Next-generation sequencing to identify molecular alterations in DNA repair and chromatin maintenance genes associated with pathologic complete response (pT0) to neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) in muscle-invasive bladder cancer (MIBC).

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 4538-4538 ◽  
Author(s):  
Elizabeth R. Plimack ◽  
Roland Dunbrack ◽  
Timothy Brennan ◽  
Qiong Wei ◽  
Roman Yelensky ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Dna Repair ◽  
Next Generation Sequencing ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Next Generation ◽  
Muscle Invasive Bladder Cancer ◽  
Molecular Alterations ◽  
Muscle Invasive ◽  
Generation Sequencing

scholarly journals Prognostic Factors of Non-Muscle Invasive Bladder Cancer: A Study Based on Next-generation Sequencing

2020 ◽  
Author(s):  
Yanxiang Shao ◽  
Xu Hu ◽  
Zhen Yang ◽  
Thongher Lia ◽  
Weixiao Yang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Prognostic Factors ◽  
Next Generation Sequencing ◽  
Invasive Bladder Cancer ◽  
Next Generation ◽  
Muscle Invasive Bladder Cancer ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Muscle Invasive ◽  
Generation Sequencing

Abstract ObjectiveTo investigate the genetic prognostic factors for the recurrence of non-muscle invasive bladder cancer. Materials and MethodsThe patients underwent transurethral resection of bladder tumor and received bacillus Calmette–Guérin (BCG) or epirubicin. Next-generation sequencing was performed and alterations of genes, pathways, and tumor mutation burden were recorded. Associations between these clinicopathological and genetic variants were estimated, and prognostic factor identified.ResultsA total of 58 cases were included in our study, and 46 patients underwent treatment with BCG. FGFR3 was the most frequently altered gene (48%), and more commonly detected in intermediate-risk patients. Univariate Cox analysis demonstrated that 10 genes were significantly correlated with BCG failure, while NEB, FGFR1 and SDHC were independent recurrence predictors. Besides, epigenetic-related gene pathway mutations were negatively correlated with recurrence (hazard ratio: 0.198, P=0.023). DNA damage response and repair gene alterations were positively correlated with tumor burden, while altered TP53 was most frequent among these genes and significant correlated with high tumor burden.ConclusionBCG instillation significantly reduced the rate of recurrence compared with epirubicin in this population. Potential biomarkers and therapeutic targets were found with the help of next-generation sequencing; correlations between DDR genes alterations and high tumor mutation burden were also demonstrated.

scholarly journals Implications of targeted next-generation sequencing for bladder cancer: report of four cases

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Mohamed K. Khalifa ◽  
Noha M. Bakr ◽  
Amal Ramadan ◽  
Khaled M. Abd Elwahab ◽  
Esam Desoky ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Next Generation Sequencing ◽  
Cancer Patients ◽  
Treatment Strategy ◽  
Invasive Bladder Cancer ◽  
Next Generation ◽  
Muscle Invasive Bladder Cancer ◽  
Blood Samples ◽  
Muscle Invasive ◽  
Generation Sequencing

Abstract Background Bladder cancer is considered heterogeneous diseases with two major subgroups: non-muscle- invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). It is a major healthcare problem, and it is one of the leading causes of mortality worldwide. Genetic mutations are not only a cause for carcinogenesis but are also a way for treatment strategy. The present study aimed to investigate breast cancer (BRCA genes) tumor suppressor gene mutations in bladder cancer tissue and combined blood samples for patients who developed secondary tumor after or during trimodal therapy. Fresh tissue samples and their matched blood samples were collected from four patients with bladder cancer. The objective regions for the examined genes (BRCA1 and BRCA2) were sequenced using next-generation sequencing (NGS); generated BAM files were uploaded to the cloud-based Ionreporter server, and the Oncomine BRCA-specific plugin was used to analyze the paired normal and tumor sample for each patient using the default plugin parameters. Results Intronic BRCA1 mutation c.5050-104 C >T was reported among the four investigated bladder cancer patients, and three somatic mutations were reported as follows: two of them were found to be benign rs1064793056 and rs28897679 on the Clinivar database and one nonsense pathogenic variant rs80357006. BRCA 2 gene mutation reported an exonic synonymous mutation rs397507876 in the tissue and germline DNA. Patients were treated with trimodal; however, three bladder cancer patients who reported BRCA mutations developed secondary tumors. Conclusion Identification of mutational BRCA changes in bladder cancer is a promising marker for better treatment strategy. Further studies are encouraged on a large cohort of bladder cancer patients to confirm our findings.

