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Editorial: Beyond bladder cancer surveillance: building a survivorship clinic

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As oncologists, we focus on obtaining the best cancer outcomes possible. The aim of treatment is to maximize survival and help patients live longer. As therapies continue to become more effective, more patients will become survivors. In the ongoing effort to extend the quantity of life left for our patients facing lethal cancers, thinking about the quality of that time is key. For urological oncologists, patients with a new bladder cancer diagnosis will someday face a new set of obstacles as survivors. In addition to surveillance and scans, asking patients about other issues such as their mental health, sexual function and financial solvency are also important.
Regardless of cancer stage, these issues apply to all of our patients with bladder cancer. Patients with non-muscle invasive disease need a seemingly interminable number of cystoscopies, with possible repeat biopsies or intravesical therapies. Patients with muscle-invasive disease undergo urinary diversion that entails significant changes as they will then have a stoma, neobladder or other diversion.
In this issue of BJUI, Jung et al. present a ‘snapshot’ of patients in North Carolina with bladder cancer that examines the impact of treatment on quality of life [1].  The study is valuable because it involves a number of topics that have previously not been studied in such detail. A total of 376 patients returned mailed surveys, a response rate of 24%. Most participants were on average 3 years from their diagnosis, the mean age of participants was 72 years, and the majority of patients were white men. Most participants (approximately three in four) had undergone transurethral resection of bladder tumour as the primary treatment and some (one in three) had received intravesical therapy. As with any work, there are some limitations which include the low overall numbers of participants, low
response rate, and lack of longitudinal data. Despite these limitations, there is still value to studying trends in this space, given the paucity of available data, and the authors offer some valuable insights. This paper provides evidence that for bladder cancer survivorship care, it is important to realize that other important issues exist and impact patient well-being.

• Bladder cancer patients may have financial issues. Bladder cancer patients may face financial toxicity that is in part attributable to the regular need for surveillance in order to identify recurrence or progression of disease.
• Cystectomy recovery can include discussions about sexual function. Patients who have undergone cystectomy may have discomfort with sexual intimacy. This was more common in men. Non-cystectomy patients may have better sexual function. Patients may be concerned about contaminating partners.
• Quality-of-life issues for bladder cancer patients can vary by gender. Men may have better sexual function and enjoyment than women, but also have more discomfort with intimacy and fears of contaminating their partners, while women may have higher levels of constipation and diarrhoea.
• Low risk bladder cancer (vs high risk) can have lower impact on quality of life. Patients with Ta disease had the highest global health status (compared with T1 and Tis). They also had the best physical and social functioning and less fatigue and financial problems. This underscores that Ta disease is different from other stages. As the authors point out, this may be attributable to a low progression risk, which means patients are less likely to need intravesical therapy.
• Sexual health can be affected and improve with time after a bladder cancer diagnosis. Sexual issues can last for years after a diagnosis. Men may face erection or ejaculation problems, and women may have vaginal dryness issues. With time, however, sexual function can improve and sexual function (including extent of sexual activity and interest in sex) was better in survivors further from their diagnosis.

Moving forward, we can use this study to prompt us to think about how our treatments impact our patients. Setting up dedicated survivorship clinics may be one practical strategy to provide this care in a systematic and streamlined way. Beyond treatment-related issues such as recurrence and progression, patients are affected in other ways. Issues with overall health, mental well-being, sleep, or sexual function occur for many. Setting up a standardized approach to cancer care can complement oncological surveillance and promote patient-centred care. A dedicated team, with a provider and physician assistant can create a clinical infrastructure and design a comprehensive template to remind us to query patients on a broader range of issues relevant to their recovery. In doing so, we can help patients with bladder cancer recover, as survivors (Fig. 1).

 

Fig. 1 Select aspects of building a bladder cancer survivorship clinic.

