[2021EAU] Progress in precise diagnosis and precise treatment of prostate cancer

*Only for medical professionals to read for reference.
The 36th European Association of Urology (EAU) Conference in 2021 will be held online from July 8th to 12th.
Among them, prostate cancer is a high-risk disease for men worldwide, with about 300 articles Research reports
.

Accurate diagnosis and precise treatment of prostate cancer are new research hotspots, which have frequently appeared in recent international conferences.
Next, I will share with you the four research results related to advanced prostate cancer in this EAU conference, many of which are from Chinese research.
The voice of the team is more worthy of our attention
.

P0430 The effect of cell-free DNA (cfDNA) and androgen receptor amplification on the prognosis of castration-resistant prostate cancer.
This is a report from a Japanese research team
.

The purpose of this study was to explore the prognostic significance of total cell-free DNA and androgen receptor amplification (AR-amp) for castration-resistant prostate cancer (CRPC) patients
.

The researchers retrospectively analyzed 42 patients with non-prostate cancer, 57 patients with localized prostate cancer who did not receive androgen deprivation therapy (ADT), 97 patients with castration-sensitive prostate cancer (CSPC) who received ADT, and 97 patients Total cfDNA and AR-amp levels in CRPC patients
.

Kaplan-Meier analysis and multivariate Cox regression analysis were used to evaluate the correlation of these cfDNA biomarkers with disease status and overall survival
.

Finally, a simple risk model was established, using total cfDNA and AR-amp to predict poor prognosis
.

The results of the study showed that the median total cfDNA and AR-amp levels of CRPC patients were 387pg/μL and 1.
07 copies, respectively.
The total cfDNA and AR-amp levels of CRPC patients were significantly higher than the limitations of patients without prostate cancer and without ADT treatment.
Prostate cancer and CSPC patients receiving ADT (Figure 1)
.

And the higher the total amount of cfDNA and the level of AR-amp predicts a worse clinical outcome (Figure 2)
.

Figure 1 Total cfDNA and AR-amp levels Figure 2 The relationship between total cfDNA and AR-amp levels and OS The above results indicate that total cfDNA and AR-amp levels are potential biomarkers for poor prognosis in CRPC patients
.

P0431 Exploration of biomarkers for neoadjuvant treatment of metastatic/localized hormone-sensitive prostate cancer This is a report from the research team of Guo Hongqian at Nanjing Gulou Hospital
.

In clinical work, through neoadjuvant therapy, metastatic and localized hormone-sensitive prostate cancer (HSPC) has a high clinical downgrade rate
.

However, previous studies have shown that patients with DDR defects in mHSPC have a poor prognosis for ADT treatment
.

The purpose of this study is to explore whether the genomic changes of Chinese HSPC patients and DDR deficiency are related to the outcome of neoadjuvant therapy
.

The study collected 54 HSPC patients (32 local HSPC, 22 mHSPC), of which 18 received ADT + abiraterone treatment, 36 received ADT + docetaxel treatment
.

A total of 8 cfDNA and 46 FFPE (Formalin-Fixed and Parrffin Embedded) samples were generated in this study.
All samples were designed for next-generation sequencing using 66 gene panels (target coverage ≥1000)
.

Panel genes are mainly divided into three categories: DDR pathway (BRCA, ATM, CDK12, etc.
), endocrine-related genes (AR, FOXA1, NCOR, etc.
) and other prostate-related genes
.

Fisher's test was used to evaluate the correlation between treatment downtime and gene mutations
.

The results of the study show that the frequency of gene mutations in the Chinese HSPC cohort after treatment is different from that in Europe.
FOXA1 (38%) and SPOP (27%) are the most common gene mutations, and the mutation frequency of TP53 (11%) is much lower than previously reported 30.
1%~34%
.

HSPC with HR deficiency accounted for 28%, and DDR deficiency accounted for 33%
.

There are no different genetic changes in metastatic and localized HSPC, and neoadjuvant therapy has limited effect in reducing staging rate (p.
value=0.
5625)
.

In patients with PSA>20ng/ml at the time of diagnosis, NCOR2 mutations increased (p.
value=0.
014675), while NCOR2 mutations were not related to treatment downtime (p.
value=0.
543541)
.

In terms of pathways and gene types, DDR pathway mutations (p.
value=0.
364479) and endocrine-related gene mutations (p.
value=0.
749196) were not significantly correlated with neoadjuvant therapy response
.

However, the clinical effective rate of neoadjuvant therapy is as high as 68.
12%, suggesting that gene mutation may not be a key factor affecting the outcome of neoadjuvant therapy
.

