Predictive models of response to neoadjuvant chemotherapy in muscle-invasive bladder cancer using nuclear morphology and tissue architecture.
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SUBMITTER: Mi H
PROVIDER: S-EPMC8484511 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundNeoadjuvant chemotherapy (NAC) prior to radical cystectomy (RC) remains standard treatment for select patients with muscle-invasive bladder cancer (MIBC). Although computed tomography (CT) is often obtained prior to RC, its ability to predict pathologic response is poorly characterized.ObjectiveThe purpose of this study is to evaluate the predictive value of CT in assessing disease burden after NAC.MethodsPatients with MIBC having received NAC prior to RC were identified. Pre- and post-NAC CT scans were reviewed by an abdominal radiologist. The correlation between pathologic complete response (PCR) and radiologic complete response (RCR) was determined as the primary aim. As a secondary aim, the correlation between pathologic partial response (PPR) and radiologic partial response (RPR) was determined. Logistic regression analysis was utilized to determine the predictive value of CT in determining disease burden at RC.ResultsA total of 141 patients were identified for analysis. PCR and PPR was achieved in 34% and 16% of patients, respectively. The positive predictive value of post-NAC CT was 53.5% for PCR and 28.8% for PPR. The negative predictive value of post-NAC CT was 73.5% for PCR and 46.2% for PPR. There was no significant association between RCR and PCR (OR 1.13, p = 0.67). Similarly, there was no meaningful association between RPR and PPR, lymph node involvement, or presence of extravesical disease.ConclusionsCT findings correlate poorly with final pathology at RC and should not be used to evaluate local disease burden.
| S-EPMC11181745 | biostudies-literature
Project description:IntroductionIdentifying neoadjuvant chemotherapy (NAC) response in patients with muscle invasive bladder cancer (MIBC) has had limited success based on clinicopathological features and molecular subtyping. Identification of chemotherapy responsive cohorts would facilitate delivery to those most likely to benefit.ObjectiveDevelop a molecular signature that can identify MIBC NAC responders (R) and non-responders (NR) using a cohort of known NAC response phenotypes, and better understand differences in molecular pathways and subtype classifications between NAC R and NR.Materials and methodsPresented are the messenger RNA (mRNA) and microRNA (miRNA) differential expression profiles from initial transurethral resection of bladder tumor (TURBT) specimens of a discovery cohort of MIBC patients consisting of 7 known NAC R and 11 NR, and a validation cohort consisting of 3 R and 5 NR. Pathological response at time of cystectomy after NAC was used to classify initial TURBT specimens as R (pT0) versus NR (≥pT2). RNA and miRNA from FFPE blocks were sequenced using RNAseq and qPCR, respectively.ResultsThe discovery cohort had 2309 genes, while the validation cohort had 602 genes and 13 miRNA differentially expressed between R and NR. Gene set enrichment analysis identified mitochondrial gene expression, DNA replication initiation, DNA unwinding in the R discovery cohort and positive regulation of vascular associated smooth muscle cell proliferation in the NR discovery cohort. Canonical correlation (CC) analysis was applied to differentiate R versus NR. 3 CCs (CC13, CC16, and CC17) had an AUC >0.65 in the discovery and validation dataset. Gene ontology enrichment showed CC13 as nucleoside triphosphate metabolic process, CC16 as cell cycle and cellular response to DNA damage, CC17 as DNA packaging complex. All patients were classified using established molecular subtypes: Baylor, UNC, CIT, Lund, MD Anderson, TCGA, and Consensus Class. The MD Anderson p53-like subtype, CIT MC4 subtype and Consensus Class stroma rich subtype had the strongest correlation with a NR phenotype, while no subtype had a strong correlation with the R phenotype.ConclusionsOur results identify molecular signatures that can be used to differentiate MIBC NAC R versus NR, salient molecular pathway differences, and highlight the utility of molecular subtyping in relation to NAC response.
| S-EPMC9629806 | biostudies-literature
Project description:Despite cisplatin-based neoadjuvant chemotherapy (NAC) 60% of patients with muscle-invasive bladder cancer still have residual invasive disease at radical cystectomy (RC). The NAC-induced biological alterations in these cisplatin-resistant tumors remain largely unstudied. We analyzed gene expression from 133 patients with residual invasive disease after cisplatin-based NAC. H&E and immunohistochemistry were used to confirm tissue sampling and gene expression analysis. Established molecular subtyping models proved to be inconsistent in their classification of the post-NAC samples. Unsupervised consensus clustering revealed four distinct consensus clusters (CC). The CC1-Basal and CC2-Luminal subtypes expressed genes consistent with a basal-like and a luminal-like phenotype, respectively. The CC3-Immune subtype had the highest immune activity, including T-cell infiltration and checkpoint molecule expression, but lacked both basal and luminal markers. The CC4-Scar-like subtype expressed genes associated with wound-healing/ scarring and was associated with favorable prognosis.