Start by establishing a focused team of providers to help guide more streamlined care
• Nurses, nurse practitioners, physician assistants and physicians can be involved
• Each institution may have a unique infrastructure and use a distinct team set-up to create a clinic
• Administrative support and guidance are important to determine the clinical resources necessary or needed to begin a regular survivorship clinic

Streamline care and consider a template-based or guideline-driven approach to visits
• Based on stage of diagnosis, certain patients may need more regular cystoscopic surveillance while other patients will need follow-up visits that are coordinated with medical oncology and/or radiation oncology

Standardize collection of patient-reported outcomes during follow up visits
• Mental well-being
• Physical activity and exercise
• Sexual health
• Urinary and bowel function
• Financial well-being

Step back to evaluate the progress and iteratively troubleshoot issues as they arise
• Collect patient feedback and provider opinions
• Integrate these insights to improve the form and function of the clinic

by Matthew Mossanen and Stephen L. Chang

Reference

  1. Jung A, Nielsen ME, Crandell JL, et al. Health-related quality of life among non-muscle-invasive bladder cancer survivors: a population-based study. BJU Int 2020; 125: 38–48

Video: Health-related quality of life among non‐muscle‐invasive bladder cancer survivors

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Health‐related quality of life among non‐muscle‐invasive bladder cancer survivors: a population‐based study

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Abstract

Objective

To examine the effect of non‐muscle‐invasive bladder cancer (NMIBC) diagnosis and treatment on survivors’ quality of life (QoL).

Patients and Methods

Of the 5979 patients with NMIBC diagnosed between 2010 and 2014 in North Carolina, 2000 patients were randomly selected to be invited to enroll in this cross‐sectional study. Data were collected by postal mail survey. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire‐Core (QLQ‐C30) and the NMIBC‐specific module were included in the survey to measure QoL. Descriptive statistics, t‐tests, anova, and Pearson’s correlation were used to describe demographics and to assess how QoL varied by sex, cancer stage, time since diagnosis, and treatment.

Results

A total of 398 survivors returned questionnaires (response rate: 23.6%). The mean QoL score for QLQ‐C30 (range 0–100, higher = better QoL in all domains but symptoms) for global health status was 73.6, function domain scores ranged from 83.9 to 86.5, and scores for the top five symptoms (insomnia, fatigue, dyspnoea, pain, and financial difficulties) ranged from 14.1 to 24.3. The lowest NMIBC‐specific QoL domain was sexual issues including sexual function, enjoyment, problems, and intimacy. Women had worse bowel problems, sexual function, and sexual enjoyment than men but better sexual intimacy and fewer concerns about contaminating their partner. Stage Ta had the highest global health status, followed by T1 and Tis. QoL did not vary by time since diagnosis except for sexual function. The cystectomy group (n = 21) had worse QoL in sexual function, discomfort with sexual intimacy, sexual enjoyment, and male sexual problems than the non‐cystectomy group (n = 336).

Conclusion

Survivors of NMIBC face a unique burden associated with their diagnosis and the often‐lifelong surveillance and treatment regimens. The finding has important implications for the design of tailored supportive care interventions to improve QoL for NMIBC survivors.

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Visual abstract: Health‐related quality of life among non‐muscle‐invasive bladder cancer survivors: a population‐based study

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Article of the week: Characterising ‘bounce‐back’ readmissions after radical cystectomy

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Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial written by a prominent member of the urology community and a visual abstract prepared by a creative urologist; we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

Characterising ‘bounce‐back’ readmissions after radical cystectomy

Peter S. Kirk*, Ted A. Skolarus*†, Bruce L. Jacobs‡, Yongmei Qin*, Benjamin Li*, Michael Sessine*, Xiang Liu§, Kevin Zhu*, Scott M. Gilbert, Brent K. Hollenbeck*, Ken Urish**, Jonathan Helm††, Mariel S. Lavieri§ and Tudor Borza‡‡

