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Globally, prostate cancer is the second most common malignant tumor in men
.
Traditionally, prostate cancer genetic profiling is based on biopsy of the primary or metastatic site
.
However, biopsy is invasive and sometimes technically infeasible; due to the heterogeneity within and between tumors, the results of biopsy specimens cannot represent the molecular mutations of the entire tumor burden
.
The ideal detection method is minimally invasive, regularly repeatable, so that the "drivers" of the disease can be described at any time, including androgen receptor (AR) levels, and the state of the most relevant signaling pathways in prostate cancer
.
In recent years, an emerging detection method is the detection of cell-free DNA (cfDNA) of tumors
.
This article discusses the correlation between AR levels and resistance to treatment strategies, and AR level detection is expected to be used in clinical practice
.
Plasma AR levels and drug resistance have been supported by a large amount of evidence, and AR mutations are one of the resistance mechanisms of AR inhibitors
.
In hormone-sensitive prostate cancer (HSPC), androgen deprivation therapy is the standard treatment.
Even if the disease progresses to castration-resistant prostate cancer (CRPC), the AR signaling pathway is still a key molecular driver and therapeutic target
.
The resistance of prostate cancer after castration involves a variety of mechanisms, but it is mainly driven by AR mutations.
In the later stages of prostate cancer, amplification, mutation, spliceosome and coexisting mutations appear more often (Figure 1)
.
Figure 1 AR-dependent mechanisms leading to prostate resistance.
Most patients with AR signaling pathway mutations have increased AR copy numbers
.
At present, there is no randomized controlled clinical research data on plasma AR for CRPC, but there are multiple retrospective studies that have evaluated the clinical significance of circulating AR by dividing patients into two groups (normal AR copy number and increased AR copy number)
.
Studies have shown that in CRPC patients without chemotherapy or docetaxel treatment, the increase in plasma AR is significantly related to enzalutamide/abiraterone resistance, which is mainly manifested in worse overall survival or progression-free survival.
PSA response is reduced
.
An exploratory analysis found that patients with increased AR copy number benefit more from taxane therapy, while patients with normal AR benefit more from AR targeted therapy
.
The results suggest that AR detection can be used as a potential biomarker for CRPC patients
.
A recent META analysis found that increased cfDNA AR copy number can be used as an effective biomarker for predicting the efficacy of AR targeted therapy and taxane therapy
.
Studies have also explored the correlation between AR status and the dose of cabazitaxel.
Compared with normal AR, patients with increased AR copy number have worse clinical outcomes when using the initial reduced dose
.
Studies suggest that the increase in AR copy number response to taxane drugs may be dose-dependent, suggesting that regardless of the number of treatment lines, plasma AR levels may play a role in changing clinical treatment decisions such as AR targeted therapy or taxane.
To potential role
.
Other AR mutations such as AR point mutations may lead to drug resistance
.
Studies have found multiple point mutations.
T878A and W742C are the most common mutations, which may affect the ligand binding area and lead to flutamide/bicalutamide resistance
.
The F877L point mutation may lead to apatamide/enzalutamide resistance
.
T878A and L702H point mutations are associated with abiraterone resistance: after T878A mutation, progesterone can activate the AR signaling pathway; and after L702H mutation, glucocorticoids such as prednisone can activate the AR signaling pathway, so abiraterone can be considered Used in conjunction with docetaxel
.
AR-V7 is the most common mutation: it lacks a ligand binding domain, but retains the ability to bind DNA and activate transcriptional DNA, thus leading to constitutive activation of the AR signaling pathway, which leads to increased tumor cell transcription and proliferation
.
Summary This article provides evidence for the correlation between AR level and CRPC outcome, but there are still some problems to be resolved
.
First, the optimal cutoff value for AR increase varies with copy number detection methods and tumor characteristics
.
A META analysis showed that there was a non-linear relationship between the number of plasma AR copies and survival; Annala et al.
/Enzalutamide treatment response is different
.
Research suggests that there are different dose-response effects when using AR targeted therapy
.
In short, plasma AR level detection is a genetic marker with minimally invasive characteristics, or it can be used as a potential method to monitor tumor gene mutation profiles during treatment
.
AR levels are associated with resistance to abiraterone/enzalutamide after treatment without chemotherapy or docetaxel, and may be used as a marker for hormone therapy and taxane treatment options
.
So far, no predictive biomarkers in CRPC have been approved
.
Changes in clinical practice require level I evidence, and the use of AR testing to guide treatment decisions needs to be further confirmed in large phase III studies
.
References Conteduca V, et al.
Circulating Androgen Receptor for Prognosis and Treatment Selection in Prostate Cancer.
Eur Urol Oncol (2021), https://doi.
org/10.
1016/j.
euo.