scholarly journals Prognostic factors of non-muscle invasive bladder cancer: a study based on next-generation sequencing

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yanxiang Shao ◽  
Xu Hu ◽  
Zhen Yang ◽  
Thongher Lia ◽  
Weixiao Yang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Prognostic Factors ◽  
Next Generation Sequencing ◽  
Tumor Burden ◽  
Next Generation ◽  
Muscle Invasive Bladder Cancer ◽  
Tumor Mutation Burden ◽  
Mutation Burden ◽  
Muscle Invasive ◽  
Generation Sequencing

Abstract Objective To investigate the genetic prognostic factors for the recurrence of non-muscle invasive bladder cancer. Materials and methods The patients underwent transurethral resection of bladder tumor and received bacillus Calmette–Guérin (BCG) or epirubicin. Next-generation sequencing was performed and alterations of genes, pathways, and tumor mutation burden were recorded. Associations between these clinicopathological and genetic variants were estimated, and prognostic factor identified. Results A total of 58 cases were included in our study, and 46 patients underwent treatment with BCG. FGFR3 was the most frequently altered gene (48%), and more commonly detected in intermediate-risk patients. Univariate Cox analysis demonstrated that 10 genes were significantly correlated with BCG failure, while NEB, FGFR1 and SDHC were independent recurrence predictors. Besides, epigenetic-related gene pathway mutations were negatively correlated with recurrence (hazard ratio: 0.198, P = 0.023). DNA damage response and repair gene alterations were positively correlated with tumor burden, while altered TP53 was most frequent among these genes and significant correlated with high tumor burden. Conclusion BCG instillation significantly reduced the rate of recurrence compared with epirubicin in this population. Potential biomarkers and therapeutic targets were found with the help of next-generation sequencing; correlations between DDR genes alterations and high tumor mutation burden were also demonstrated.

Neoadjuvant accelerated MVAC (AMVAC) in patients with muscle invasive bladder cancer: Results of a multicenter phase II study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4526-4526 ◽  
Author(s):  
Elizabeth R. Plimack ◽  
Jean H. Hoffman-Censits ◽  
Rosalia Viterbo ◽  
Richard Evan Greenberg ◽  
David Chen ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Invasive Disease ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Metastatic Setting ◽  
Grade 3 ◽  
Muscle Invasive ◽  
Intent To Treat