2019-01-01 | GSE124305 | GEO
Project description:BackgroundBladder-sparing chemoradiation therapy is a definitive first-line treatment option for muscle-invasive bladder cancer. Randomized trials have demonstrated that the addition of neoadjuvant chemotherapy to radical cystectomy or radiation monotherapy results in a survival benefit. Whether neoadjuvant chemotherapy improves outcomes when used with definitive chemoradiation is unknown.Patients and methodsWe identified 2566 patients in the National Cancer Data Base with cT2-4N0M0 urothelial cell carcinoma of the bladder treated with definitive intent concurrent chemoradiation from 2004 to 2015. The exposure of interest was receipt of neoadjuvant chemotherapy versus those without neoadjuvant chemotherapy. The primary outcome was overall survival defined from the time of diagnosis. Kaplan-Meier and multivariable Cox proportional hazard analyses were used to compare survival between groups. Sensitivity analyses tested (1) an interaction term for clinical T stage and (2) defining survival from start of radiation (as opposed to time of diagnosis) to address potential leading time bias.ResultsWe identified 462 patients treated with neoadjuvant chemotherapy followed by chemoradiation and 2104 patients treated with chemoradiation alone. With a median follow-up of 6.2 years, we found no difference in survival between groups: 5-year or 10-year overall survival of 30.6% (95% confidence interval [CI], 28.4%-32.9%) in the neoadjuvant group versus 31.8% (95% CI, 27.0%-36.8%) in the standard chemoradiation therapy group and 13.3% (95% CI, 11.2%-15.5%) in the neoadjuvant group versus 13.0% (95% CI, 8.4%-18.7%) in the standard chemoradiation therapy group, respectively (log-rank P = .19). On multivariable analysis we found no association between receipt of neoadjuvant chemotherapy and overall survival (hazard ratio, 1.01; 95% CI, 0.88-1.15; P = .921). The sensitivity analyses did not identify any differential effect by clinical T stage nor by defining survival from start of radiation.ConclusionThese results do not support the routine addition of neoadjuvant chemotherapy to definitive chemoradiation for bladder cancer, and optimizing the chemotherapy sequencing and regimens for bladder-preserving approaches to muscle invasive bladder cancer should continue to be studied under prospective clinical trials.
| S-EPMC8376795 | biostudies-literature
Project description:Background and objectiveNeoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care in muscle-invasive bladder cancer (MIBC). Pathological response has been associated with longer survival, but no currently available clinicopathological variables can identify patients likely to respond, highlighting the need for predictive biomarkers. We sought to identify a predictive signature of response to NAC integrating clinical score, taxonomic subtype, and gene expression.Material and methodsFrom 1994 to 2014, pre-treatment tumor samples were collected from MIBC patients (stage T2-4N0/+M0) at two Spanish hospitals. A clinical score was determined based on stage, hydronephrosis and histology. Taxonomic subtypes (BASQ, luminal, and mixed) were identified by immunohistochemistry. A custom set of 41 genes involved in DNA damage repair and immune response was analyzed in 84 patients with the NanoString nCounter platform. Genes related to pathological response were identified by LASSO penalized logistic regression. NAC consisted of cisplatin/methotrexate/vinblastine until 2000, after which most patients received cisplatin/gemcitabine. The capacity of the integrated signature to predict pathological response was assessed with AUC. Overall survival (OS) and disease-specific survival (DSS) were analyzed with the Kaplan-Meier method.ResultsLASSO selected eight genes to be included in the signature (RAD51, IFNγ, CHEK1, CXCL9, c-MET, KRT14, HERC2, FOXA1). The highest predictive accuracy was observed with the inclusion in the model of only three genes (RAD51, IFNɣ, CHEK1). The integrated clinical-taxonomic-gene expression signature including these three genes had a higher predictive ability (AUC=0.71) than only clinical score plus taxonomic subtype (AUC=0.58) or clinical score alone (AUC=0.56). This integrated signature was also significantly associated with OS (p=0.02) and DSS (p=0.02).ConclusionsWe have identified a predictive signature for response to NAC in MIBC patients that integrates the expression of three genes with clinicopathological characteristics and taxonomic subtypes. Prospective studies to validate these results are ongoing.