2020.
12.
00
.
Traditionally, prostate cancer genetic profiling is based on biopsy of the primary or metastatic site
.
However, biopsy is invasive and sometimes technically infeasible; due to the heterogeneity within and between tumors, the results of biopsy specimens cannot represent the molecular mutations of the entire tumor burden
.
The ideal detection method is minimally invasive, regularly repeatable, so that the "drivers" of the disease can be described at any time, including androgen receptor (AR) levels, and the state of the most relevant signaling pathways in prostate cancer
.
In recent years, an emerging detection method is the detection of cell-free DNA (cfDNA) of tumors
.
This article discusses the correlation between AR levels and resistance to treatment strategies, and AR level detection is expected to be used in clinical practice
.
Plasma AR levels and drug resistance have been supported by a large amount of evidence, and AR mutations are one of the resistance mechanisms of AR inhibitors
.
In hormone-sensitive prostate cancer (HSPC), androgen deprivation therapy is the standard treatment.
Even if the disease progresses to castration-resistant prostate cancer (CRPC), the AR signaling pathway is still a key molecular driver and therapeutic target
.
The resistance of prostate cancer after castration involves a variety of mechanisms, but it is mainly driven by AR mutations.
In the later stages of prostate cancer, amplification, mutation, spliceosome and coexisting mutations appear more often (Figure 1)
.
Figure 1 AR-dependent mechanisms leading to prostate resistance.
Most patients with AR signaling pathway mutations have increased AR copy numbers
.
At present, there is no randomized controlled clinical research data on plasma AR for CRPC, but there are multiple retrospective studies that have evaluated the clinical significance of circulating AR by dividing patients into two groups (normal AR copy number and increased AR copy number)
.
Studies have shown that in CRPC patients without chemotherapy or docetaxel treatment, the increase in plasma AR is significantly related to enzalutamide/abiraterone resistance, which is mainly manifested in worse overall survival or progression-free survival.
PSA response is reduced
.
An exploratory analysis found that patients with increased AR copy number benefit more from taxane therapy, while patients with normal AR benefit more from AR targeted therapy
.
The results suggest that AR detection can be used as a potential biomarker for CRPC patients
.
A recent META analysis found that increased cfDNA AR copy number can be used as an effective biomarker for predicting the efficacy of AR targeted therapy and taxane therapy
.
Studies have also explored the correlation between AR status and the dose of cabazitaxel.
Compared with normal AR, patients with increased AR copy number have worse clinical outcomes when using the initial reduced dose
.
Studies suggest that the increase in AR copy number response to taxane drugs may be dose-dependent, suggesting that regardless of the number of treatment lines, plasma AR levels may play a role in changing clinical treatment decisions such as AR targeted therapy or taxane.
To potential role
.
Other AR mutations such as AR point mutations may lead to drug resistance
.
Studies have found multiple point mutations.
T878A and W742C are the most common mutations, which may affect the ligand binding area and lead to flutamide/bicalutamide resistance
.
The F877L point mutation may lead to apatamide/enzalutamide resistance
.
T878A and L702H point mutations are associated with abiraterone resistance: after T878A mutation, progesterone can activate the AR signaling pathway; and after L702H mutation, glucocorticoids such as prednisone can activate the AR signaling pathway, so abiraterone can be considered Used in conjunction with docetaxel
.
AR-V7 is the most common mutation: it lacks a ligand binding domain, but retains the ability to bind DNA and activate transcriptional DNA, thus leading to constitutive activation of the AR signaling pathway, which leads to increased tumor cell transcription and proliferation
.
Summary This article provides evidence for the correlation between AR level and CRPC outcome, but there are still some problems to be resolved
.
First, the optimal cutoff value for AR increase varies with copy number detection methods and tumor characteristics
.
A META analysis showed that there was a non-linear relationship between the number of plasma AR copies and survival; Annala et al.
/Enzalutamide treatment response is different
.
Research suggests that there are different dose-response effects when using AR targeted therapy
.
In short, plasma AR level detection is a genetic marker with minimally invasive characteristics, or it can be used as a potential method to monitor tumor gene mutation profiles during treatment
.
AR levels are associated with resistance to abiraterone/enzalutamide after treatment without chemotherapy or docetaxel, and may be used as a marker for hormone therapy and taxane treatment options
.
So far, no predictive biomarkers in CRPC have been approved
.
Changes in clinical practice require level I evidence, and the use of AR testing to guide treatment decisions needs to be further confirmed in large phase III studies
.
References Conteduca V, et al.
Circulating Androgen Receptor for Prognosis and Treatment Selection in Prostate Cancer.
Eur Urol Oncol (2021), https://doi.
org/10.
1016/j.
euo.
2020.
12.
00
