2021 ASCO-GU: Future | Advances in precision diagnosis and treatment of prostate cancer

*Only for medical professionals to read for reference.
February 11-13, 2021, on the occasion of the Chinese New Year, the American Society of Clinical Oncology Symposium on Urogenital System Oncology (ASCO-GU) was held in the cloud, covering the field of urinary oncology around the world Experts gathered in this academic gala through online virtual conferences to participate in the grand event.

This conference announced a number of research results in the field of urinary tumors.
Among them, the precise diagnosis of prostate cancer, genetic testing, liquid biopsy and targeted therapy are one of the hot spots of this conference.
Therefore, this article focuses on the focus of the ASCO-GU 2021 conference.
The research content is integrated and reported.

Abstract25: Liquid biopsy may become an important supplementary method for whole-gene testing for mCRPC patients.
In clinical practice, whole-genome testing (CGP) using tumor tissues (including metastases) of prostate cancer patients is currently the most commonly used genetic testing method.
.

However, in clinical practice, the tumor tissues of some patients cannot be obtained, which has caused the limitations of clinical application of genetic testing.

At present, the use of next-generation sequencing (NGS) technology to detect circulating tumor cells (CTC) in the plasma of patients with metastatic castration-resistant prostate cancer (mCRPC) is an important non-invasive genetic testing method.

The results of a study published at this ASCO-GU conference analyzed whether the results of liquid biopsy and tissue biopsy are consistent [1].

This study is by far the largest liquid biopsy study of advanced prostate cancer.
A total of 3334 prostate cancer patients’ plasma was collected, most of which were from TRITON2/3 [The subjects of the study were mainly new endocrine therapy and paclitaxel chemotherapy and the presence of DNA repair genes Defective mCRPC patients, all patients were given Rucaparib 600 mg bid, and the primary endpoint was objective response rate (ORR) and prostate specific antigen (PSA) response rate] mCRPC patients in the study.The results of the study showed that circulating tumor DNA (ctDNA) was detected in the plasma of 3129 patients (94%), and BRCA1/2 gene mutations were found in 295 patients (8.
5%).

And the study found that compared with tumor tissue biopsy, liquid biopsy has a higher proportion of AR mutations, and the detection efficiency of rare AR rearrangements, in-frame deletions and other gene mutations is higher.

According to the results of the consistency study, 93% of patients with BRCA1/2 gene mutations found in tissue biopsy also had BRCA1/2 gene mutations in their liquid biopsy.
Figure 1 shows that BRCA1/2 and BRCA1/2 gene mutations were found in tissue biopsy and liquid biopsy.
The detection results of other currently known hot gene mutations (RB1, CDK12, PIK3CA, PTEN, etc.
) basically coincide.

Compared with tissue biopsy, the mutation rate of ATM, CHEK2 and other genes was significantly higher than that of tissue biopsy (Figure 1).

In summary, liquid biopsy may become an important supplementary method for whole genetic testing for mCRPC patients.

Figure 1 The frequency and correlation of gene mutation detection in liquid biopsy and tissue biopsy Abstract49: Analysis of gene detection patterns in mCRPC patients: A real-world study from the United States was approved by the U.
S.
Food and Drug Administration (FDA) in May 2020, PARP Inhibitors olaparib and rucaparib have become targets for mCRPC patients with homologous recombination repair (HRR) gene mutations who have previously received abiraterone or enzalutamide treatment drug.

Based on the results of the PROfound study, olaparib is suitable for mCRPC patients with homologous recombination repair (HRR) gene mutations; based on the results of the TRITON2/3 study, olaparib is suitable for patients with BRCA gene mutations.

There are 15 HRR genes, among which BRCA1, BRCA2 and ATM gene mutations occur most frequently.

This ASCO-GU published a real-world study on the genetic/genomic detection characteristics of mCRPC[2].
The study observed 346 mCRPC patients from January to August 2020, and found only 132 mCRPC patients (38%) received HRR genetic testing.

