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In recent years, significant progress has been made in the field of bladder cancer research.
The second-generation sequencing (NGS) technology identified the most mutated genes in bladder cancer.
This wealth of information can help identify driver mutations, identify treatment targets, and have a clearer understanding of the patient's prognosis and treatment direction.
Similarly, the clinical understanding of bladder cancer cells has also increased.
The identification of cell characteristics and different types of cell populations, and the quantification of normal and abnormal cell types in tumors can help to better predict treatment response.
Significant progress has also been made in non-invasive diagnostic methods including liquid biopsy, and these methods may have great practical value in the evaluation of minimal residual disease (MRD) after treatment and early diagnosis.
Immune checkpoint inhibitors (ICIs) are effective in treating bladder cancer, and have been proven to cure some patients with bladder cancer and significantly reduce adverse events.
These developments provide patients with better monitoring opportunities, unique treatment options and greater hope of survival.
In this review, the researchers introduced the latest advances in molecular and translational research in the biology of bladder cancer, and discussed its current or future potential clinical applications in the management of bladder cancer.
Figure 1 Pathological and molecular characteristics of bladder cancer.
Genetic modification of bladder cancer.
NGS technology provides abundant molecular information for tumor molecular classification in patients with bladder cancer.
Full transcriptome mRNA analysis of patient tumor tissue samples allows researchers to establish the molecular classification of bladder cancer.
Bladder cancer is one of the cancers with the highest mutation rate after lung cancer and skin cancer, the most important of which is the mutation of the gene promoter encoding telomerase reverse transcriptase (TERT), which occurs with a frequency of 70%-80%.
In turn, identifying frequent mutations has facilitated the development of new treatment methods and urine and blood tests for early detection of disease and monitoring after treatment.
Epigenetic modification of bladder cancer also shows significant epigenetic disorders, such as changes in DNA methylation.
The Cancer Genome Atlas (TCGA) analysis of samples from patients with myometrial invasive bladder cancer (MIBC) identified clusters of DNA hypomethylation and hypermethylation.
Compared with higher grade MIBC, DNA hypomethylation appears to be more common in stage 1 and 2 MIBC and non-muscular invasive bladder cancer (NMIBC), while DNA hypermethylation is associated with tumor suppressor genes (such as TP53, RB1, CDKN2A) It is related to CDH1) silence and aggressive diseases.
Therefore, classifying MIBC based on DNA methylation characteristics may help identify predictive biomarkers and determine treatments.
Genomic analysis also found that bladder cancer has a higher mutation load than most cancers, especially the proteins encoded by chromatin remodeling genes, such as histone demethylase KDM6A, histone methyltransferase (KMT2C and KMT2D) , Histone acetyltransferase (CREBBP and EP300) and EWI/SNF chromatin remodeling complex (ARID1A) (Figure 2).
Figure 2 The main genomic changes of bladder cancer.
Tumor microenvironment researchers have also explored the impact of tumor microenvironment (TME) on tumor progression and treatment response in preclinical studies.
Although the research of TME is still in the emerging stage in the field of bladder cancer, the advancement of imaging and single-cell analysis technology helps to further clarify the importance of stromal and infiltrating immune cell types in cancer progression and therapeutic intervention.
Figure 3 Population characteristics of non-malignant cell types that affect the progression of bladder cancer.
Ethnic and socioeconomic factors: In the past few decades, although patient management has been greatly improved, there are still significant ethnic differences in the overall survival of bladder cancer patients.
Data analysis found that black patients are more likely to have MIBC than white patients.
However, the overall survival rate and relapse-free survival rate of white and black patients were not significantly different, indicating that the above racial differences may be partly due to social factors that affect patients' access to medical care.
Further research is needed.
Biological gender characteristics: After considering all risk variables, compared with male patients, female patients may have a higher risk of disease progression, recurrence, and death, but this is still controversial.
Some studies have proposed the following hypothesis: varying degrees of exposure to environmental hazards, sex steroid hormone regulation, and molecular differences can explain the differences in morbidity and mortality.