The above research results indicate that the frequency of gene mutations in Chinese HSPC patients is different from previous reports, and that DDR deficiency/endocrine-related gene mutations have nothing to do with the clinical outcome of neoadjuvant therapy
.

P0432 Genome heterogeneity of prostate cancer patients with visceral metastasis This is a report from the research team of Professor Xue Wei from Shanghai Renji Hospital
.

Metastatic prostate cancer, especially with visceral metastasis, seriously affects the survival of prostate cancer (PCa) patients
.

Liver and lung are the most common metastatic sites for prostate cancer
.

Previous studies have shown that visceral metastasis of prostate cancer presents a heterogeneous prognosis, which depends on different metastasis sites.
Compared with lung metastasis, the lethality of liver metastasis is significantly increased
.

The purpose of this study is to explore prostate cancer patients with bone-only metastasis (bmPCa), liver metastasis (hmPCa), and lung metastasis without liver involvement (pulmonary metastasis without liver involvement, pmPCa).
Genomic characteristics
.

The researchers used hybrid capture technology to detect genomic changes in 50 genes, including androgen receptor (AR), DNA damage mutations (DDR), and clinically relevant driving factors
.

The researchers successfully performed ctDNA sequencing on 109 blood samples and 29 metastatic tissue samples from 129 patients with metastatic castration-resistant prostate cancer (mCRPC)
.

Different mCRPC genome profiles were observed at different metastatic sites
.

Compared with bmPCa, the prevalence of RB1 and PTEN mutations in prostate cancer with visceral metastasis is higher (RB1, 12.
1% vs 1.
0%, p=0.
015; PTEN, 9.
09% vs 2.
08%, p=0.
105)
.

When comparing by metastasis site, it was found that pmPCa rarely had AR mutations, while hmPCa had a higher mutation rate (0.
0% vs 42.
1%, p=0.
01)
.

Among the overall DDR gene mutations, hmPCa has the highest mutation frequency (68.
4%) (Figure 3)
.

Figure 3 The mCRPC gene map of different metastasis sites and the total DDR gene mutations.
The above research results show that through PCa genome analysis of different metastasis sites, the frequency of AR mutations in pmPCa is extremely low, the incidence of DDR pathway defects in hmPCa is high, and the incidence of DDR pathway defects in vmPCa is high.
The mutation rate of PTEN is high
.

The study also found the genomic diversity of bmPCa, hmPCa and pmPCa.
The results of this study provide new clues for the heterogeneous prognosis of visceral metastases, and suggest potential therapeutic targets for hmPCa and pmPCa
.

P0433 Analysis of BRCA germline mutations in Chinese prostate cancer patients This is a report from the research team of Professor Yu Zhixian from the First Affiliated Hospital of Wenzhou Medical University
.

Previous studies have shown that patients with prostate cancer (PCa) with BRCA2 mutations are more aggressive
.

However, these reports are mostly concentrated in foreign populations, and large-scale studies on BRCA mutations in PCa populations in China are still limited
.

The study included 1940 PCa patients from four centers in China, and selected 172 patients with BRCA germline mutations
.

Retrospective analysis of these patients' gene mutation map, type, related somatic mutations and frequency of BRCA germline mutations
.

The results of the study showed that the frequency of BRCA1 and BRCA2 germline mutations in Chinese prostate cancer patients were 2.
89% (56/1940) and 6.
13% (119/1940), among which metastatic castration-resistant prostate cancer (mCRPC) at the time of diagnosis was Mainly 54.
65% (94/172)
.

The total pathogenicity rates of BRCA1 and BRCA2 variant strains were 17.
46% (11/63) and 56.
55% (82/145), respectively
.

Among all somatic mutations related to BRCA2 germline mutations, FOXA1 (7.
4% in cDNA sequencing and 52% in tissue samples) and NCOR2 (7.
4% and 24%) have the highest mutation frequency; TP53 is related to BRCA1 germline mutations Major somatic mutations (25% and 17%)
.

The pathogenicity of BRCA1 germline mutations in Chinese PCa patients (0.
46%) is lower than that in American patients (1.
41% for African Americans and 0.
87% for Caucasians)
.

The pathogenicity of BRCA2 germline mutations (3.
71%) is higher than that of American patients (African American 2.
8%) and British patients (Young-onset, 1.
01%) (Figure 4)
.