| S-EPMC10426739 | biostudies-literature
Project description:PurposePrevious studies have noted increased utilization of perioperative chemotherapy over time. The goal of this study was to determine trends in perioperative chemotherapy use within a contemporary population.Materials and methodsThe National Cancer Database was queried for patients diagnosed with cT2-4N0M0 urothelial muscle invasive bladder cancer from 2011 to 2015 and underwent subsequent radical cystectomy. We retrospectively analyzed factors associated with perioperative chemotherapy and evaluated overall treatment trends in the use of neoadjuvant and adjuvant chemotherapy. Linear regression, logistic regression, Cox regression, and Kaplan-Meier analysis were performed.ResultsIn total, 7,101 patients met inclusion criteria for analysis. The use of perioperative chemotherapy increased from 46.4% in 2011 to 57.2% in 2015 (p=0.003). Neoadjuvant chemotherapy use increased from 22.9% to 32.3% (p=0.007) over the time period analyzed, while adjuvant chemotherapy use experienced no significant change (23.5% to 24.9%, p=0.182). Logistic regression demonstrated that increased age and Charlson Comorbidity Index were predictors of not receiving chemotherapy (p<0.05), while those with increasing T stage, income above $48,000, and insurance other than Medicaid or Medicare were more likely to receive perioperative chemotherapy (p<0.05). Kaplan-Meier analysis revealed patients receiving neoadjuvant chemotherapy had the best 5-year overall survival at 48.3% compared to adjuvant chemotherapy (42.6%) or no chemotherapy (37.8%) (p<0.001).ConclusionsThe increasing use of perioperative chemotherapy noted in prior studies has continued through 2015. Neoadjuvant chemotherapy appears to drive this increase while adjuvant chemotherapy utilization remains unchanged. Clinical and socioeconomic factors affect utilization of perioperative chemotherapy.
| S-EPMC7606117 | biostudies-literature
Project description:Background and Objective: Neoadjuvant chemotherapy (NAC) followed by cystectomy is the standard of care in muscle-invasive bladder cancer (MIBC). Pathological response has been associated with longer survival, but no currently available clinicopathological variables can identify patients likely to respond, highlighting the need for predictive biomarkers. We sought to identify a predictive signature of response to NAC integrating clinical score, taxonomic subtype, and gene expression. Material and Methods: From 1994 to 2014, pre-treatment tumor samples were collected from MIBC patients (stage T2-4N0/+M0) at two Spanish hospitals. A clinical score was determined based on stage, hydronephrosis and histology. Taxonomic subtypes (BASQ, luminal, and mixed) were identified by immunohistochemistry. A custom set of 41 genes involved in DNA damage repair and immune response was analyzed in 84 patients with the NanoString nCounter platform. Genes related to pathological response were identified by LASSO penalized logistic regression. NAC consisted of cisplatin/methotrexate/vinblastine until 2000, after which most patients received cisplatin/gemcitabine. The capacity of the integrated signature to predict pathological response was assessed with AUC. Overall survival (OS) and disease-specific survival (DSS) were analyzed with the Kaplan-Meier method. Results: LASSO selected eight genes to be included in the signature (RAD51, IFNγ, CHEK1, CXCL9, c-MET, KRT14, HERC2, FOXA1). The highest predictive accuracy was observed with the inclusion in the model of only three genes (RAD51, IFNɣ, CHEK1). The integrated clinical-taxonomic-gene expression signature including these three genes had a higher predictive ability (AUC=0.71) than only clinical score plus taxonomic subtype (AUC=0.58) or clinical score alone (AUC=0.56). This integrated signature was also significantly associated with OS (p=0.02) and DSS (p=0.02). Conclusions: We have identified a predictive signature for response to NAC in MIBC patients that integrates the expression of three genes with clinicopathological characteristics and taxonomic subtypes. Prospective studies to validate these results are ongoing.
2023-06-20 | GSE235067 | GEO
Project description:PurposeReduced quality of life after cystectomy has made bladder preservation a popular research topic for muscle-invasive bladder cancer (MIBC). Previous research has indicated significant tumor downstaging after neoadjuvant chemotherapy (NAC). However, maximal transurethral resection of bladder tumor (TURBT) was performed before NAC to define the pathology, impacting the real evaluation of NAC. This research aimed to assess real NAC efficacy without interference from TURBT and apply combined modality therapies guided by NAC efficacy.Materials and methodsPatients with cT2-4aN0M0 MIBC were confirmed by cystoscopic biopsy and imaging. NAC efficacy was assessed by imaging, urine cytology, and cystoscopy with multidisciplinary team discussion. Definite responders (≤ T1) underwent TURBT plus concurrent chemoradiotherapy. Incomplete responders underwent radical cystectomy or partial cystectomy if feasible. The primary endpoint was the bladder preservation rate.ResultsFifty-nine patients were enrolled, and the median age was 63 years. Patients with cT3-4 accounted for 75%. The median number of NAC cycles was three. Definite responders were 52.5%. The complete response (CR) was 10.2%, and 59.3% of patients received bladder-sparing treatments. With a median follow-up of 44.6 months, the 3-year overall survival (OS) was 72.8%. Three-year OS and relapse-free survival were 88.4% and 60.0% in the bladder-sparing group but only 74.3% and 37.5% in the cystectomy group. The evaluations of preserved bladder function were satisfactory.ConclusionAfter stratifying MIBC patients by NAC efficacy, definite responders achieved a satisfactory bladder-sparing rate, prognosis, and bladder function. The CR rate reflected the real NAC efficacy for MIBC. This therapy is worth verifying through multicenter research.
