rapid clinical progression. Most patients die within 2 years despite aggressive chemotherapeutic regimens. Neuroendocrine carcinoma is one of the most common of the minor subtypes and can present as a primary tumor or transformed after ADT. These correlate with poor prognosis due to activation of multiple signaling pathways and lack of androgen receptor.12-14 These subtypes are usually associated with relatively lower prostate-specific antigen (PSA) values despite the presence of distant metastatic disease.
PSA and PSA Kinetics
PSA is the most utilized biomarker to diagnose, classify risk, and monitor treatment response of prostate cancer. It could also serve as a predictive marker for duration of response after ADT.15 Data from Southwest Oncology Group Trial 9346 (SWOG 9346, INT-0162) demonstrated that patients who achieved PSA nadir (<0.2 ng/mL) at 7 months after ADT had significantly better OS compared with patients who did not (hazard ratio [HR] 0.17; P<.0001). Patients who achieved a PSA between 0.2 and 4.0 ng/mL also had significantly better OS (HR 0.30; P<.0001).16 Sasaki et al conducted a study of primary continuous ADT in patients with bone metastasis. Patients who achieved PSA nadir (<0.2 ng/mL) had a significantly longer OS (HR 3.73; P=.003). Time to nadir (TTN) PSA was also a good predictive marker for disease progression. In the same study, TTN >9 months was associated with increased OS compared with TTN <9 months both in patients who achieved PSA nadir and those who did not.17 Many studies have reported different significant PSA nadir and TTN to predict OS18,19 and androgen-independent progression.20,21 PSA nadir <0.1 ng/mL was shown to be a predictive marker for better response and delayed development of CRPC in intermittent ADT.22 To date, there is no optimal PSA nadir or TTN cutoff after ADT to predict OS. In general, we believe that rapid PSA reduction correlates with more prostate cancer cell death, a longer remission period, and increased OS. Many studies have shown that longer TTN correlates with longer OS. The possible explanation is tumor heterogeneity which contains a large number of PSA producing CRPC, which was initially suppressed with ADT then a subset of aggressive cancer cells regrow rapidly in low androgen environment.18,23 This knowledge could be used to select second-line hormonal manipulations versus chemotherapies.
Androgen, Androgen Receptor, and Androgen-Responsive Elements
Androgen is the main driver of prostate cancer cell growth. Measuring 6-month post-ADT testosterone level showed a positive correlation with survival along with GS and 6-month post-ADT PSA.24 However, the adrenal gland produces androgens, which could contribute to prostate cancer cell growth after initiating ADT.25 In a later stage, the prostate cancer cell can produce androgen intracellularly and stimulate cell proliferation. Measuring intratumoral androgen could be a potential marker of response, but data have been inconsistent.26,27 To date, there is no recommendation for using the androgen level to measure response to second-line hormonal manipulation.
Unlike breast cancer, in which the estrogen receptor has been well established as a prognostic and predictive marker, the androgen receptor (AR) in prostate cancer has not been validated in large studies to be a predictive marker of ADT. AR expression was uniformly positive in all pretreated prostate cancer but was lost in CRPC and more frequently lost in neuroendocrine-differentiated cancer cells.28 In pretreated patients, high AR content is a favorable prognostic factor29 and predictor of response.30 It was also demonstrated that lower GS cancer cells have a higher level of AR expression.29 The same study also showed that patients with tumors that had more than 48% AR-expressing cells had a better outcome. This clearly demonstrates that there is cell heterogeneity in a tumor that may have higher-grade (low AR-expressing) and lower-grade (high AR-expressing) elements. This leads to the hypothesis that the higher the percentage of high-grade cells in a tumor (which are essentially less sensitive to hormonal manipulation by ADT), the faster that tumor becomes castration resistant.
However, Sun et al studied variations of AR and estrogen receptor alpha and beta by using single nucleotide polymorphisms (SNPs), and results showed that common genetic variations were not associated with aggressiveness and response to ADT.31 AR expression and function can be changed over the course of treatment. In post-ADT, resistant mechanisms develop as follows:
- Increased AR gene amplification: Tumor adapts to grow in a low androgen state and up-regulates AR by gene amplification, especially a tumor that has initially responded well to ADT and has a response duration of more than 12 months.32,33
- AR gene mutations: This mechanism helps prostate cancer cells evade ADT. Mutation occurs in multiple sites of AR gene.34,35 Mutated AR can be activated by many types of hormonal agonists/antagonists or even the absence of steroid.35,36
Androgen-Responsive Elements (AREs): After Androgen Binds to AR
The androgen/AR complex binds to a specific promoter region of AREs in order to regulate gene expression and cell growth.37 Huang et al studied 55 common SNPs within AREs in 601 patients treated with ADT. After multivariate analysis, FBOX32 rs7830622 (HR 1.69; P=.004) and FLT1 rs9508016 (HR 1.52; P=.028) remained as significant predictive factors for all-cause mortality. Combination of SNPs showed a higher HR of 3.33, P<.001. However, this study was conducted in a Chinese population.38 Bao et al studied 19 prostate cancer variants in the same patient cohort. After multivariate analysis, rs16901979 remained a significant predictor for prostate cancer–specific mortality (HR 0.58; P=.002) and all-cause mortality (HR 0.64; P=.002).39 These results suggest that an integrated conventional and genetic variant predictive model can accurately predict outcome of prostate cancer patients receiving ADT.