These testing packages basically cover the testing of BRCA1, BRCA2, and ATM, with detection rates of 90%, 89% and 55% respectively.

The results of the study showed that the positive rates of single mutations of BRCA1, BRCA2, and ATM in mCRPC were 10%, 10%, and 12%, respectively (Figure 2).

Figure 2 HRR gene detection rate and mutation positive rate of mCRPC patients.
Through analysis, it is found that among the 72 doctors participating in the study, most of the HRR gene test prescriptions issued by oncologists and community doctors, genetic testing may become a routine method in clinical practice Therefore, we call on urologists to pay more attention to genetic testing and targeted therapy.

Abstract150: To explore the impact of HRR gene mutations on the prognosis of patients with metastatic hormone-sensitive prostate cancer (mHSPC).
In the past, we know little about the clinical outcome of mHSPC patients with HRR gene mutations.
A single report was announced at the ASCO GU conference.
Central, retrospective study results [3], aimed at exploring the correlation between HRR mutations and the prognosis of mHSPC patients.

This study included 151 mHSPC patients who had undergone HRR genetic testing between 2015 and 2020 (45.
7% of patients were treated with androgen deprivation therapy (ADT) alone, and 27.
8% of patients were treated with androgen receptor inhibitors (ARSI).
26.
5% were treated with docetaxel), the primary study endpoint was the time to castration resistance, and the secondary study endpoint was the time from different types of homologous recombination repair defects (HRD) to castration resistance, and median overall survival Period (OS) and so on.

The results of the study showed that the time to castration resistance was significantly shorter in mHSPC patients with HRD than in wild-type (WT) mHSPC patients (12.
7 vs 16.
1 months, HR=1.
95, P=0.
002) (Figure 3). Figure 3 The time to castration resistance in the HRD group and the WT group In terms of median OS, there was no significant difference between mHSPC patients with HRD and wild-type mHSPC patients (53.
3 vs 68.
2 months, HR=0.
98, P=0.
96) (Figure 4).

Figure 4 HRD group and WT group median OS through the HRR gene stratification analysis, compared with other HRR gene mutations, patients with BRCA2, CDK12 or both mutations have significantly shorter time to castration resistance (Table 1).

HRR gene mutations are correlated with the poor prognosis of mHSPC patients.

Table 1 Time from different types of HRD to castration resistance Abstract151: Clinical and genomic characteristics of SPOP mutant prostate cancer SPOP (spotted poxvirus and zinc finger protein) is an important ubiquitination ligase, which mainly affects two A broad category of basic cellular activities, including genome modification and cell signal transduction.

SPOP plays an important anti-tumor effect in prostate cancer cells.
SPOP gene mutations can induce tumors.

SPOP gene point mutations can be detected in 6%-15% of prostate cancer patients.
In recent years, SPOP gene mutations have attracted widespread attention.
SPOP gene mutations have defined a new subtype of prostate cancer.

Previous studies have shown that compared with wild-type SPOP (wtSPOP), patients with mutant SPOP (mtSPOP) have a better response to ADT and a better response to abiraterone [4].

In this retrospective analysis published by ASCO GU [5], 63 prostate cancer patients from a single center at Johns Hopkins University were selected.
These patients were diagnosed from primary tumors (48 cases) and metastases (13 cases).
), SPOP mutations were detected in liquid biopsy (2 cases), the purpose is to further observe the clinical and genomic characteristics of single-center mtSPOP prostate cancer patients. The results of the study showed that among the 63 patients in the mtSPOP queue, compared with other races (Asian, Caucasian), mtSPOP mutations accounted for a higher proportion of African Americans, and F133 was the most common type of SPOP mutation ( 59%), the tumor suppressor gene APC mutation is the most common concomitant type (24%) (Table 2), and no patients with TMPRSS2-ERG fusion (0%) were observed in this cohort.