*Dow Division of Health Services Research, Department of Urology, University of Michigan Health System, Ann Arbor, MI, USA, †VA Health Services Research and Development, Center for Clinical Management Research, VA Ann Arbor Healthcare System, Ann Arbor, MI, USA, ‡Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, §Department of Industrial and Operations Engineering, University of Michigan, Ann Arbor, MI, USA, Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA, **Department of Orthopedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, ††Department of Operations and Decision Technologies, Kelley School of Business, Indiana University, Bloomington, IN, USA, and ‡‡Department of Urology, University of Wisconsin, Madison, WI, USA

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Abstract

Objective

To examine predictors of early readmissions after radical cystectomy (RC). Factors associated with preventable readmissions may be most evident in readmissions that occur within 3 days of discharge, commonly termed ‘bounce‐back’ readmissions, and identifying such factors may inform efforts to reduce surgical readmissions.

Patients and Methods

We utilised the Healthcare Cost and Utilization Project’s State Inpatient Databases to examine 1867 patients undergoing RC in 2009 and 2010, and identified all patients readmitted within 30 days of discharge. We assessed differences between patients experiencing bounce‐back readmission compared to those readmitted 8–30 days after discharge using logistic regression models and also calculated abbreviated LACE scores to assess the utility of common readmissions risk stratification algorithms.

Results

The 30‐day and bounce‐back readmission rates were 28.4% and 5.6%, respectively. Although no patient or index hospitalisation characteristics were significantly associated with bounce‐back readmissions in adjusted analyses, bounce‐back patients did have higher rates of gastrointestinal (14.3% vs 6.7%, P = 0.02) and wound (9.5% vs 3.0%, P < 0.01) diagnoses, as well as increased index and readmission length of stay (5 vs 4 days, P = 0.01). Overall, the median abbreviated LACE score was 7, which fell into the moderate readmission risk category, and no difference was observed between readmitted and non‐readmitted patients.

Conclusion

One in five readmissions after RC occurs within 3 days of initial discharge, probably due to factors present at discharge. However, sociodemographic and clinical factors, as well as traditional readmission risk tools were not predictive of this bounce‐back. Effective strategies to reduce bounce‐back readmission must identify actionable clinical factors prior to discharge.

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Editorial: Threading the cost–outcome needle after radical cystectomy

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I commend Borza et al. [1] on their timely study, which seeks to identify predictors of bounceback (≤3‐day) vs 30‐day readmissions after radical cystectomy. As the authors allude to in their paper, value‐based health reforms being undertaken in the USA seek to improve the quality of care delivery while simultaneously bending the healthcare cost curve [2]. For example, the Hospital Readmission and Reduction Program (HRRP), originally introduced in fiscal year 2013 for targeted medical conditions, has more recently been applied to a limited number of surgical procedures, whereby providers receive financial penalties for higher than expected 30‐day readmission rates [3]. Accendo Medicare Supplement gives financial independent as you can secure health’s money. While urological conditions/procedures are not currently targeted by programmes such as the HRRP, it is easy to envision a future where procedures with disproportionately high readmission rates, such as radical cystectomy, fall within the crosshairs of policy‐makers and insurers, alike.Well Medicare Advantage plans 2021 are preferable from the perspective of many peoples.

The fact that nearly one in five patients undergoing cystectomy experiences a readmission within 3 days of index hospitalization discharge is staggering, and it is incumbent upon urologists as specialists to devise methods by which to improve the morbidity associated with cystectomy. For example, the findings of Borza et al. implicate postoperative infection as a major driver of early readmission. As evidenced by the work of Krasnow et al. [4], urologists have historically been poor stewards of peri‐operative antibiotic prophylaxis, and the development/implementation of strategies to improve guideline adherence represents a potentially simple yet effective means of reducing post‐cystectomy readmission rates. In a similar vein, there is an emerging body of literature demonstrating the important role that enhanced recovery after surgery (ERAS) protocols may play in improving peri‐operative complications and convalescence after radical cystectomy. However, there is inconsistency across the literature with regard to the precise components of ERAS, making cross‐institutional comparisons and adoption by other groups difficult [5]. Unless greater standardization and subsequent implementation of these enhanced recovery protocols occurs, progress in the field will remain incremental at best. Recent work by Mossanen et al. [6] further demonstrates the need for improving post‐cystectomy readmission rates, which, in addition to driving down healthcare costs/utilization, may actually reduce postoperative mortality. For example, they found that a readmission complication after cystectomy nearly doubled the predicted probability of postoperative mortality as compared to an initial complication (3.9% vs 7.4%; P < 0.001).