Once a patient is diagnosed as having CRPC, abiraterone and enzalutamide are approved agents for treatment in the pre- and post-docetaxel setting. Antonarakis et al studied androgen-receptor isoform encoded by splice variant 7 (AR-V7) in circulating tumor cells, which lack a ligand-binding domain but has an active transcription factor. Patients who had positive AR-V7 had a poor PSA response to both abiraterone and enzalutamide compared with patients with negative AR-V7 (0% vs 68%; P=.004, and 0% vs 53%; P=.004, respectively). These findings translate into shorter progression-free survival and OS in both groups.40 However, this study was done in a small patient population and requires a larger-scale prospective validation.
Circulating Tumor Cells
Initially, circulating tumor cells (CTCs) were utilized as a prognostic and predictive marker in mCRPC after chemotherapy. Patients who had CTC ≥5 cells/7.5 mL of blood had significantly poorer prognosis (median OS 11.5 vs 21.7 months; P<.001).41 Patients who had CTC <5 cells/7.5 mL after chemotherapy demonstrated an increased median survival of 20.7 months versus 9.5 months for patients whose CTC did not decline. Okegawa et al conducted a single-institution study in treatment-naive metastatic prostate cancer in Japan that showed CTC ≥5 cells/7.5 mL of blood was associated with a shorter androgen responsiveness time of 17 months compared with 32 months in patients with CTC <5 cells/7.5 mL.42 Goodman Jr et al conducted a prospective study in 33 treatment-naive metastatic prostate cancer patients in a western population. After multivariate analysis, baseline CTC remained an independent predictive marker for duration and depth of responsiveness to ADT. This study also suggested a CTC cutpoint of 3 cells/7.5 mL of blood instead of the traditional 5 cells/7.5 mL of blood in a treatment-naive group in order to maximize a predictive value. However, this was a very small patient cohort, and more prospective studies are needed to validate this finding.43
The androgen signaling pathway was also studied in CTC. After selective candidate gene products, PSA and prostate-specific membrane antigen remained markers consistently up-regulated following AR activation and AR suppression, respectively.44 Miyamoto et al studied an androgen signaling pattern using a combination of these markers in both treatment-naive and CRPC patients. Results showed that the androgen signaling pathway was uniformly expressed in treatment-naive patients and heterogeneously expressed in CRPC patients, likely due to acquired resistance, which led to inconsistent response to ADT. However, active AR signaling during a treatment with abiraterone was also associated with poor treatment outcome.45
Due to insufficient predictive factors for ADT responsiveness, genetic variations were studied using SNPs. Yang et al studied androgen transporter genes in 538 patients receiving ADT. Patients who carried SLCO2B1 and SLCO2B3 genotypes had a significantly shorter time to progression on ADT.46 Kohli et al studied germline mutations associated with sex steroid biosynthesis and metabolisms using a total of 746 SNPs in 304 patients with advanced prostate cancer receiving ADT. After multivariate analysis and censor for false discovery rates of 0.10 or more, 2 of the 4 TRMT11-tagged SNPs (rs1268121 and rs6900796) were found to be associated with time to ADT failure.47 Fraga et al studied variants of hypoxia-inducible factor 1 alpha (HIF1A), which regulates cellular response to hypoxia and induces cancer progression, in 754 prostate cancer patients. Results showed that patients who carried the HIF1A +1722 T-allele had an increased risk for developing resistance to ADT after multivariate analysis (odds ratio [OR] 6.0; P=.001) and for developing distant metastasis (OR 2.0; P=.027).48
Prostate cancer usually has heterogeneity in the cells that comprise the tumor. Although many biomarkers have been studied, none has been validated in a prospective fashion. In the genomic era, with the assistance of high-throughput sequencing and data management, more genetic variants could be discovered and incorporated into the prognostic/predictive model along with traditional biomarkers. So far, there is no biomarker-guided strategy for advanced prostate cancer treatment except up-front ADT. Data suggest that lower GS cancers tend to express more AR and thus may be associated with better outcomes from hormone manipulation. Higher GS cancers tend to express lower AR and are thus less amenable to a good outcome. This is consistent with the outcome strictly based on the biology/morphology of the disease. This is substantiated by the recently reported ECOG-3805 trial by Sweeney et al that demonstrated a significant survival advantage to applying docetaxel up-front with ADT in hormone-sensitive metastatic prostate cancer when compared with ADT alone (HR 0.61; median OS 57.6 vs 44 months; P=.0003).49
There is an unmet need to develop strategies to identify the tumors that would respond to first-line and second-line hormonal manipulations for long periods. This would also allow for the appropriate early use of cytotoxic agents in the other group of patients. The aggressive cancer cells tend to be of Gleason grades 4 and 5 pattern and the unusual histologies per the available data. Despite that knowledge, there is a lack of enthusiasm to apply cytotoxic chemotherapies up-front in those patients with high-grade disease, especially when the tumor volume is low. If high-grade elements could be eliminated by early application of cytotoxic agents in the adjuvant or neoadjuvant setting, we could see higher rates of cures in this disease in the near future. l
Dr Danchaivijitr is a Hematology/Oncology Fellow at Roswell Park Cancer Institute. His clinical interests are genitourinary cancer and new drug developments.
Dr George is a Medical Oncologist, Assistant Professor of Medicine and Oncology at Roswell Park Cancer Institute. He is a clinical/translational investigator with focus on prostate and kidney cancer. His interests include aggressive variants of prostate cancer and developing novel treatment strategies in both prostate and kidney cancer.
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