Molecular biomarkers to predict response to neoadjuvant chemotherapy for bladder cancer

Buttigliero, Consuelo; Tucci, Marco; Vignani, Francesca; Scagliotti, Giorgio Vittorio; Maïo, Massimo Di

doi:10.1016/j.ctrv.2017.01.002

Cited by 48 publications

(32 citation statements)

References 78 publications

(92 reference statements)

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“…Notably, less malignant variants of UC tend to recur quite frequently and high-grade lower stage tumours may progress to invasive cancers. For these reasons, improved diagnostic and prognostic biomarkers are desirable, especially to monitor for recurrences, to identify patients with a poor prognosis and to select appropriate treatments for individual patients [1]. …”

Section: Introductionmentioning

confidence: 99%

Diagnostic and prognostic value of long noncoding RNAs as biomarkers in urothelial carcinoma

Droop¹,

Szarvas²,

Schulz³

et al. 2017

PLoS ONE

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Many long noncoding RNAs (lncRNAs) are deregulated in cancer and contribute to oncogenesis. In urothelial carcinoma (UC), several lncRNAs have been reported to be overexpressed and proposed as biomarkers. As most reports have not been confirmed independently in large tissue sets, we aimed to validate the diagnostic and prognostic value of lncRNA upregulation in independent cohorts of UC patients. Thus, expression of seven lncRNA candidates (GAS5, H19, linc-UBC1, MALAT1, ncRAN, TUG1, UCA1) was measured by RT-qPCR in cell lines and tissues and correlated to clinicopathological parameters including follow-up data (set 1: N n = 10; T n = 106). Additionally, publicly available TCGA data was investigated for differential expression in UC tissues (set 2: N n = 19; T n = 252,) and correlation to overall survival (OS). All proposed candidates tended to be upregulated in tumour tissues, with the exception of MALAT1, which was rather diminished in cancer tissues of both data sets. However, strong overexpression was generally limited to individual tumour tissues and statistically significant overexpression was only observed for UCA1, TUG1, ncRAN and linc-UBC1 in tissue set 2, but for no candidate in set 1. Altered expression of individual lncRNAs was associated with overall survival, but not consistently between both patient cohorts. Interestingly, lower expression of TUG1 in a subset of UC patients with muscle-invasive tumours was significantly correlated with worse OS in both cohorts. Further analysis revealed that tumours with low TUG1 expression are characterized by a basal-squamous-like subtype signature accounting for the association with poor outcome. In conclusion, our study demonstrates that overexpression of the candidate lncRNAs is found in many UC cases, but does not occur consistently and strongly enough to provide reliable diagnostic or prognostic value as an individual biomarker. Subtype-dependent expression patterns of lncRNAs like TUG1 could become useful to stratify patients by molecular subtype, thus aiding personalized treatments.

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Section: Introductionmentioning

confidence: 99%

Diagnostic and prognostic value of long noncoding RNAs as biomarkers in urothelial carcinoma

Droop¹,

Szarvas²,

Schulz³

et al. 2017

PLoS ONE

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“…35,36 The sensitivity of tumor cells to chemotherapeutic drugs influences tumor prognosis. 37,38 In this study, we found that systemic chemotherapy did not improve the 5-year survival rate of MIBC patients. Alternatively, STAG2(-) patients receiving chemotherapy demonstrated higher 3-year survival than those not receiving chemotherapy (45.5% vs. 16.7%).…”

Section: Discussionmentioning

confidence: 54%

STAG2 Coupled With p53 Alteration Has a Significant Impact on Bladder Cancer Recurrence and Progression

