How to predict the survival prognosis of urothelial cancer treatment?

*Only for medical professionals to read for reference, explore effective biomarkers, and provide appropriate treatment plans for different urothelial cancer patients
.

In recent years, the treatment of urothelial carcinoma (UC) has progressed rapidly, and certain breakthroughs have been made in immunotherapy, antibody-conjugated drugs (ADC), and targeted therapy drugs, which have greatly improved the survival and prognosis of patients
.

However, screening the benefited population is still the focus of UC treatment, and finding effective biomarkers is crucial
.

This article counts the progress of biomarkers in the UC field in 2021 for readers
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UC immunotherapy-related biomarkers ctDNA, memory CD8(+) T cells, TP53 nonsense mutations, etc.
are related to the prognosis of immune checkpoint inhibitor (ICI) treatment IMvigor010 is a global multi-center, open-label, randomized phase III clinical trial , To evaluate the role of atelizumab in the adjuvant treatment of muscular invasive urothelial carcinoma (MIUC)
.

Recently, Nature published the results of an exploratory biomarker analysis of circulating tumor DNA (ctDNA)-minimal residual disease (MRD) prediction ability in the IMvigor010 study [1]
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The results show that individualized ctDNA analysis can not only identify MRD with high accuracy, but also predict the outcome of immunotherapy
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Postoperative ctDNA-MRD positive patients are more likely to benefit from immune adjuvant therapy
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In addition, a systematic review and meta-analysis [2] showed that high levels of memory CD8(+) T cells are associated with better progression-free survival (PFS, HR 0.
64) and overall survival (OS) in cancer patients receiving immunotherapy.
, HR 0.
37) is significantly correlated
.

And after excluding other interfering factors such as chemotherapy, radiotherapy and targeted therapy, memory CD8(+) T cells still have significant prognostic value in cancer patients given immunotherapy alone
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Therefore, memory CD8(+) T cells may be a promising predictor of immunotherapy for cancer patients
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A study at the European Academy of Urology (EAU) Congress in 2021 evaluated the potential predictive value of TP53 nonsense mutations as a biomarker for UC anti-PD-1/PD-L1 therapy [3]
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The results showed that TP53 nonsense mutations have significant significance in promoting CD8+ T cell infiltration, activating effector T cells and increasing PD-L1 expression by reducing the expression of p53 and miR-34a
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TP53 nonsense mutation may be used as a predictive biomarker of UC anti-PD-1/PD-L1 treatment response
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Antibiotic use, changes in CDKN2A are associated with poor prognosis of ICI treatment.
It has been previously established that antibiotic exposure (which can change the gut microbiota) will have a negative impact on the outcome of patients receiving ICl
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At the European Society of Medical Oncology (ESMO) conference in 2021, a population-based study explored this again [4]
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The study used the population-level management data of the Ontario Institute of Clinical Evaluation Science, included all adult solid tumor patients who started ICl treatment from June 2012 to October 2018, and collected usage statement data within 1 year and 60 years before ICI started.
Antibiotic exposure during the day
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The analysis found that many cancer patients were exposed to antibiotics before receiving ICI, and the antibiotic exposure before ICI started, especially the fluoroquinolone exposure was associated with poor OS, and dose effects were observed
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Therefore, clinicians may need to take interventions to change the gut microbiome to help improve the outcome of ICl-treated patients who have previously been exposed to antibiotics
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In addition, a study at the 2021 American Society of Clinical Oncology Symposium on Urogenital Cancer (ASCO-GU) [5] showed that CDKN2A changes are associated with shorter OS and time to treatment failure (TTF) in UC patients, suggesting CDKN2A Changes can be used as predictive biomarkers for UC patients receiving ICI therapy
.

AutoAbs feature analysis may predict the safety of ICI treatment.
ICI treatment can lead to severe immune-related adverse events (irAE)
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At the ESMO conference in 2021, in order to explore the predictors of irAE, researchers customized an autoantigen (autoAg) microarray to analyze autoantibodies related to autoimmune diseases in patients receiving ICI treatment [6]
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For patients with solid tumors who received ICI in clinical trials, plasma was collected at baseline (before ICI), 3-4, 6-8, 24 weeks after the start of ICI, and at the end of treatment, and healthy control samples were used for comparison
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It was found that the baseline analysis of autoAb and the early changes after ICI can identify patients at high risk of irAE and distinguish patients at risk of organ-specific toxicity
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If confirmed, integrating autoAbs feature analysis into clinical practice and clinical trials may be able to better select patients for ICI treatment
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Molecular typing is related to exploring the survival benefit of neoadjuvant chemotherapy (NAC) in patients with muscular invasive bladder cancer (MIBC) before radical cystectomy (RC)
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However, previous studies have shown that molecular typing may affect the patient's response to treatment
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Therefore, relevant biomarkers are needed in clinical practice to predict the response of MIBC patients to NAC treatment
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A study reported by the EAU Conference in 2021[7] included a total of 601 MIBC patients, of which 247 received NAC+RC treatment and 354 received only RC treatment
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The results showed that the 3-year OS rate of Luminal patients who did not receive NAC vs.
received NAC was 65% vs 63% (p=0.
7)
.