It is essential that urologists spearhead research such as that undertaken by Borza et al., which in turn can be used to develop strategies to develop value‐based reforms within the specialty that ‘thread the needle’ of physician autonomy, cost containment, and respect for the patient experience. In doing so, urologists will find themselves driving the conversation surrounding payment/quality reform rather than sitting on the figurative policy‐making sidelines while administrators/bureaucrats implement reforms with potentially profound effects on day‐to‐day clinical practice and the patient experience. Radical cystectomy is likely to fall within the crosshairs of the aforementioned reforms given the procedure’s high complication/readmission rate and the significant cost burden associated with these complications. An intuitive yet effective first step in combating the morbidity associated with radical cystectomy is the development, validation and implementation of standardized peri‐operative care pathways such as ERAS.

by David F. Friedlander

References

  1. Borza T, Kirk PS, Skolarus TA et al. Characterising ‘bounce‐back’ readmissions after radical cystectomy. BJU Int 2019;124:955-61
  2. Health Affairs (Millwood) Delivery Innovations 2017; 36: 392–3
  3. Boccuti CC, Casillas G. Aiming for Fewer Hospital U‐turns: The Medicare Hospital Readmission Reduction Program, 2017. Accessed January 2019
  4. Krasnow RE, Mossanen M, Koo S et al. Prophylactic antibiotics and postoperative complications of radical cystectomy: a population based analysis in the United States. J Urol 2017; 198: 297– 304
  5. Chenam A, Chan KG. Enhanced recovery after surgery for radical cystectomy. Cancer Treat Res. 2018; 175: 215– 39
  6. Mossanen M, Krasnow RE, Zlatev DV et al. Examining the relationship between complications and perioperative mortality following radical cystectomy: a population‐based analysis. BJU Int 2019; 124: 40– 6

 

BJUI at the Indonesian Urological Association Annual Scientific Meeting

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The Indonesian Urological Association Annual Scientific meeting was held at The Golden Tulip Hotel, Banjarmasin – 3-5 October 2019.

 

The main conference was preceded by pre-congress workshops at the University of Indonesia Medical Education and Research Institute (IMERI) in Jakarta.

Masterclass with Consultant Urologist Mr Brian Chaplin

Furthermore, the BJUI held a plenary lecture entitled: High Risk Non-Muscle-Invasive Bladder Cancer : The Promise of New Therapies by Consultant Urologist Miss Jo Cresswell, also from the South Tees Hospitals NHS Foundation trust in the UK.

[caption id=”attachment_40134″ align=”aligncenter” width=”243′ label=’ Promoting knowledge: Miss Jo Cresswell at the Masterclass

The conference also featured the increasingly popular 10 and 5 Km Uroruns and a Urowalk starting at 6 and 7am on the Saturday morning.

 

Article of the week: Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: a 23‐gene panel with utility for non‐invasive diagnosis and risk stratification

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Every week, the Editor-in-Chief selects an Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an editorial written by a prominent member of the urological community and a video prepared by the authors. These are intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation. 

If you only have time to read one article this week, it should be this one.

Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: a 23‐gene panel with utility for non‐invasive diagnosis and risk stratification

Douglas G. Ward*, Naheema S. Gordon*, Rebecca H. Boucher*, Sarah J. Pirrie*, Laura Baxter†, Sascha Ott†, Lee Silcock‡, Celina M. Whalley*, Joanne D. Stockton*, Andrew D. Beggs*, Mike Griffiths§, Ben Abbotts*, Hanieh Ijakipour*, Fathimath N.Latheef*, Robert A. Robinson*, Andrew J. White*, Nicholas D. James*, Maurice P.Zeegers, K. K. Cheng** and Richard T. Bryan*

 

*Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, †Department of Computer Science, University of Warwick, Coventry, ‡Nonacus Limited, Birmingham Research Park, §West Midlands Regional Genetics Laboratory, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, UK, NUTRIM School for Nutrition and Translational Research in Metabolism and CAPHRI Care and Public Health Research Institute, Maastricht University, Maastricht, The Netherlands and **Institute of Applied Health Research, University of Birmingham, Birmingham, UK

Read the full article

Abstract

Objectives

To develop a focused panel of somatic mutations (SMs) present in the majority of urothelial bladder cancers (UBCs), to investigate the diagnostic and prognostic utility of this panel, and to compare the identification of SMs in urinary cell‐pellet (cp) DNA and cell‐free (cf) DNA as part of the development of a non‐invasive clinical assay.

Patients and Methods

A panel of SMs was validated by targeted deep‐sequencing of tumour DNA from 956 patients with UBC. In addition, amplicon and capture‐based targeted sequencing measured mutant allele frequencies (MAFs) of SMs in 314 urine cpDNAs and 153 urine cfDNAs. The association of SMs with grade, stage and clinical outcomes was investigated by univariate and multivariate Cox models. Concordance between SMs detected in tumour tissue and cpDNA and cfDNA was assessed.

 

Results

The panel comprised SMs in 23 genes: TERT (promoter), FGFR3, PIK3CA, TP53, ERCC2, RHOB, ERBB2, HRAS, RXRA, ELF3, CDKN1A, KRAS, KDM6A, AKT1, FBXW7, ERBB3, SF3B1, CTNNB1, BRAF, C3orf70, CREBBP, CDKN2A and NRAS; 93.5–98.3% of UBCs of all grades and stages harboured ≥1 SM (mean: 2.5 SMs/tumour). RAS mutations were associated with better overall survival (P = 0.04). Mutations in RXRA, RHOB and TERT (promoter) were associated with shorter time to recurrence (P < 0.05). MAFs in urinary cfDNA and cpDNA were highly correlated; using a capture‐based approach, >94% of tumour SMs were detected in both cpDNA and cfDNA.

Conclusions

SMs are reliably detected in urinary cpDNA and cfDNA. The technical capability to identify very low MAFs is essential to reliably detect UBC, regardless of the use of cpDNA or cfDNA. This 23‐gene panel shows promise for the non‐invasive diagnosis and risk stratification of UBC.

Read more Articles of the week

 

Editorial: Non‐invasive diagnosis and monitoring of urothelial bladder cancer: are we there yet?

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In this issue of BJUI, Ward et al. [1] describe the development of DNA‐based urinary biomarkers for urothelial carcinoma (UC). The genomics of UC have been well characterized through interrogation of tumour issues in institutional series (e.g. the Memorial Sloan Kettering Cancer Center [MSKCC] experience), multi‐institutional collaborations (e.g. The Cancer Genome Atlas [TCGA]) and commercial platforms (e.g. the Foundation Medicine experience) [2]. Until recently, these have been largely academic pursuits, with possible impact on prognostication but limited clinical applicability and utility for therapy selection and monitoring of response; however, with the US Food and Drug Administration approval of erdafitinib several weeks ago, patients with advanced UC will routinely receive genomic assessment for FGFR2/3 mutation or fusion, the targets for this therapy [3]. In due time, it is anticipated that multiple other putative targets with associated therapies (e.g. ERBB2, CDKN2A), as well as potential predictive biomarkers, may also warrant testing.

