Smoking status and PD-L1 mRNA-expression as a predictor of response to neoadjuvant chemotherapy in patients diagnosed with muscle invasive bladder cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 530-530
Author(s):  
Moritz Reike ◽  
Hendrik Juette ◽  
Ralph Wirtz ◽  
Philipp Erben ◽  
Karl Tully ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Mrna Expression ◽  
Smoking Status ◽  
Expression Patterns ◽  
Invasive Bladder Cancer ◽  
Study Cohort ◽  
Muscle Invasive Bladder Cancer ◽  
Former Smokers ◽  
Muscle Invasive

530 Background: Patients with muscle-invasive bladder cancer (MIBC) that underwent neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) show improved overall survival. Patients with a pathological complete response (pCR) usually have the best prognosis. In the literature, impaired response to immune checkpoint therapy has been reported in active smokers. The aim of our study was to examine the association of smoking status with pCR at RC after NAC. Moreover, we investigated the interaction of smoking status and Programmed Death Ligand 1 (PD-L1) mRNA expression at transurethral resection (TUR) and pCR prediction at RC after NAC. Methods: Clinical Data and formalin fixed paraffin embedded tumor tissue samples from TUR and RC of 49 patients with MIBC were retrospectively analyzed. Using RT-PCR PD-L1 mRNA expression was measured in 40-∆Ct values and normalized against the control gene CALM2. Smoking status was defined as never, former and active. After NAC, RC was performed and the specimens were evaluated for pCR, defined as ypT0N0M0. Statistical analyses comprised nonparametric and chi2 testing, partition models and spearman correlation analyses. Results: The study cohort had a median age of 63 years and consisted of 38/49 (78%) males. Regarding smoking status 11/49 (22%) were never, 17/49 (35%) were former and 21/49 (43%) were active smokers. After NAC, 17/49 patients (35%) had a pCR. Never/former smokers did not show a higher rate of pCR compared to active smokers (43%vs.24%, p=0.16). Comparing smoking status (never/former vs. active smokers) within the subgroup showing high PD-L1 expression (≥32.1∆Ct), a higher rate of pCR was found in never/former smokers (58% vs. 25%, p=0.047). Conclusions: Never and former smokers with MIBC that show high PD-L1 mRNA expression patterns are more likely to show pCR at RC after NAC. Smoking cessation is important for the management of MIBC patients undergoing NAC and RC.

Association of KRT20 and KRT5 with response to neoadjuvant chemotherapy in patients diagnosed with muscle invasive bladder cancer.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 562-562
Author(s):  
Florian Roghmann ◽  
Moritz Reike ◽  
Ralph Wirtz ◽  
Maximilian Kriegmair ◽  
Philipp Erben ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Mrna Expression ◽  
Expression Patterns ◽  
High Risk Group ◽  
Invasive Bladder Cancer ◽  
Study Cohort ◽  
Muscle Invasive Bladder Cancer ◽  
Tissue Samples ◽  
Muscle Invasive

562 Background: Patients with muscle-invasive bladder cancer (MIBC) that underwent neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) show improved overall survival. Those with a pathological complete response (pCR) usually have the best prognosis. In the literature, improved response to NAC has been associated with basal tumor characteristics in MIBC so far. The aim of the present study was to examine the association of luminal (KRT20) and basal (KRT5) mRNA expression patterns at transurethral resection (TUR) with pCR at RC after NAC in a contemporary cohort of consecutive MIBC patients. Methods: Clinical Data and formalin fixed paraffin embedded tumor tissue samples from TUR and RC of 49 patients with MIBC were retrospectively analyzed. Using RT-PCR KRT20 and KRT5 mRNA expression were measured in 40-∆Ct values and normalized against the control gene CALM2. Statistical analyses comprised nonparametric and chi2 testing, partition models and spearman correlation analyses. Results: The study cohort had a median age of 63 years and consisted of 38/49 (78%) males. After NAC, 17/49 (35%) patients had cPR. Using partition models, we found that patients with high-KRT20 (≥39.5 ∆Ct) had a higher chance of pCR (57% vs. 26%, p=0.04). Using a cutoff for KRT5 at <38.1 ∆Ct within the subgroup of patients with low-KRT20 (<39.5 ∆Ct, n=35), we found poorest response among low-KRT20/low-KRT5 compared to low-KRT20/high-KRT5 and high-KRT20 (13% vs. 37% vs. 57%, p=0.29), respectively. For low-KRT20/low-KRT5, low-KRT20/high-KRT5 and high-KRT20 median KRT5 was 34.8 vs. 39.5 vs. 34.1 ∆Ct ( p=0.001) and median KRT20 was 37.9 vs. 32.9 vs. 40.1 ∆Ct,( p=0.001), respectively. Conclusions: Patients with MIBC showing high expression of KRT20 were more likely to show pCR at RC after NAC. Moreover, we were able to identify a high risk group of patients with lowKRT20/lowKRT5 that was less likely to achieve pCR at RC after NAC. Our findings are contradicting previous studies and need further verification in larger cohorts. However, our results might be useful for treatment stratification in MIBC patients.