Non-Luminal patients who did not receive NAC vs.
NAC had a 3-year OS rate of 61% vs 71% (p=0.
1); the results of cancer-specific survival (CSS) rates were similar.
Non-Luminal patients received NAC for 3 years CSS rate increased by 11% (77% vs 66%)
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The results of this study show that for MIUC patients, Non-Luminal type can benefit more from NAC; Luminal type accepts or does not accept NAC, there is no significant difference in prognosis
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Genotype classification helps to screen MIBC patients who can benefit from NAC
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Bacille Calmette-Guerin (BCG) treatment-related biomarkers explore BCG as the standard treatment for high-risk non-muscular invasive bladder cancer (NMIBC).
However, there are still 40%-60% of patients who relapse or develop disease progression after BCG treatment
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A study at the EAU Conference in 2021 was a predictive biomarker for the response of high-risk NMIBC patients to BCG perfusion in the bladder [8]
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The results found that urine IL-10 and blood TNF-α can significantly predict ICR; after BCG induction, IL-10, CTLA4, TFs (GATA3+, T-bet+, and FoxP3+) and the GATA3+/T-bet+ ratio can independently predict BCG.
Further development of the reaction
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Another study [9] analyzed the somatic characteristics of the response and recurrence of BCG bladder perfusion treatment of NMIBC, and found that high tumor mutation burden, ARID1A and CCNE1 mutations may be valuable markers for predicting BCG response
.

Clinicopathological characteristics At the EAU conference in 2021, a study reported by Chinese scholars [10] aimed to analyze the germline mutation pattern of cancer susceptibility genes, and was included in the largest upper urinary tract urothelial carcinoma (UTUC) cohort to date.
Explore their clinical relevance
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A total of 309 Chinese UTUC patients were included in the study, and the genomic DNA obtained from white blood cells was sequenced using a multi-gene panel
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The researchers analyzed 105 genes associated with cancer susceptibility and compared the frequency of pathogenic/possibly pathogenic (P/LP) germline mutations in UTUC patients with Western participants in previous studies
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The results found that a large proportion of Chinese UTUC patients have hereditary P/LP mutations, most of which occur in the DDR gene
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These data emphasize the importance of reproductive system testing of UTUC patients, which will provide empirical evidence for precise prevention and guidance of personalized medicine
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Another study [13] analyzed the tumor and matched blood DNA of 118 UC patients from China [including 45 UTUC patients and 73 urothelial carcinoma of the bladder (UCB) patients]
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The results found that there are significant differences in the mutations of UTUC and UCB.
For example, the INRRL1 and RP1L1 mutations only occur in UCB; compared with UCB, KMT2 C, LRP1B, NCOR1, ZFHX4, KDR, NF1, NOTCH1 and UCB are more likely to be observed in UTUC.
FAM135B gene mutation; 82.
22% of UTUC patients have at least one mutation that can be targeted, of which 53.
33% of patients can choose targeted drug therapy; 82.
19% of UCB patients have at least one mutation that can be targeted, of which 54.
79% Patients can use targeted drugs
.

The results of this study indicate that the genetic profiles of UTUC and bladder cancer are different, which may have important implications for the site-specific management of UC
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All in all, in order to improve the efficacy and safety of UC treatment, it is very important to find effective biomarkers
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With the continuous exploration of new biomarkers, it will help more precise and individualized treatment of UC
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References [1]Powles T, Assaf ZJ, Davarpanah N, et al.
ctDNA guiding adjuvant immunotherapy in urothelial carcinoma.
Nature.
2021;595(7867):432-437.
[2]Prognostic impact of memory CD8(+) T cells on immunotherapy in human cancers: A systematic review and meta-analysis.
2021 ESMO 106P.
[3]Nonsense-mutation in TP53 improves clinical benefits of PD-1/PD-L1 blockade immunotherapy in advanced urothelial carcinoma through up-regulating PD- L1 expression via miR-34a.
2021 EAU P0451.
[4]Impact of antibiotic (ATB) exposure prior to immune checkpoint inhibitor (ICI) treatment on overall survival (OS): A population-based study.
2021 ESMO 1671MO.
[5] CDKN2A alterations as markers of immune checkpoint blockade (ICB) resistance in urothelial carcinoma (UC).
2021 ASCO-GU Abstract475.
[6]Autoimmune panels as predictors of immune-related adverse events (irAEs) in patients (pts) treated with immune checkpoint inhibitors (ALERT).
2021 ESMO 989P.
[7]Luminal primary muscle-invasive bladder cancer patients are less likely to benefit from platinum-based neoadjuvant chemotherapy.
2021 EAU P0830.
[8]Can we predict of the response of high risk non muscle invasive bladder cancer patients to intravesical bacillus calmette-guerin? The role of immunological markers.
2021 EAU P0769.
[9]Somatic features of response and relapse in non-muscle invasive bladder cancer treated with intravesical Bacillus Calmette–Guérin.
2021 EAU P0445.
[10]The germline mutation landscape of cancer susceptibility genes in Chinese patients with upper tract urothelial carcinoma.
2021 EAU P0771.
[11]Comparison of clinicopathological features in metastatic upper tract urothelial carcinoma and urothelial carcinoma of the bladder.
2021 EAU P0471.
This material is supported by AstraZeneca and is only for reference by medical professionals.
NS Number: CN-89042 Validity: 12/01/ 2022*This article is only used to provide scientific information to medical professionals, and does not represent the views of this platform