In preclinical models, sex chromosomes and hormones play an important role in the development of bladder cancer.
Molecular diagnosis The current diagnostic criteria for bladder cancer are cystoscopy and urine cytology.
Urine cytology provides an opportunity to evaluate organ eluate and is non-invasive.
However, it lacks sufficient sensitivity for low-grade bladder cancer.
The development of highly accurate, cost-effective non-invasive examination methods for the diagnosis and monitoring of bladder cancer is a major demand for clinical diagnosis, especially for early and low-grade urothelial tumors.
Treatment progress 1.
NMIBC increases the residence time in the bladder and absorbs therapeutic drugs: Compared with MIBC, one of the main advantages of non-systemic chemotherapy for NMIBC is that it can only be applied to the bladder lumen (intravesical chemotherapy), making the body other The normal tissues of the site are protected from the toxic effects of chemotherapy drugs.
In addition, intravesical chemotherapy is as effective as transurethral cystectomy in reducing disease recurrence.
Mitomycin C, epirubicin, thiotepa, gemcitabine and doxorubicin are currently the most commonly used drugs.
Although effective, the efficacy still needs to be further improved.
In order to improve the efficacy, researchers tried to increase the residence time of the drug in the bladder cavity by implanting a carrier, thereby increasing the local diffusion time of the drug.
Immunotherapy: For patients with NMIBC who are at high risk of recurrence, the current standard treatment is to instill BCG (BCG) into the bladder.
This therapy can reduce the risk of disease recurrence and progression, and prolong the survival of high-risk patients.
It can also be used as a maintenance therapy for intermediate-risk and high-risk NMIBC patients.
However, since radical cystectomy with lifestyle changes is currently the most common treatment option, the treatment of BCG-refractory patients has become the biggest challenge in this field.
Therefore, researchers are evaluating the feasibility of BCG in combination with other treatments.
Recently, the FDA approved pembrolizumab for the treatment of BCG-refractory NMIBC patients or patients who are unable or unwilling to undergo cystectomy.
Studies have shown that 46% of responding patients who received pembrolizumab had a complete remission that lasted for at least 12 months.
2.
MIBC molecular markers: The main goal of MIBC treatment is to prevent or successfully treat local and metastatic recurrence.
The current standard treatment of MIBC is radical cystectomy after neoadjuvant platinum chemotherapy.
Finding a predictor of chemotherapy sensitivity is one of the needs of the MIBC field.
To determine that patients who are sensitive to chemotherapy are not only beneficial to the patient’s survival, but also to avoid unnecessary toxicity and the delay of radical cystectomy due to chemotherapy resistance.
Immunotherapy: MIBC is a malignant tumor with high mutation burden.
Other tumors with high mutation burden include melanoma and non-small cell lung cancer, which respond well to ICIs.
Atelizumab has been approved for MIBC patients.
Recently, the PD-L1 inhibitor Avelumab has been approved for the first-line maintenance treatment of MIBC patients who have successfully undergone chemotherapy, and Avelumab has also been approved by the FDA for MIBC patients who have progressed after chemotherapy.
Conclusion and Prospects For decades, there has been little progress in the treatment of bladder cancer.
However, in the past 7 years, the development of patient tumor molecular analysis and immunotherapy has enabled us to see unprecedented progress.
The former has important clinical application value in urine detection for evaluating the recurrence of bladder cancer.
In addition to urine testing, molecular analysis can also be used on blood samples to help monitor recurrence.
ICIs have made significant clinical progress in almost all cancers.
ICIs are replacing traditional therapeutic drugs and become the new first-line and second-line treatment options for bladder cancer, marking the huge potential and hope of immunotherapy in bladder cancer. Current challenges include the search for biomarkers and the development of more effective ICIs, small molecule therapies, and combinations based on other biological therapies.
References: Linda Tran, Jin-Fen Xiao, Neeraj Agarwal ,et al.
Advances in bladder cancer biology and therapy[J].
Nat Rev Cancer.
