Clinical Restaging and Tumor Sequencing are Inaccurate Indicators of Response to Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer

Becker, Russell E.N.; Meyer, Alexa; Brant, Aaron; Reese, Adam C.; Biles, Michael J.; Harris, Kelly T.; Netto, George J.; Matoso, Andrés; Hoffman-Censits, Jean H.; Hahn, Noah M.; Choi, Woonyoung; McConkey, David J.; Pierorazio, Phillip M.; Johnson, Michael H.; Schoenberg, Mark; Kates, Max; Baras, Alex; Bivalacqua, Trinity J.

doi:10.1016/j.eururo.2020.07.016

Cited by 53 publications

(27 citation statements)

References 16 publications

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“…Cystoscopy, while considered invasive and uncomfortable, can be used to evaluate tumor response to neoadjuvant chemotherapy or chemoradiation. However, cystoscopy prior to radical cystectomy frequently under-stages disease burden [ 16 , 17 ], creating a major barrier to testing and implementing personalized bladder-sparing treatment paradigms. Furthermore, patients managed with bladder-sparing treatment remain at significant risk for recurrence [ 15 ], thus requiring frequent monitoring with invasive cystoscopy [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

“…However, cystoscopy prior to radical cystectomy frequently under-stages disease burden [ 16 , 17 ], creating a major barrier to testing and implementing personalized bladder-sparing treatment paradigms. Furthermore, patients managed with bladder-sparing treatment remain at significant risk for recurrence [ 15 ], thus requiring frequent monitoring with invasive cystoscopy [ 17 ]. Therefore, it is critical that we advance our standard of care to enable improved accuracy and reduced morbidity when assessing and monitoring localized bladder cancer.…”

Section: Introductionmentioning

confidence: 99%

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Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study

et al. 2021

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Background The standard of care treatment for muscle-invasive bladder cancer (MIBC) is radical cystectomy, which is typically preceded by neoadjuvant chemotherapy. However, the inability to assess minimal residual disease (MRD) noninvasively limits our ability to offer bladder-sparing treatment. Here, we sought to develop a liquid biopsy solution via urine tumor DNA (utDNA) analysis. Methods and findings We applied urine Cancer Personalized Profiling by Deep Sequencing (uCAPP-Seq), a targeted next-generation sequencing (NGS) method for detecting utDNA, to urine cell-free DNA (cfDNA) samples acquired between April 2019 and November 2020 on the day of curative-intent radical cystectomy from 42 patients with localized bladder cancer. The average age of patients was 69 years (range: 50 to 86), of whom 76% (32/42) were male, 64% (27/42) were smokers, and 76% (32/42) had a confirmed diagnosis of MIBC. Among MIBC patients, 59% (19/32) received neoadjuvant chemotherapy. utDNA variant calling was performed noninvasively without prior sequencing of tumor tissue. The overall utDNA level for each patient was represented by the non-silent mutation with the highest variant allele fraction after removing germline variants. Urine was similarly analyzed from 15 healthy adults. utDNA analysis revealed a median utDNA level of 0% in healthy adults and 2.4% in bladder cancer patients. When patients were classified as those who had residual disease detected in their surgical sample (n = 16) compared to those who achieved a pathologic complete response (pCR; n = 26), median utDNA levels were 4.3% vs. 0%, respectively (p = 0.002). Using an optimal utDNA threshold to define MRD detection, positive utDNA MRD detection was highly correlated with the absence of pCR (p < 0.001) with a sensitivity of 81% and specificity of 81%. Leave-one-out cross-validation applied to the prediction of pathologic response based on utDNA MRD detection in our cohort yielded a highly significant accuracy of 81% (p = 0.007). Moreover, utDNA MRD–positive patients exhibited significantly worse progression-free survival (PFS; HR = 7.4; 95% CI: 1.4–38.9; p = 0.02) compared to utDNA MRD–negative patients. Concordance between urine- and tumor-derived mutations, determined in 5 MIBC patients, was 85%. Tumor mutational burden (TMB) in utDNA MRD–positive patients was inferred from the number of non-silent mutations detected in urine cfDNA by applying a linear relationship derived from The Cancer Genome Atlas (TCGA) whole exome sequencing of 409 MIBC tumors. We suggest that about 58% of these patients with high inferred TMB might have been candidates for treatment with early immune checkpoint blockade. Study limitations included an analysis restricted only to single-nucleotide variants (SNVs), survival differences diminished by surgery, and a low number of DNA damage response (DRR) mutations detected after neoadjuvant chemotherapy at the MRD time point. Conclusions utDNA MRD detection prior to curative-intent radical cystectomy for bladder cancer correlated significantly with pathologic response, which may help select patients for bladder-sparing treatment. utDNA MRD detection also correlated significantly with PFS. Furthermore, utDNA can be used to noninvasively infer TMB, which could facilitate personalized immunotherapy for bladder cancer in the future.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study

et al. 2021

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“…NAC refers to the method of systemic chemotherapy on patients before surgery to improve their tumor condition and prepare for later surgery by preoperative chemotherapy. It was proven to be effective in reducing the tumor stage, shrinking the tumor, and improving the surgical success rate in various malignant tumors such as breast cancer and bladder cancer [ 20 , 21 ]. At present, the clinical benefit of NAC followed by TME in LARC is also a crucial issue of medical attention.…”