| S-EPMC8524034 | biostudies-literature
Project description:Background and aimNeoadjuvant chemotherapy (NAC) followed by radical cystectomy is the current gold standard treatment for muscle-invasive urothelial bladder cancer (MIBC). Nonetheless, some MIBC patients showed limited pathological response after NAC. Herein, we used whole-exome sequencing (WES) to identify genetic mutations in MIBC that can predict NAC response.MethodsForty MIBC patients were enrolled in this study, in which 33 were successfully examined by WES and Sanger sequencing in the discovery cohort (n=13) and the validation cohort (n=20), respectively. ANNOVAR software was used to identify the potential mutations based on the data of WES. In addition, tumor-specific somatic mutations including single nucleotide variants and indels were called with the muTECT and Strelka software. The mutational analysis of specific genes was carried out based on the data from cBioPortal for Cancer Genomics.ResultsIn the discovery cohort, the mutation frequencies of TP53, MED16, DRC7, CEND1, ATAD5, SETD8, and PIK3CA were significantly higher in 13 MIBC patients. Specifically, the presence of somatic mutations of APC, ATM, CDH9, CTNNB1, METTL3, NBEAL1, PTPRH, RNASEL, and FBXW7 in NAC responder signifies that these mutations were potential predictors of pathological response to NAC. Furthermore, somatic mutations of CCDC141, PIK3CA, CHD5, GPR149, MUC20, TSC1, and USP54 were exclusively identified in NAC nonresponders, suggesting that these mutations may participate in the process of NAC resistance. In the validation cohort, the somatic mutations of CDH9, METTL3, and PTPRH were significantly enriched in NAC responders while the somatic mutation of CCDC141 was significantly enriched in NAC nonresponders. Furthermore, survival analysis revealed that the patients expressing mutated METTL3 have a longer overall survival and disease- or progression-free survival than the patients acquiring wild-type METTL3.ConclusionThe somatic mutation of METTL3 can be a potential predictive biomarker of NAC response in MIBC patients.Relevance for patientsMIBC patients bearing mutated METTL3 display a pathological response to NAC and have a significantly longer overall survival or disease/progression-free survival as compared to the patients bearing wild-type METTL3. Thus, the somatic mutation of METTL3 is a potential biomarker for predicting response to NAC in MIBC patients, assisting doctors in making the clinical decision.
| S-EPMC8259609 | biostudies-literature
Project description:Background: MIBC is an aggressive disease, with 5-year survival rates ranging from 36 to 48% for p T3/p T4/p N+tumors. Perioperative treatment can improve overall survival, with more robust evidence in favor of neoadjuvant chemotherapy. Few randomized studies have compared neoadjuvant and adjuvant therapy in bladder cancer. Consequently, it has been difficult to establish the benefit of adjuvant chemotherapy (AC) in MIBC. Methods: Data from patients with muscle invasive bladder cancer (>pT2) collected from 2005 to 2012 within the RISC data base (Retrospective International Study of Cancers of the Urothelial Tract) were evaluated. Overall survival (OS), cancer specific survival (CSS), and disease-free survival (DFS) between NC and AC generated using the Kaplan-Meier method were compared for MIBC by log-rank test. All patients in this analysis received either NC or AC. Results: A total of 656 patients with MIBC (325 treated with AC and 331 with NC) were analyzed. The median DFS was 34.6 months (95% CI:25.3-43.9) for NC vs. 24.9 months (95% CI: 19.4-30.5) with AC, with a reduction in the risk of disease progression of 21% in favor of NC (HR: 0.78, 95% CI: 0.63-0.96, P = 0.02). There were no significant differences in terms of CSS (HR: 1.06, 95% CI: 0.79-1.43, P: 0.70), and OS (HR: 1.08, 95% CI: 0.83-1.39, P = 0.57). Conclusions: This study demonstrates superiority in DFS for NC compared to AC. The positive prognostic impact of complete pathological response to NC was confirmed.
| S-EPMC6252384 | biostudies-literature