The evolving landscape in advanced UC makes a non‐invasive biomarker particularly attractive. The authors of the present commentary have previously reported results from a series of 369 patients with advanced UC, demonstrating that genomic alterations in ctDNA could be identified in 91% of patients using a commercially available 73-gene panel [4]. More recently, Christensen et al. [5] assessed a cohort of 68 patients receiving neoadjuvant chemotherapy for muscle‐invasive disease, demonstrating 100% sensitivity and 98% specificity for the detection of relapsed disease with a patient‐specific ctDNA assessment (sequenced to a median target coverage of 105 000×) after cystectomy. Impressively, the data also showed that the dynamics of ctDNA appeared to be more useful than pathological downstaging in predicting relapse.

In contrast to these studies, Ward et al. have developed a 23‐gene panel based on frequently expressed genes in a cohort of 916 UC tissue specimens, largely derived from patients with non‐muscle‐invasive disease. Ultimately, with a cohort of 314 patients with DNA derived from a urinary cell pellet, sequencing identified 645 (71.4%) of 903 mutations detected in tumour. Using urinary supernatant, 353 (80.7%) of 437 mutations were detected. These relatively high sensitivities, if they can be interpreted as such, are promising but do not rise to the level of replacing existing strategies for UC detection, staging and monitoring. Notably, another study demonstrated that urinary ctDNA can be detected with high sensitivity and specificity in patients with localized early‐stage bladder cancer and for after‐treatment surveillance, providing the foundation for further studies evaluating the role of ctDNA in non‐invasive detection, genotyping and monitoring [6].

Beyond its use as a diagnostic tool, it is hoped that urinary ctDNA may also find applications in the selection of therapeutics. To this end, Ward et al. identified FGFR3, PIK3CA, ERCC2 and ERBB2 mutations in 45%, 32%, 14% and 7% of patients, respectively. The frequency of FGFR3 alteration decreased with increasing stage and grade, ranging from 72% in pTaG1 disease to just 13% in ≥pT2 disease, consistent with other reports [7]. These results may guide forthcoming studies evaluating FGFR inhibitors in non‐muscle‐invasive, muscle‐invasive and metastatic disease, where studies are ongoing. In reviewing the potential link between genomic alterations and clinical outcomes, perhaps the most curious finding is that between RAS mutations and improved overall survival (P = 0.04), the only such association found in multivariate analysis. These results stand in sharp contrast to reports in lung cancer, colorectal cancer and multiple other tumour types [8]. A closer look at the deleterious nature and functional impact of NRAS and KRAS mutations seen in this series is certainly warranted, along with further external validation in a more homogenous and larger patient population. There is also the potential application of monitoring treatment response by assessing eradication of urinary ctDNA, a hypothesis that is being evaluated in ongoing studies [9].

How will the results of this and other emerging urinary biomarker studies eventually make their way to the clinic? The answer is simple: incorporation of these biomarkers in prospective therapeutic trials. As the bladder cancer investigative community formulates novel trials for non‐muscle‐invasive and muscle‐invasive disease using targeted therapies, an excellent opportunity exists to correlate urinary, blood and tissue‐based biomarkers and to assess their relative predictive capabilities and clinical utility. Furthermore, with clinical surrogate endpoints likely to drive regulatory approval (e.g. landmark complete response rates for non‐muscle‐invasive disease, or pT0N0 rate for muscle‐invasive disease), a validated urinary biomarker could ultimately offer an alternative biological surrogate endpoint [10]. In an era of genomic revolution, prospective validation can help establish the potential clinical utility of promising biomarkers and help realize the dream of ‘precision oncology’.