Section: Discussionmentioning

confidence: 99%

Neoadjuvant Chemotherapy plus Bevacizumab Combined with Total Mesorectal Excision in Treating Locally Advanced Rectal Cancer Patients with BRAF Mutation: Clinical Benefit and Safety

Song

Wang

et al. 2021

Computational and Mathematical Methods in Medicine

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Objective. To investigate clinical benefit and safety of neoadjuvant chemotherapy (NAC) plus bevacizumab combined with total mesorectal excision (TME) in treating patients with BRAF-mutated locally advanced rectal cancer (LARC). Methods. This study included LARC patients with BRAF mutation admitted to the Oncology Department of Fujian Medical University Cancer Hospital, Fujian Cancer Hospital, between June 2013 and December 2018. Patients in the control group received a standard treatment regimen of TME combined with NAC ( n = 45 ), and patients in the observation group received NAC plus bevacizumab combined with TME ( n = 55 ). The short-term clinical efficacy of the two groups after NAC treatment was observed and compared, including differences in the pathological downstaging rate. The incidence of perioperative complications and adverse reactions during neoadjuvant therapy was compared to evaluate the safety of the treatment. Besides, the relapse-free survival (RFS) and overall survival (OS) of patients were analyzed to evaluate the long-term clinical benefit of the treatment. Results. Compared with the control group, the ypT staging rate ( p = 0.014 ) in the observation group was markedly lower. In addition, patients in the observation group had a prominently lower overall incidence of complications ( p < 0.001 ) during the perioperative period and a remarkably lower incidence of leukopenia ( p = 0.037 ) during neoadjuvant therapy. In terms of long-term clinical benefit, the RFS of patients in the observation group was evidently longer ( p = 0.037 ) than that in the control group. Conclusion. Compared with TME plus NAC treatment, the short-term and long-term clinical benefits are higher and safety is more favorable of NAC plus bevacizumab combined with TME in treating LARC patients.

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“…A recent retrospective study, from a prospectively-maintained single institution database, investigated the reliability of staging post NAC. 39 In this study, 114 patients underwent TURBT after NAC and prior to RC. They showed that post-NAC TURBT failed to reliably predict ypT stage at RC since up to 32% of patients were falsely downstaged to NMIBC on post-NAC TURBT.…”

Section: Response To Neoadjuvant Therapiesmentioning

confidence: 99%

Multiparametric magnetic resonance imaging for bladder cancer: a comprehensive systematic review of the Vesical Imaging-Reporting and Data System (VI-RADS) performance and potential clinical applications

Séguier

Puech

Kool

et al. 2021

Therapeutic Advances in Urology

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Background: The Vesical Imaging-Reporting and Data System (VI-RADS) score is a novel standardized approach to image and report bladder cancer (BC) with multiparametric MRI (mpMRI). Objectives: To describe and evaluate the performance of the VI-RADS score using mpMRI and assess its potential clinical applications and limitations. Methods: A systematic review was conducted using the MEDLINE and EMBASE electronic bibliographic databases between June 2020 and December 2020. All reports deemed relevant to describe the VI-RADS score and assess its performance and applications were retrieved. Results presentation stands as narrative, purely descriptive synthesis based on aggregate studies data. Results: A total of 20 relevant studies were retrieved: three meta-analyses, five prospective studies, and twelve retrospective studies. The retrospective studies covered 1676 patients, while the prospective studies included a total number of 468 patients. Pooled sensitivity, specificity to differentiate muscle-invasive from non-muscle-invasive bladder cancer, ranged from 74.1% to 97.3%, and 77% to 100%, respectively. The chosen VI-RADS score thresholds for this discrimination varied across studies. The interreader agreement ranged from 0.73 to 0.95. Currently, the potential clinical applications of VI-RADS consist of initial BC risk stratification, assessment of neoadjuvant therapies response, and bladder sparing approaches, although further validation is required. Conclusions: The VI-RADS score helps to discriminate muscle invasive from non-muscle invasive BC with good performance and reproducibility. A simple algorithm based on four basic questions may enhance its popularization. Further studies are required to validate the clinical applications.

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Clinical Restaging and Tumor Sequencing are Inaccurate Indicators of Response to Neoadjuvant Chemotherapy for Muscle-invasive Bladder Cancer

Cited by 53 publications

References 16 publications

Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study

Urine tumor DNA detection of minimal residual disease in muscle-invasive bladder cancer treated with curative-intent radical cystectomy: A cohort study

Neoadjuvant Chemotherapy plus Bevacizumab Combined with Total Mesorectal Excision in Treating Locally Advanced Rectal Cancer Patients with BRAF Mutation: Clinical Benefit and Safety

Multiparametric magnetic resonance imaging for bladder cancer: a comprehensive systematic review of the Vesical Imaging-Reporting and Data System (VI-RADS) performance and potential clinical applications

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