4526 Background: Standard methotrexate, vinblastine, doxorubicin and cisplatin (MVAC) demonstrates a survival benefit in the neoadjuvant setting for patients (pts) with muscle invasive bladder cancer (MIBC). Compared with standard MVAC, AMVAC yielded higher response rates with less toxicity in the metastatic setting. Methods: Pts with MIBC, cT2-T4a, and N0-N1 with CrCl >=50 and adequate hepatic and marrow function were eligible. Pts received 3 cycles of AMVAC (methotrexate 30 mg/m2, vinblastine 3 mg/m2, doxorubicin 30 mg/m2, cisplatin 70mg/m2) on day 1, with pegfilgrastim 6 mg day 2 or 3, every 2 weeks. Pts with CrCl < 60 could receive cisplatin split over 2 days. Radical cystectomy (RC) with lymph node dissection was performed 4-8 weeks after the last dose of chemotherapy. Primary endpoint was pathologic complete response (pCR) rate. Results: Accrual is complete with 44 MIBC pts enrolled at 2 institutions (FCCC, TJU) over a 25 month period. Median age 64 (range 45-83). Three withdrew from study early and are not evaluable for response (2 physician discretion, 1 withdrawal of consent). An additional 8 are currently receiving treatment on study with toxicity and response data pending. Of the 33 evaluable pts for whom final data is available, 30 received all 3 cycles of AMVAC at full dose. Three pts received < 3 cycles due to grade 3 fatigue (1), low platelets (1), and disease progression precluding RC (1). 32/33 pts underwent RC, all within 8 weeks of last chemotherapy. Median time from start of chemotherapy to RC was 9.7 wks (range 4.6-13 wks). 13/33 pts (39.4%, 95% CI, 22.7-56.1%) had a pCR. An additional 3 (9.1%) were downstaged to non muscle invasive disease. For the intent to treat cohort (n=36) 8 pts had grade 3-4 AMVAC related adverse events, the most common being anemia (3), fatigue (3) and neutropenia (2) and overall pCR rate was 36.1%. (95% CI, 20.4-51.8%). All pts will have completed study treatment by April 2012. Final results will be presented. Conclusions: Neoadjuvant AMVAC is well tolerated and preliminary results show a pCR rate similar to that reported for standard 12-week MVAC, suggesting that AMVAC for three cycles (6 weeks) is a safe and efficient alternative.

Impact of angiotensin inhibitors on pathologic complete response with neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 432-432
Author(s):  
Jonathan Thomas ◽  
Gregory Russell Pond ◽  
Catherine Curran ◽  
Dory Freeman ◽  
Praful Ravi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Bladder Cancer ◽  
Angiotensin Receptor Blockers ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Invasive Bladder Cancer ◽  
Antitumor Effects ◽  
Muscle Invasive Bladder Cancer ◽  
Pathologic Features ◽  
Muscle Invasive

432 Background: The renin-angiotensin system (RAS) is involved in regulation of angiogenesis, cell proliferation, desmoplasia and immunosuppression. Angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARB) may have antitumor effects partly by inhibiting transforming growth factor (TGF)-β, a major resistance mechanism in bladder cancer. Methods: Patients (pts) with muscle invasive bladder cancer (MIBC) treated or not treated with ACEi/ARB while receiving preceding radical cystectomy (RC) were assessed for pathologic complete response (pCR) defined as pT0N0 and overall survival (OS). Pathologic features, performance status, clinical stage, type and number of cycles of NAC, and presence of grade ≥3 toxicities were collected retrospectively. The Kaplan-Meier method was used to estimate overall survival (OS). Logistic and Cox regression was used to explore factors potentially prognostic for pCR and OS respectively. Results: 187 patients received NAC followed by RC. The mean age at the time of NAC was 65. 71% were male and 29% were female. Of the 187 patients, 61% received Cisplatin/Gemcitabine and 28.3% received dose dense MVAC. Of patients receiving NAC, 53 (28%) had a pCR. The 5-year OS was 64%. There were 41 (21.9%) patients taking an ACEi and 24 (12.8%) patients taking an ARB at the start of NAC. Of the 41 patients who took an ACEi, 17 (41.5%) had a pCR; of the 146 patients who did not take an ACEi, 36 (24.7%) had a pCR. ACEi intake during NAC was the only factor associated with pCR on multivariable analysis (odds ratio of 2.17 [95% CI 1.05-4.48] p = 0.037). pCR was the only factor shown to be associated with significantly improved OS (Hazard Ratio 0.18 [95% CI 0.07-0.45] p = < 0.001). After adjusting for pCR, ACEi was not significantly prognostic of OS (HR = 1.12, 95% CI = 0.60 to 2.09, p = 0.72). ARB intake while receiving NAC was not associated with pCR or OS. Conclusions: ACEi intake was associated with significantly increased pCR in patients with MIBC receiving NAC, and pCR was the only significant factor associated with OS. We hypothesize that ACEi may augment the activity of NAC and increase pCR, which translates to improved OS. ACEi intake was not associated with improvement in OS potentially due to competing causes of mortality in patients requiring ACEi. Our data requires validation.

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