Figure 4 The pathogenicity rate of BRCA1 and BRCA2 mutations in different races.
The above research results show that the BRCA1/2 germline mutation rate of Chinese PCa patients is different from that of African Americans and Caucasians.
Patients with BRCA2 germline mutations tend to have more Aggressive
.

Compared with BRCA1, BRCA2 mutation has a higher pathogenicity rate.
FOXA1, NCOR2 and TP53 are the three gene types with the highest mutation rate
.

The results of this study on BRCA germline mutations in the Chinese population can provide more references for clinical treatment decisions for Chinese PCa patients
.

Experts comment that prostate cancer has always been the malignant tumor with the highest incidence in European and American countries.
Androgen dependence is an important feature of prostate cancer.
The overall survival period of prostate cancer is longer, but once it metastasizes, the prognosis is poor
.

In recent years, precision diagnosis, genetic testing, liquid biopsy, and targeted therapy have become hot topics in the field of prostate cancer.
At this year’s EAU conference, relevant research is still a hot topic for everyone’s attention.
Fortunately, this At the conference, we heard more and more voices from the Chinese research team
.

With the continuous development of research and the maturity of liquid biopsy technology, AR amplification and mutations in plasma cfDNA of CRPC patients are related to their response to new endocrine drugs and drug resistance [5-9].
Analysis from the blood of CRPC patients The AR status of the cfDNA obtained in the sample predicts the prognosis of the patient, which is not only simple and easy to operate, but also provides a wealth of information
.

Perhaps in the future, cfDNA will be an effective biomarker in CRPC precision medicine, bringing unlimited possibilities for precision treatment of CRPC patients
.

Endocrine therapy is the earliest neoadjuvant therapy before radical prostatic cancer surgery.
Researchers use neoadjuvant endocrine therapy before surgery to reduce the volume of the prostate and the degree of lesion infiltration
.

As early as the 1960s, some scholars tried to use neoadjuvant endocrine therapy to improve the pathological outcome and prognosis of patients with prostate cancer
.

Subsequently, a large number of researchers have carried out related explorations on neoadjuvant endocrine therapy, but the results of the study all indicate that neoadjuvant endocrine therapy alone can only improve the pathological outcome without significant benefit to the survival outcome
.

However, at present, neoadjuvant endocrine therapy for prostate cancer has not yet shown a particularly significant short-term or long-term benefit advantage.
It may be that our choice of treatment population is still not precise enough
.

The research team from Nanjing Gulou Hospital explored the relationship between the frequency of gene mutations in Chinese HSPC patients and the clinical outcomes of neoadjuvant therapy.
The results showed that DDR deficiency/endocrine-related gene mutations have nothing to do with the clinical outcome of neoadjuvant therapy, so how to make a better selection It is a challenge and an opportunity for Chinese doctors to find prostate cancer patients who can get better treatment results or cure through neoadjuvant + surgery
.

The incidence of prostate cancer in my country is much lower than that in European and American countries, but it has shown an upward trend and rapid growth in recent years.
Unlike European and American countries, only about 30% of new cases in my country are clinically limited patients at the time of diagnosis, and the rest are Patients with locally advanced or extensive metastases, these patients cannot receive local radical treatment, and the prognosis is poor
.

The results of the research team of Professor Xue Wei from Shanghai Renji Hospital provide new clues for the heterogeneous prognosis of visceral metastases in advanced prostate cancer, and suggest potential therapeutic targets for hmPCa and pmPCa
.

At present, the application of genetic testing in prostate cancer is still in the exploratory stage.
By exploring the genetic heterogeneity of different metastatic sites, we can find truly clinically valuable and meaningful mutant genes, so as to help patients open a new window of treatment.
It is undoubtedly the glorious mission of Chinese doctors
.

With the approval of two PARP inhibitors rucaparib and olaparib last year, it opened the era of precision targeted therapy for advanced prostate cancer.
However, the large-scale clinical trials of TRITON2 and PROfound included mostly European and American patients.
For Chinese patients , Can such excellent clinical effects be achieved if directly "foreign for Chinese use"? Professor Zhixian Yu’s team from Wen Fuyi explored the BRCA mutations in Chinese prostate patients
.

The results of the study found that the pathogenicity of BRCA1 germline mutations in Chinese PCa patients is lower than that of American patients, while the pathogenicity of BRCA2 germline mutations is higher than that of American patients and British patients
.

The research results of BRCA germline mutations in the Chinese population can provide more references for clinical treatment decisions of Chinese PCa patients
.

At the same time, this also means that the development and application of targeted drugs in the future may enter a more in-depth and more precise era, especially for Chinese patients, how to make targeted drugs truly "precise and not miss the target" is Issues that we should think about in the future
.