2021 Feb;21(2):104-121.
The second-generation sequencing (NGS) technology identified the most mutated genes in bladder cancer.
This wealth of information can help identify driver mutations, identify treatment targets, and have a clearer understanding of the patient's prognosis and treatment direction.
Similarly, the clinical understanding of bladder cancer cells has also increased.
The identification of cell characteristics and different types of cell populations, and the quantification of normal and abnormal cell types in tumors can help to better predict treatment response.
Significant progress has also been made in non-invasive diagnostic methods including liquid biopsy, and these methods may have great practical value in the evaluation of minimal residual disease (MRD) after treatment and early diagnosis.
Immune checkpoint inhibitors (ICIs) are effective in treating bladder cancer, and have been proven to cure some patients with bladder cancer and significantly reduce adverse events.
These developments provide patients with better monitoring opportunities, unique treatment options and greater hope of survival.
In this review, the researchers introduced the latest advances in molecular and translational research in the biology of bladder cancer, and discussed its current or future potential clinical applications in the management of bladder cancer.
Figure 1 Pathological and molecular characteristics of bladder cancer.
Genetic modification of bladder cancer.
NGS technology provides abundant molecular information for tumor molecular classification in patients with bladder cancer.
Full transcriptome mRNA analysis of patient tumor tissue samples allows researchers to establish the molecular classification of bladder cancer.
Bladder cancer is one of the cancers with the highest mutation rate after lung cancer and skin cancer, the most important of which is the mutation of the gene promoter encoding telomerase reverse transcriptase (TERT), which occurs with a frequency of 70%-80%.
In turn, identifying frequent mutations has facilitated the development of new treatment methods and urine and blood tests for early detection of disease and monitoring after treatment.
Epigenetic modification of bladder cancer also shows significant epigenetic disorders, such as changes in DNA methylation.
The Cancer Genome Atlas (TCGA) analysis of samples from patients with myometrial invasive bladder cancer (MIBC) identified clusters of DNA hypomethylation and hypermethylation.
Compared with higher grade MIBC, DNA hypomethylation appears to be more common in stage 1 and 2 MIBC and non-muscular invasive bladder cancer (NMIBC), while DNA hypermethylation is associated with tumor suppressor genes (such as TP53, RB1, CDKN2A) It is related to CDH1) silence and aggressive diseases.
Therefore, classifying MIBC based on DNA methylation characteristics may help identify predictive biomarkers and determine treatments.
Genomic analysis also found that bladder cancer has a higher mutation load than most cancers, especially the proteins encoded by chromatin remodeling genes, such as histone demethylase KDM6A, histone methyltransferase (KMT2C and KMT2D) , Histone acetyltransferase (CREBBP and EP300) and EWI/SNF chromatin remodeling complex (ARID1A) (Figure 2).
Figure 2 The main genomic changes of bladder cancer.
Tumor microenvironment researchers have also explored the impact of tumor microenvironment (TME) on tumor progression and treatment response in preclinical studies.
Although the research of TME is still in the emerging stage in the field of bladder cancer, the advancement of imaging and single-cell analysis technology helps to further clarify the importance of stromal and infiltrating immune cell types in cancer progression and therapeutic intervention.
Figure 3 Population characteristics of non-malignant cell types that affect the progression of bladder cancer.
Ethnic and socioeconomic factors: In the past few decades, although patient management has been greatly improved, there are still significant ethnic differences in the overall survival of bladder cancer patients.
Data analysis found that black patients are more likely to have MIBC than white patients.
However, the overall survival rate and relapse-free survival rate of white and black patients were not significantly different, indicating that the above racial differences may be partly due to social factors that affect patients' access to medical care.
Further research is needed.
Biological gender characteristics: After considering all risk variables, compared with male patients, female patients may have a higher risk of disease progression, recurrence, and death, but this is still controversial.
Some studies have proposed the following hypothesis: varying degrees of exposure to environmental hazards, sex steroid hormone regulation, and molecular differences can explain the differences in morbidity and mortality.