Identification of molecular biomarkers of cisplatin-based chemosensitivity in patients undergoing neoadjuvant chemotherapy for muscle-invasive bladder cancer.

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 374-374
Author(s):  
Paras Hemant Shah ◽  
Annette Lee ◽  
Xinhua Zhu ◽  
Thomas Paul Bradley ◽  
Manish Arvind Vira ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Mrna Expression ◽  
Kegg Pathway ◽  
Excision Repair ◽  
Expression Profiles ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Tumor Specimen ◽  
Muscle Invasive

374 Background: Although survival benefit of cisplatin-based neoadjuvant chemotherapy for muscle-invasive bladder cancer (MIBC) has been demonstrated, a significant proportion of patients do not respond. Identification of chemoresponsive cohorts would avoid morbidity and delayed surgical intervention in patients unlikely to derive benefit. We evaluate the role of miRNA and mRNA expression profiles in initial TURBT specimens of patients who receive neoadjuvant chemotherapy prior to undergoing radical cystectomy. Differences in expression patterns between complete responders (pT0) and nonresponders (pT2 ≤ ) at time of cystectomy may help stratify patients being considered for neoadjuvant chemotherapy. Methods: FFPE tissue was isolated from initial TURBT specimens of patients with clinically localized MIBC treated with cisplatin-based neoadjuvant chemotherapy. Tissue from 9 patients with T2 ≤ disease was compared with specimen from 10 pT0 patients at time of cystectomy specimen. Differential expression of 754 miRNAs and mRNA was analyzed utilizing real time quantitative polymerase chain reaction. miRNA expression profiles were compared between complete responder and nonresponder groups. mRNA in tumor specimen was sequenced from both groups with 76 base pair paired-end reads using NextSeq technology. KEGG Pathway analyses helped identify differential gene expression between complete responders and nonresponders. Results: Significant upregulation of miRNA 1203, miRNA 1304, and miRNA 580 was observed nonresponders versus complete responders. KEGG pathway analysis revealed significant upregulation of the hsa03430 pathway, implicated in DNA mismatch repair, the hsa03420 pathway, implicated in nucleotide excision repair, and the hsa03410 pathway, involved in base excision repair, among pT0 patients. Conclusions: Differential miRNA and mRNA expression within the initial tumor specimen of patients with complete pathologic regression versus progression indicates a possible role in determining-neoadjuvant chemo-sensitivity.

scholarly journals KRT20, KRT5, ESR1 and ERBB2 Expression Can Predict Pathologic Outcome in Patients Undergoing Neoadjuvant Chemotherapy and Radical Cystectomy for Muscle-Invasive Bladder Cancer

2021 ◽  
Vol 11 (6) ◽  
pp. 473
Author(s):  
Hendrik Jütte ◽  
Moritz Reike ◽  
Ralph M. Wirtz ◽  
Maximilian Kriegmair ◽  
Philipp Erben ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Mrna Expression ◽  
Radical Cystectomy ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Cancer Management ◽  
Erbb2 Expression ◽  
Erbb2 Mrna ◽  
Muscle Invasive