In the mHSPC patient type, the median progression-free survival (PFS) time of the first-line treatment with ADT alone in the mtSPOP patient is longer (median PFS 41 months, 95% Cl 24-73); in the mCRPC patient type, the mtSPOP patient uses Abiraterone had a better response than enzalutamide [median PFS 15.
3 months (95% Cl 7.
5-NR) vs 7.
4 months (95% Cl 6.
6-NR)].

Currently, research to evaluate the response of SPOP to immunotherapy is underway.

Table 2 Clinical and genomic characteristics of patients with mutant SPOP prostate cancer.
Abstract165: Overview of CDK12 gene mutation map of mCRPC.
Reports related to immunotherapy are still the hot spots of this conference to determine whether patients with prostate cancer can get immune checkpoint inhibitors (ICI) Benefit from treatment is still an unmet clinical need.

The latest study found that a new molecular subtype of advanced prostate cancer is caused by the loss of somatic biallelic function of the tumor suppressor gene CDK12, which encodes cyclin-dependent kinase 12.

CDK12 maintains DNA repair by regulating DNA damage response genes (BRCA1, FANCD2 and ATR), and its inactivation is related to ICI sensitivity.

The specific loss-of-function genomic alteration (GA) in CDK12 is related to the mechanism of fusion-induced neoantigen production and is one of the biomarkers for predicting the effectiveness of ICI.

A study published at this year’s ASCO GU conference [6] aims to use whole genome testing (CGP) to compare the genetic profiles of mutated CDK12 (CDK12mut+) and non-CDK12 mutated (CDK12mut-) prostate cancer patients.

The results of the study showed that 315 (6.
4%) mCRPC patients had CDK12mut+ and CDK12mut+ mCRPC patients had significantly fewer TMPRSS2 genome changes: ERG (P<0.
0001), TP53 (P<0.
0001), PTEN (P<0.
0001), ATM (P= 0.
001), PIK3CA (P=0.
003), RB1 (P=0.
02), BRCA2 (P<0.
0001) and APC (P=0.
002).

CDK12mut+ mCRPC patients’ CCND1 (P<0.
0001), BRAF (P=0.
007), ERBB2 (P<0.
001) and cell cycle regulation genes MDM2/4 (P<0.
0001), CDK4 (P<0.
0001), CDK6 (P= 0.
002) The frequency of occurrence is higher.

High microsatellite instability (MSI-H) state was more common in CDK12mut+ cases (P=0.
007), median tumor mutation burden (TMB) was significantly increased (P<0.
001), and low PD-L1 expression was more common (P=0.
02) ).

High PD-L1 expression (50%) was relatively rare in both study cohorts (Table 3).

Among them, MSI-H status, median TMB and PD-L1 expression may be related to the additional benefits of ICI, and further prospective studies are needed.

Table 3 CDK12mut+ and CDK12mut-two cohorts of genome maps 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 time of prostate cancer is longer, but once it appears Metastasis, 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 ASCO GU conference, related research is also contending.

In the past, genetic testing was mostly based on tissue biopsy of prostate cancer tumors or metastases.
Because it is invasive and samples may not be available clinically, many clinical and scientific researchers have conducted research on non-invasive and easy-to-operate liquid biopsy. Many studies on ASCO-GU show that liquid biopsy and tissue biopsy have a good overlap and consistency from multiple angles.

Therefore, liquid biopsy can replace tissue biopsy to some extent, and has certain guiding value for the prognosis of prostate cancer.

In recent years, with the deepening of research, important driver gene mutations such as BRCA1/2 have been discovered, and targeted therapies such as PARP inhibitors have received more and more attention in prostate cancer.

Last year, two PARP inhibitors, Nilapali and Lucapari were approved for use in some mCRPC patients with HRR gene mutations, which opened the prelude to the targeted therapy of prostate cancer.
Therefore, this year's ASCO-GU related research emerges endlessly.

HRR genes, especially BRCA1/2 and ATM genes, which are clinically significant, are important goals of genetic testing.
Patients with mutant genes may benefit from PARP inhibitors.