In preclinical models, sex chromosomes and hormones play an important role in the development of bladder cancer.
Molecular diagnosis The current diagnostic criteria for bladder cancer are cystoscopy and urine cytology.
Urine cytology provides an opportunity to evaluate organ eluate and is non-invasive.
However, it lacks sufficient sensitivity for low-grade bladder cancer.
The development of highly accurate, cost-effective non-invasive examination methods for the diagnosis and monitoring of bladder cancer is a major demand for clinical diagnosis, especially for early and low-grade urothelial tumors.
Treatment progress 1.
NMIBC increases the residence time in the bladder and absorbs therapeutic drugs: Compared with MIBC, one of the main advantages of non-systemic chemotherapy for NMIBC is that it can only be applied to the bladder lumen (intravesical chemotherapy), making the body other The normal tissues of the site are protected from the toxic effects of chemotherapy drugs.
In addition, intravesical chemotherapy is as effective as transurethral cystectomy in reducing disease recurrence.
Mitomycin C, epirubicin, thiotepa, gemcitabine and doxorubicin are currently the most commonly used drugs.
Although effective, the efficacy still needs to be further improved.
In order to improve the efficacy, researchers tried to increase the residence time of the drug in the bladder cavity by implanting a carrier, thereby increasing the local diffusion time of the drug.
Immunotherapy: For patients with NMIBC who are at high risk of recurrence, the current standard treatment is to instill BCG (BCG) into the bladder.
This therapy can reduce the risk of disease recurrence and progression, and prolong the survival of high-risk patients.
It can also be used as a maintenance therapy for intermediate-risk and high-risk NMIBC patients.
However, since radical cystectomy with lifestyle changes is currently the most common treatment option, the treatment of BCG-refractory patients has become the biggest challenge in this field.
Therefore, researchers are evaluating the feasibility of BCG in combination with other treatments.
Recently, the FDA approved pembrolizumab for the treatment of BCG-refractory NMIBC patients or patients who are unable or unwilling to undergo cystectomy.
Studies have shown that 46% of responding patients who received pembrolizumab had a complete remission that lasted for at least 12 months.
2.
MIBC molecular markers: The main goal of MIBC treatment is to prevent or successfully treat local and metastatic recurrence.
The current standard treatment of MIBC is radical cystectomy after neoadjuvant platinum chemotherapy.
Finding a predictor of chemotherapy sensitivity is one of the needs of the MIBC field.
To determine that patients who are sensitive to chemotherapy are not only beneficial to the patient’s survival, but also to avoid unnecessary toxicity and the delay of radical cystectomy due to chemotherapy resistance.
Immunotherapy: MIBC is a malignant tumor with high mutation burden.
Other tumors with high mutation burden include melanoma and non-small cell lung cancer, which respond well to ICIs.
Atelizumab has been approved for MIBC patients.
Recently, the PD-L1 inhibitor Avelumab has been approved for the first-line maintenance treatment of MIBC patients who have successfully undergone chemotherapy, and Avelumab has also been approved by the FDA for MIBC patients who have progressed after chemotherapy.
Conclusion and Prospects For decades, there has been little progress in the treatment of bladder cancer.
However, in the past 7 years, the development of patient tumor molecular analysis and immunotherapy has enabled us to see unprecedented progress.
The former has important clinical application value in urine detection for evaluating the recurrence of bladder cancer.
In addition to urine testing, molecular analysis can also be used on blood samples to help monitor recurrence.
ICIs have made significant clinical progress in almost all cancers.
ICIs are replacing traditional therapeutic drugs and become the new first-line and second-line treatment options for bladder cancer, marking the huge potential and hope of immunotherapy in bladder cancer. Current challenges include the search for biomarkers and the development of more effective ICIs, small molecule therapies, and combinations based on other biological therapies.
References: Linda Tran, Jin-Fen Xiao, Neeraj Agarwal ,et al.
Advances in bladder cancer biology and therapy[J].
Nat Rev Cancer.
2021 Feb;21(2):104-121.