by Rohit K. Jain, Petros Grivas and Sumanta K. Pal

References

  1. Ward DG, Gordon NS, Boucher RH et al. Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: a 23‐gene panel with utility for non‐invasive diagnosis and risk stratification. BJU Int 2019
  2. Schiff JP, Barata PC, Yu EY, Grivas P. Precision therapy in advanced urothelial cancer. Expert Rev Precis Med Drug Dev 2019; 4: 81– 93
  3. FDA grants accelerated approval to erdafitinib for metastatic urothelial carcinoma [press release] 2019.
  4. Agarwal N, Pal SK, Hahn AW et al. Characterization of metastatic urothelial carcinoma via comprehensive genomic profiling of circulating tumor DNA. Cancer 2018; 124: 2115– 24
  5. Christensen E, Birkenkamp‐Demtroder K, Sethi H et al. Early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra‐deep sequencing of plasma cell‐free DNA in patients with urothelial bladder carcinoma. J Clin Oncol 2019; 37: 1547– 57
  6. Dudley JC, Schroers‐Martin J, Lazzareschi DV et al. Detection and surveillance of bladder cancer using urine tumor DNA. Cancer Discov 2019; 9: 500– 9
  7. Tomlinson DC, Baldo O, Harnden P, Knowles MA. FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. J Pathol 2007; 213: 91– 8
  8. Zhuang R, Li S, Li Q et al. The prognostic value of KRAS mutation by cell‐free DNA in cancer patients: a systematic review and meta‐analysis. PLoS One 2017; 12: e0182562
  9. Abbosh PH, Plimack ER. Molecular and clinical insights into the role and significance of mutated DNA repair genes in bladder cancer. Bladder Cancer 2018; 4: 9– 18
  10. Jarow JP, Lerner SP, Kluetz PG et al. Clinical trial design for the development of new therapies for nonmuscle‐invasive bladder cancer: report of a Food and Drug Administration and American Urological Association public workshop. Urology 2014; 83: 262– 4

 

 

Video: Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA

/by

Targeted deep sequencing of urothelial bladder cancers and associated urinary DNA: a 23‐gene panel with utility for non‐invasive diagnosis and risk stratification

Read the full article

Abstract

Objectives

To develop a focused panel of somatic mutations (SMs) present in the majority of urothelial bladder cancers (UBCs), to investigate the diagnostic and prognostic utility of this panel, and to compare the identification of SMs in urinary cell‐pellet (cp) DNA and cell‐free (cf) DNA as part of the development of a non‐invasive clinical assay.

Patients and Methods

A panel of SMs was validated by targeted deep‐sequencing of tumour DNA from 956 patients with UBC. In addition, amplicon and capture‐based targeted sequencing measured mutant allele frequencies (MAFs) of SMs in 314 urine cpDNAs and 153 urine cfDNAs. The association of SMs with grade, stage and clinical outcomes was investigated by univariate and multivariate Cox models. Concordance between SMs detected in tumour tissue and cpDNA and cfDNA was assessed.

Results

The panel comprised SMs in 23 genes: TERT (promoter), FGFR3, PIK3CA, TP53, ERCC2, RHOB, ERBB2, HRAS, RXRA, ELF3, CDKN1A, KRAS, KDM6A, AKT1, FBXW7, ERBB3, SF3B1, CTNNB1, BRAF, C3orf70, CREBBP, CDKN2A and NRAS; 93.5–98.3% of UBCs of all grades and stages harboured ≥1 SM (mean: 2.5 SMs/tumour). RAS mutations were associated with better overall survival (P = 0.04). Mutations in RXRA, RHOB and TERT (promoter) were associated with shorter time to recurrence (P < 0.05). MAFs in urinary cfDNA and cpDNA were highly correlated; using a capture‐based approach, >94% of tumour SMs were detected in both cpDNA and cfDNA.

Conclusions

SMs are reliably detected in urinary cpDNA and cfDNA. The technical capability to identify very low MAFs is essential to reliably detect UBC, regardless of the use of cpDNA or cfDNA. This 23‐gene panel shows promise for the non‐invasive diagnosis and risk stratification of UBC.

 

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