Patients with muscle-invasive bladder cancer (MIBC) that underwent neoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) show improved overall survival, especially those with pathological complete response (pCR). The response to NAC according to molecular subtypes has been discussed. Molecular targets such as estrogen receptor (ESR1) and human epidermal growth factor receptor 2 (ERBB2) play an important role in breast cancer management and have also been associated with urothelial bladder cancer. Hence, the association of Keratin 20 (KRT20) Keratin 5 (KRT5), ESR1, and ERBB2 mRNA expression in MIBC at transurethral resection (TUR-BT) with pCR after NAC was analyzed retrospectively. Formalin-fixed paraffin-embedded tumour tissue samples from TUR-BT of 54 patients (42 males, 12 females, median age of 64) with MIBC were analyzed for KRT20, KRT5, ESR1, and ERBB2 mRNA expression. After NAC, RC was performed, and the specimens were evaluated for pCR. Statistical analyses comprised nonparametric and chi2 testing, partition models, and Spearman correlation analyses. After NAC, 22 out of 54 patients (40.7%) had pCR. Tumours with an elevated expression of markers associated with luminal differentiation (KRT20, ERBB2, ESR1) were associated with a higher chance of pCR (55% vs. 15.8%, p = 0.009). Elevated ERBB2 expression was positively correlated with luminal expression features such as KRT20, and negatively with basal characteristics such as KRT5. Patients with MIBC showing a high expression of ERBB2, ESR1, or KRT20 have a significantly higher chance of pCR following NAC. These findings might improve patient selection for NAC in MIBC.

scholarly journals Intratumoral heterogeneity of surrogate molecular subtypes in urothelial carcinoma in situ of the urinary bladder: implications for prognostic stratification of high-risk non-muscle-invasive bladder cancer

2021 ◽  
Author(s):  
Stefan Garczyk ◽  
Felix Bischoff ◽  
Ursula Schneider ◽  
Reinhard Golz ◽  
Friedrich-Carl von Rundstedt ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
High Risk ◽  
Carcinoma In Situ ◽  
Molecular Subtypes ◽  
Smoking Status ◽  
Invasive Bladder Cancer ◽  
Muscle Invasive Bladder Cancer ◽  
Prognostic Stratification ◽  
Muscle Invasive

AbstractReliable factors predicting the disease course of non-muscle-invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) are unavailable. Molecular subtypes have potential for prognostic stratification of muscle-invasive bladder cancer, while their value for CIS patients is unknown. Here, the prognostic impact of both clinico-pathological parameters, including CIS focality, and immunohistochemistry-based surrogate subtypes was analyzed in a cohort of high-risk NMIBC patients with CIS. In 128 high-risk NMIBC patients with CIS, luminal (KRT20, GATA3, ERBB2) and basal (KRT5/6, KRT14) surrogate markers as well as p53 were analyzed in 213–231 biopsies. To study inter-lesional heterogeneity of CIS, marker expression in independent CIS biopsies from different bladder localizations was analyzed. Clinico-pathological parameters and surrogate subtypes were correlated with recurrence-free (RFS), progression-free (PFS), cancer-specific (CSS), and overall survival (OS). Forty-six and 30% of CIS patients exhibited a luminal-like (KRT20-positive, KRT5/6-negative) and a null phenotype (KRT20-negative, KRT5/6-negative), respectively. A basal-like subtype (KRT20-negative, KRT5/6-positive) was not observed. A significant degree of inter-lesional CIS heterogeneity was noted, reflected by 23% of patients showing a mixed subtype. Neither CIS surrogate subtype nor CIS focality was associated with patient outcome. Patient age and smoking status were the only potentially independent prognostic factors predicting RFS, PFS, OS, and PFS, respectively. In conclusion, further clarification of heterogeneity of surrogate subtypes in HR NMIBC and their prognostic value is of importance with regard to potential implementation of molecular subtyping into clinical routine. The potential prognostic usefulness of patient age and smoking status for high-risk NMIBC patients with CIS needs further validation.

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