Different responses to neoadjuvant chemotherapy in urothelial carcinoma molecular subtypes

Sjödahl, Gottfrid; Abrahamsson, Johan; Holmsten, Karin; Bernardo, Carina; Chebil, Gunilla; Eriksson, Pontus; Johansson, Iva; Kollberg, Petter; Lindh, Claes; Lövgren, Kristina; Marzouka, Nour Al Dain; Olsson, Hans; Höglund, Mattias; Ullén, Anders

doi:10.1101/2021.05.11.21255912

Cited by 9 publications

(8 citation statements)

References 41 publications

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“…However, other work with larger and more heterogeneous cohorts has found prognostic and predictive associations for the Lund taxonomy. [2][3][4][5][6][7][8][18][19][20][21][22][23][24] Importantly, additional work using GATA3, KRT5, and p16 IHC to identify Uro, GU, and basal subtypes found significant differences in disease-specific survival between the basal and Uro subtypes, suggesting the potential clinical utility of a three-antibody assay. 33 Critical to future investigations is the validation of a robust and efficient assay such as the IHC-based classification models described here.…”

Section: Discussionmentioning

confidence: 99%

“…6,18 Moreover, among luminal tumors, those with genomic instability have demonstrated better responses to neoadjuvant chemotherapy and immunotherapy. 21,23,24 These predictive and prognostic associations highlight the potential value of distinguishing between Uro and GU luminal subtypes to fulfill the clinical potential of molecular subtyping for defining appropriate treatment strategies. However, there have also been contradictory findings with respect to the prognostic implications of these subtypes due to variable approaches to cohort assembly, subtyping taxonomy, and molecular profiling methodology.…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, bladder cancer molecular subtypes have been associated with different prognostic and predictive outcomes. [18][19][20][21][22][23][24] Broadly, tumors of the basal subtypes are aggressive and have been associated with poor prognosis, whereas luminal subtypes have been associated with improved survival. [1][2][3][4][5][6][7]18 However, the GU luminal subtype may represent an important exception, demonstrating a worse prognosis compared with its Uro (also luminal) counterpart.…”

Section: Introductionmentioning

confidence: 99%

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Immunohistochemical Assays for Bladder Cancer Molecular Subtyping: Optimizing Parsimony and Performance of Lund Taxonomy Classifiers

Hardy¹,

Ghaedi²,

Slotman³

et al. 2022

J Histochem Cytochem.

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Transcriptomic and proteomic profiling classify bladder cancers into luminal and basal molecular subtypes, with controversial prognostic and predictive associations. The complexity of published subtyping algorithms is a major impediment to understanding their biology and validating or refuting their clinical use. Here, we optimize and validate compact algorithms based on the Lund taxonomy, which separates luminal subtypes into urothelial-like (Uro) and genomically unstable (GU). We characterized immunohistochemical expression data from two muscle-invasive bladder cancer cohorts ( n=193, n=76) and developed efficient decision tree subtyping models using 4-fold cross-validation. We demonstrated that a published algorithm using routine assays (GATA3, KRT5, p16) classified basal/luminal subtypes and basal/Uro/GU subtypes with 86%–95% and 67%–86% accuracies, respectively. KRT14 and RB1 are less frequently used in pathology practice but achieved the simplest, most accurate models for basal/luminal and basal/Uro/GU discrimination, with 93%–96% and 85%–86% accuracies, respectively. More complex models with up to eight antibodies performed no better than simpler two- or three-antibody models. We conclude that simple immunohistochemistry classifiers can accurately identify luminal (Uro, GU) and basal subtypes and are appealing options for clinical implementation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Immunohistochemical Assays for Bladder Cancer Molecular Subtyping: Optimizing Parsimony and Performance of Lund Taxonomy Classifiers

Hardy¹,

Ghaedi²,

Slotman³

et al. 2022

J Histochem Cytochem.

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“…For example, Ba/Sq tumors have worse prognosis than luminal-papillary (LumP) tumors [5], which commonly show genetic alterations of FGFR3 (6). These subtypes have also been suggested to have a different sensitivity to chemotherapies, although results are currently inconsistent between studies (7)(8)(9)(10). The Ba/Sq subtype and bladder SCC are associated with EGFR activation and sensitivity to anti-EGFR treatments in preclinical models (5,(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Integrated molecular and pharmacological characterization of patient-derived xenografts from bladder and ureteral cancers identifies new potential therapies