Chen

Xu²,

Meng

et al. 2019

Preprint

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Background:There is an unmet need for additional biomarkers for stratifying tumors based on their risk of recurrence and progression. Stromal antigen 2 (STAG2) and p53 are the most common mutations in bladder cancer and their association with the prognosis of bladder cancer remains unclear.Methods:Patients were divided into two cohorts according to stage and surgical procedure. The value of combined STAG2 expression (+/-) and P53 mutation (+/-) was evaluated for prediction of recurrence in 334 patients diagnosed by transurethral resection of bladder tumor (TURBT) and for prediction of survival in 144 patients who underwent radical cystectomy and pelvic lymphadenectomy( RCPLT).Results:We found that,in the 334 TURBT-treated patients, recurrence rate was significantly greater for STAG2(+) tumors than STAG2(-) tumors (73.5% vs. 55.0%, P=0.001). Of 144 RCPLT-treated patients, 127 (88.2%) were STAG2(+), of which 71 (55.9%) survived 5 years, compared to none of the 17 STAG2(-) patients. Patients with combined STAG2(+)/P53 mutation(+) tumors had the highest recurrence rate (83.5%) while patients with STAG2(-)/P53(-) tumors had the lowest recurrence rate (50%). Patients with STAG2(+)/P53(-) tumors achieved the highest 5-year survival rate (69.7%). Systemic chemotherapy did not improve prognosis of RCPLT-treated patients, but appeared to benefit STAG2(-) patients.Conclusions: Our results suggest that combined STAG2 expression and P53 status is a valuable biomarker for BCa prognosis, accurately predicting recurrence in TURBT-treated patients. STAG2(+)/P53(-) predicted a higher five-year survival and STAG2(-) predicted low five-year survival in RCPLT-treated patients. Chemotherapy may interfere with this predictive efficacy, especially in STAG2(-) patients.

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“…Two major limitations of neoadjuvant chemotherapy are delaying cystectomy in patients with poor response to cisplatin (~30%‐50%), and the lack of available biomarkers to identify patients unlikely to respond to cisplatin . Two years after cystectomy 50% of patients relapse with metastatic disease, suggesting a high degree of initial micro‐metastasis . Metastatic MIBC has poor survival (5‐year survival ~15%) and is treated by systemic chemotherapy .…”

Section: Introductionmentioning

confidence: 99%

Vitamin D₃ enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk

Bunch

Attwood

et al. 2019

Cancer Medicine

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Background Vitamin D 3 (VitD) deficiency is linked to increased incidence and worse survival in bladder cancer ( BC a). In addition to cystectomy, patients are treated with cisplatin‐based chemotherapy, however 30%‐50% of patients do not benefit from this treatment. The effects of VitD deficiency on response to chemotherapy remain unknown. Methods To test effects of VitD supplementation on the response to cisplatin we analyzed patient serum VitD levels and correlated that with survival. In vivo, VitD deficient mice were treated with cisplatin, with or without pretreatment with the active VitD metabolite, 1,25 dihydroxyvitamin D 3 (1,25D 3 ). Lastly, using BC a cell lines, T24 and RT ‐112, the mechanism of action of 1,25D 3 and cisplatin combination treatment was determined by apoptosis assays, as well as western blot and RT ‐ PCR . Results In this study, we determined that low serum 25 hydroxyvitamin D 3 (25D 3 ) levels was significantly associated with worse response to cisplatin. Pretreating deficient mice with 1,25D 3 , reduced tumor volume compared to cisplatin monotherapy. In vitro, 1,25D 3 pretreatment increased the apoptotic response to cisplatin. 1,25D 3 pretreatment increased expression of TA p73 and its pro‐apoptotic targets, in a VDR dependent manner. VDR and its transcriptional targets were induced after 1,25D 3 treatment and further increased after the combination of 1,25D 3 and cisplatin in a TA p73 dependent manner. Conclusions Our data suggest that VitD deficiency could be a biomarker for poor response to cisplatin, and pretreating with VitD can increase the apoptotic response to cisplatin through VDR and TA p73 signaling crosstalk.

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Molecular biomarkers to predict response to neoadjuvant chemotherapy for bladder cancer

Cited by 48 publications

References 78 publications

Diagnostic and prognostic value of long noncoding RNAs as biomarkers in urothelial carcinoma

Diagnostic and prognostic value of long noncoding RNAs as biomarkers in urothelial carcinoma

STAG2 Coupled With p53 Alteration Has a Significant Impact on Bladder Cancer Recurrence and Progression

Vitamin D₃ enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk

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Molecular biomarkers to predict response to neoadjuvant chemotherapy for bladder cancer

Cited by 48 publications

References 78 publications

Diagnostic and prognostic value of long noncoding RNAs as biomarkers in urothelial carcinoma

Diagnostic and prognostic value of long noncoding RNAs as biomarkers in urothelial carcinoma

STAG2 Coupled With p53 Alteration Has a Significant Impact on Bladder Cancer Recurrence and Progression

Vitamin D3 enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk

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Vitamin D₃ enhances the response to cisplatin in bladder cancer through VDR and TAp73 signaling crosstalk