The genetic changes of prostate cancer are often more complicated, and they are often combined with changes in multiple states and multiple genes.
Our understanding of this is still relatively lacking
.

The research of predictive markers is currently underdeveloped, but we believe that as the research continues to deepen, more and more hotspot mutations and treatment methods will be known to us
.

Accurate diagnosis and precise treatment are destined to be the general trend of prostate cancer diagnosis and treatment in the future
.

Moreover, the base of prostate cancer patients in China is huge, and there is a large amount of valuable real-world data that can be used.
It is hoped that more prostate cancer patients in China can be benefited in the future
.

Expert profile Chen Wei Doctor of Urology, the First Affiliated Hospital of Wenzhou Medical University, Associate Chief Physician, Associate Professor, Master Supervisor Member of the Chinese Society of Clinical Oncology (CSCO) Prostate Cancer Expert Committee Member, Chinese Anti-Cancer Association Chinese and Western Medicine Integrated Oncology Committee Member, China Member of the Precision Group of the Special Committee of Urinary and Male Reproductive Tumors of the Anti-Cancer Association Member of the Standing Committee of the Special Committee of Urinary and Male Reproductive Tumors of Zhejiang Medical Doctor Association Member of the Special Committee of Urological and Male Reproductive Tumors of Zhejiang Association Member of the Academic Group, Member of the Urology Group of the Minimally Invasive Surgery Branch of the Wenzhou Medical Association, 2020 Zhejiang Medical Rookie, Presided and participated in a number of provincial and ministerial and municipal projects, and participated in 6 international multi-center phase 3 drug clinical trials , Published 6 SCI papers, with a total impact factor of 37.
References: [1].
2021 EAU Congress.
Abstract P0430[2].
2021 EAU Congress.
Abstract P0431[3].
2021 EAU Congress.
Abstract P0432[4].
2021 EAU Congress.
Abstract P0433[5].
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Androgen Receptor Gene Aberrations in Circulating Cell-Free DNA: Biomarkers of Therapeutic Resistance in Castration-Resistant Prostate Cancer.
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[6].
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Salvi, S.
et al.
Circulating cell-free AR and CYP17A1 copy number variations may associate with outcome of metastatic castration-resistant prostate cancer patients treated with abiraterone.
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Genomic Alterations in Cell-Free DNA and Enzalutamide Resistance in Castration-Resistant Prostate Cancer.
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Conteduca, V.
et al.
Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study.
Ann Oncol 28, 1508–1516, https://doi.
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*This article is only used to provide scientific information to medical professionals and does not represent the views of this platform*This article is only used to provide scientific information to medical professionals, and does not represent the views of this platform*This article is only used to provide scientific information to medical professionals, and does not represent the views of this platform*This article is only used to provide scientific information to medical professionals, and does not represent the views of this platform*This article is only used to provide scientific information to medical professionals, and does not represent the views of this platformGenomic Alterations in Cell-Free DNA and Enzalutamide Resistance in Castration-Resistant Prostate Cancer.
JAMA.
Oncol 2, 1598–1606, https://doi.
org/10.
1001/jamaoncol.
2016.
0494 (2016).
[9].
Conteduca, V .
et al.
Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study.
Ann Oncol 28, 1508–1516, https://doi.
org/ 10.
1093/annonc/mdx155 (2017).
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platformGenomic Alterations in Cell-Free DNA and Enzalutamide Resistance in Castration-Resistant Prostate Cancer.
JAMA.
Oncol 2, 1598–1606, https://doi.
org/10.
1001/jamaoncol.
2016.
0494 (2016).
[9].
Conteduca, V .
et al.
Androgen receptor gene status in plasma DNA associates with worse outcome on enzalutamide or abiraterone for castration-resistant prostate cancer: a multi-institution correlative biomarker study.
Ann Oncol 28, 1508–1516, https://doi.
org/ 10.
1093/annonc/mdx155 (2017).
*This article is only used to provide scientific information to medical professionals and does not represent the views of this platforma multi-institution correlative biomarker study.
Ann Oncol 28, 1508–1516, https://doi.
org/10.
1093/annonc/mdx155 (2017).
*This article is only used to provide scientific information to medical professionals and does not represent this platform Viewa multi-institution correlative biomarker study.
Ann Oncol 28, 1508–1516, https://doi.
org/10.
1093/annonc/mdx155 (2017).
*This article is only used to provide scientific information to medical professionals and does not represent this platform View