Lang

Beraud

Cabel

et al. 2022

Preprint

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BackgroundMuscle-invasive bladder cancer (MIBC) and upper urinary tract urothelial carcinoma (UTUC) are molecularly heterogeneous. Despite chemotherapies, immunotherapies or anti-FGFR treatments, these tumors are still of poor outcome. Our objective was to develop a bank of patient-derived xenografts (PDXs) recapitulating molecular heterogeneity of MIBC and UTUC, to facilitate preclinical identification of therapies.MethodsFresh tumors were obtained from patients and subcutaneously engrafted into immune-compromised mice. Patient tumors and matched PDXs were compared regarding histopathology, transcriptomic (microarrays) and genomic profiles (targeted-NGS). Several PDXs were treated with chemotherapy (cisplatin/gemcitabine) or targeted therapies (FGFR and EGFR inhibitors).Results31 PDXs were established from 1 non-MIBC, 25 MIBC, 5 upper urinary tract tumors, including 28 urothelial (UCC) and 3 squamous-cell carcinomas (SCC). Integrated genomic and transcriptomic profiling identified PDXs of 3 different consensus molecular subtypes (Basal/Squamous, Luminal papillary and Luminal unstable), and included FGFR3-mutated PDXs. High histological and genomic concordance was found between matched patient tumor/PDX. Discordance in molecular subtypes, such as a basal/squamous patient tumor giving rise to a luminal papillary PDX, was observed (n=5) at molecular and histological levels. Ten models were treated with cisplatin-based chemotherapy and we did not observe association between subtypes and response. Of the 3 basal/squamous models treated with anti-EGFR therapy, two models were sensitive and one model, of sarcomatoid variant, was resistant. Treatment of 3 FGFR3-mutant PDXs with combined FGFR/EGFR inhibitors was more efficient than anti-FGFR3 treatment alone.ConclusionsWe developed preclinical PDX models that recapitulate the molecular heterogeneity of MIBCs and UTUC, including actionable mutations, which will represent an essential tool in therapy development. Pharmacological characterization of the PDXs suggested that upper urinary tract and MIBCs, UCC but also SCC, with similar molecular characteristics could benefit from the same treatments including anti-FGFR for FGFR3-mutated tumors and anti-EGFR for basal ones and showed a benefit for combined FGFR/EGFR inhibition in FGFR3-mutant PDXs, compared to FGFR inhibition alone.

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“…Recent studies have discovered a series of biomarkers for platinum resistance, such as FOXC1 7 and Circ_0058063 8 . Other evidence also showed the subtype of BC is associated with response to chemotherapy 9 . These biomarkers are insu cient for effective treatment decisions because these studies were conducted on a molecular or cellular level and lack prognostic information.…”

mentioning

confidence: 98%

Identification and Validation of a Novel Prognostic Model Based on Platinum Resistance-Related Genes in Bladder Cancer

Hao

Wang

2022

Preprint

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Background: Bladder cancer (BC) is a heterogeneous disease with high recurrence rate. The depth of response to platinum-based chemotherapeutic agents in urothelial neoplasm tissues varies greatly. Biomarkers that have practical value in prognosis stratification and early determination of therapeutic effect are increasingly needed. Our study aimed to select a set of BC-related genes involved in both platinum resistance and survival, then use these genes to establish the prognostic model.Methods: Platinum resistance-related DEGs and tumorigenesis-related DEGs were identified. Among the intersection of them, 10 most predictive genes were acquired through Cox, lasso, and stepwise regressions followed by building a risk score model with their regression coefficients. Survival analysis and ROC plot were used to evaluate the predictive accuracy of our model. Combined with age and TMN stages, a nomogram was generated to create a graphical representation of survival rates at 1-, 3-, 5-, and 8-year in BC patients. The prognostic performance of risk score was also validated in three independent BC datasets including cisplatin-treated patients and a gastric cancer cohort with platinum-based chemotherapy. The potential mechanism of the gene-based model was explored by enrichment analysis.Results: PPP2R2B, TSPAN7, ATAD3C, SYT15, SAPCD1, AKR1B1, TCHH, AKAP12, AGLN3, and IGF2 were selected for our prognostic model. Patients in high- and low-risk groups exhibited a significant survival difference (HR = 2.7, p < 0.0001). The prognostic nomogram of predicting 3-year OS for BC patients could yield an AUC of 0.819. In the external validation dataset, the risk score also has a robust predictive ability. Conclusion: A prognostic model derived from platinum resistance-related genes was constructed, we confirmed its value in predicting platinum-based chemotherapy benefits and overall survival for BC patients. The model might assist in therapeutic decisions for bladder malignancy.Subjects: Urology, Oncology, Bioinformatics, Molecular Biology.

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Different responses to neoadjuvant chemotherapy in urothelial carcinoma molecular subtypes

Cited by 9 publications

References 41 publications

Immunohistochemical Assays for Bladder Cancer Molecular Subtyping: Optimizing Parsimony and Performance of Lund Taxonomy Classifiers

Immunohistochemical Assays for Bladder Cancer Molecular Subtyping: Optimizing Parsimony and Performance of Lund Taxonomy Classifiers

Integrated molecular and pharmacological characterization of patient-derived xenografts from bladder and ureteral cancers identifies new potential therapies

Identification and Validation of a Novel Prognostic Model Based on Platinum Resistance-Related Genes in Bladder Cancer

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