SPOP and CDK12 gene mutations may lead to new molecular subtypes of advanced prostate cancer.

Recent studies have found that SPOP can regulate DNA double-strand break repair and maintain DNA stability.

SPOP mutations can damage the homologous repair of DNA double-strand breaks and cause genome instability.
At the same time, it increases the sensitivity to DNA damage drugs (such as PARPi) [7].
SPOP mutant prostate cancer can also cause AR pathway activation, so The treatment of AR pathway is still the cornerstone of the treatment of SPOP-mutated prostate cancer.
SPOP-mutated mCRPC patients respond well to abiraterone treatment, which is of great significance to our choice of therapeutic drugs.
Whether abiraterone is suitable for hormone-sensitive stage The value of SPOP mutant prostate cancer also needs further research.

Studies have also shown that in prostate cancer, CDK12 may mainly play a role in DNA replication-related repair.
The biallelic inactivation of CDK12 produces unique gene characteristics, leading to gene fusion to induce the production of new antigens.
Such patients may be immune from immunity.
Benefit from checkpoint inhibitors [8].

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.

Expert profileProfessor Sun Ting enjoys special government allowances, Chief Physician of Urology, Nanchang University First Affiliated Hospital, Doctoral Supervisor, Member of Chinese Medical Association Urology Society Member, Chinese Medical Association Urology Society Robotics Group Member, Chinese Medical Association Urology Society Minimally Invasive Group Member Member of the Professional Committee of Urinary Endoscopy, Chinese Medical Doctor Association, Member of the Standing Committee of the Extracurricular Specialty Committee of the Chinese Integrative Medicine Physician Branch of the Chinese Medical Doctor Association, Chairman of the Jiangxi Provincial Medical Association Urology Branch, Deputy Office of the Jiangxi Provincial Institute of Urology Director, Cross-century Academic and Technical Leader of the Health System of West Yangtze River, Jiangxi Province University Young and Middle-aged Academic Leader, Jiangxi Provincial Department of Health, Young and Young Academic and Technical Leader Reference: 1.
Abstract 25: Hanna Tukachinsky, Russell Madison, Jon Chung, et al .
Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer to identify targetable BRCA alterations and AR resistance mechanisms.
2.
Abstract 49: Andrea Leith, Amanda Ribbands, Matthew Last, et al.
Genomic/genetic testing patterns for patients with metastatic castrate-resistant prostate cancer: Results from a real-world study in the United States.
3.
Abstract 150: Justin Shaya, Aaron Lee, Angelo Cabal, et al.
The prognostic significance of homologous recombination repair pathway alterations in metastatic hormone-sensitive prostate cancer.
4.
Gunther Boysen, Daniel N.
Rodrigues, Pasquale Rescigno, et al.
SPOP mutated/ CHD1 deleted lethal prostaterone cancer and 2 abirate sensitivity.
OnlineFirst on August 1 , 2018,DOI: 10.
1158/1078-0432.
5.
Abstract 151: Mari Nakazawa, Mike Fang, Pedro Issacsson Velho, et al.
SPOP mutations in prostate cancer: Clinical and genomic features.
6.
Abstract 165: Petros Grivas, Gennady Bratslavsky, Joseph M Jacob, et al.
Genomic landscape of CDK12 mutated metastatic castrate-resistant prostate cancer (mCRPC).
7.
YX Chen et al.
Response prediction biomarkers and drug combinations of PARP inhibitors in prostate cancer.
Acta Pharmacologica Sinica (2021) 0:1 – 11.
8.
Emmanuel S.
Antonarakis, MD1; Pedro Isaacsson Velho, MD1; Wei Fu, MSc,et al.
CDK12-Altered Prostate Cancer: Clinical Features and Therapeutic Outcomes to Standard Systemic Therapies, Poly (ADP-Ribose) Polymerase Inhibitors, and PD-1 Inhibitors.
JCO Precision Oncology 2020; 370-381.