Immunohistochemistry-Based Taxonomical Classification of Bladder Cancer Predicts Response to Neoadjuvant Chemotherapy

Font, Albert; Domènech, Montserrat; Benítez, Raquel; Rava, Marta; Marqués, Miriam; Ramı́rez, José Luis; Pineda, Sílvia; Domínguez‐Rodríguez, Sara; Gago, J.; Badal, Josep; Carrato, Cristina; López, Héctor Rodríguez; Quer, Ariadna; Castellano, Daniel; Malats, Núria; Real, Francisco X.

doi:10.3390/cancers12071784

Cited by 33 publications

(27 citation statements)

References 36 publications

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“…A recent study by our group, using IHC-based hierarchical clustering, classified MIBC patients treated with NAC in three clusters: BASQ-like (FOXA1/GATA3 low; KRT5/6/14 high), luminal-like (FOXA1/GATA3 high; KRT5/6/14 low), and mixed-cluster (FOXA1/GATA3 high; KRT5/6 high; KRT14 low). Patients with BASQ-like tumors were more likely to achieve a pathological response to NAC (OR 3.96; p = 0.017) [ 36 ].…”

Section: Therapeutic Implications Of Bc Molecular Subtypesmentioning

confidence: 99%

Moving towards Personalized Medicine in Muscle-Invasive Bladder Cancer: Where Are We Now and Where Are We Going?

Pardo

Porras

Plaja

et al. 2020

IJMS

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Neoadjuvant cisplatin-based chemotherapy followed by radical cystectomy is the recommended treatment, with the highest level of evidence, for patients with muscle-invasive bladder cancer (MIBC). However, only a minority of patients receive this treatment, mainly due to patient comorbidities, the relatively small survival benefit, and the lack of predictive biomarkers to select those patients most likely to benefit from this multimodal approach. In addition, adjuvant chemotherapy has been recommended for patients with high-risk MIBC, although randomized trials have not provided conclusive evidence on the impact of this approach. At present, however, this situation is changing, largely due to our improved knowledge of the molecular biology of bladder cancer, which has enabled us to identify new prognostic and predictive biomarkers that can be used to select the most appropriate treatment for each patient. Moreover, new active treatments, especially immunotherapy, have shown promising results in the neoadjuvant setting. In addition, the gene expression profile of bladder tumors can be used to classify them into different subtypes, which correlate with specific clinical-pathological characteristics and with treatment response or resistance. Therefore, the main objective for the near future is to introduce these translational breakthroughs into routine clinical practice in order to personalize treatment for each patient.

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Section: Therapeutic Implications Of Bc Molecular Subtypesmentioning

confidence: 99%

Moving towards Personalized Medicine in Muscle-Invasive Bladder Cancer: Where Are We Now and Where Are We Going?

Pardo

Porras

Plaja

et al. 2020

IJMS

Self Cite

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“…A recent study which classified molecular subtypes by IHC on TMA-cores only, reported improved chemotherapy response and survival in patients with basal/squamous-like tumors. 13 However, this study included an unknown proportion of carboplatin-based regimens, 17% clinically node-positive patients, and did not report any survival data adjusted for clinical tumor stage. This study used nearly identical markers for the basal/squamous-like subtype as used in the LundTax IHC subtyping.…”

Section: Discussionmentioning

confidence: 99%

“…Varying response to systemic treatments in molecular subtypes has been suggested by previous studies but with disparate results. [9][10][11][12][13][14] In addition, genomic alterations in DNA repair genes such as ERCC2 mutations [15][16] and ATM, RB1 or FANCC mutations 17 have been associated with improved response to neoadjuvant chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Different responses to neoadjuvant chemotherapy in urothelial carcinoma molecular subtypes

Sjödahl

Abrahamsson

Holmsten

et al. 2021

Preprint

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For muscle-invasive bladder cancer (MIBC), there are no tissue biomarkers in clinical use that identify patients sensitive or resistant to neoadjuvant chemotherapy. The present study investigates how molecular subtypes impact pathological response and survival in 149 patients receiving preoperative cisplatin-based chemotherapy. Tumor classification was performed by transcriptomic profiling and by a 13-marker immunostaining panel. Furthermore, we explored differential gene expression and chemotherapy response beyond molecular subtypes. Tumors with Genomically Unstable (GU) and Urothelial-like (Uro) subtypes had higher proportions of pathological response and superior survival outcomes as compared to the Basal-Squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Based on our findings, we suggest that urothelial cancer of the luminal-like GU- and Uro-subtypes are more responsive to cisplatin-based chemotherapy. We also found the gene coding for osteopontin (SPP1) to display a subtype-dependent effect on chemotherapy response, confirmed at the protein level by immunohistochemistry. Combined analyses of second-generation, subtype-specific biomarkers may be an additional way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC.

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“…The interplay between bladder tumour biology, chemotherapy response and resistance mechanisms are complex. Recently, it has been suggested molecular subtyping may impact patient benefit to NAC [20][21][22][23]. Molecular subtypes have been discovered that are associated with specific clinicopathological characteristics and differential sensitivity to treatments.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, identification of a reliable method to stratify NAC administration based on predicted response is of critical importance for the management of MIBC patients and may ultimately lead to future personalised medicine. Recent studies have explored DNA repair gene mutations (ERCC1, ERCC2, BRCA1) [9][10][11][12], regulators of apoptosis (survivin, Bcl-xL) [13], receptor tyrosine kinase mutations (ERBB2) [14], gene expression signatures [13,[15][16][17][18][19], molecular subtypes of bladder cancer [20][21][22][23] and alterations in the cellular mechanisms of drug uptake/transport (CTR-1, MDR1) [24,25] as potential predictors of response to NAC and offer promise for improving patient selection for such treatment and clinical outcomes. However, to date, no biomarker exists in the clinical setting to prospectively identify the patients most likely to benefit from NAC.…”

Section: Introductionmentioning

confidence: 99%

Identification of CNGB1 as a Predictor of Response to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

Hepburn

Lazzarini

Veeratterapillay

et al. 2021

Cancers

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Cisplatin-based neoadjuvant chemotherapy (NAC) is recommended prior to radical cystectomy for muscle-invasive bladder cancer (MIBC) patients. Despite a 5–10% survival benefit, some patients do not respond and experience substantial toxicity and delay in surgery. To date, there are no clinically approved biomarkers predictive of response to NAC and their identification is urgently required for more precise delivery of care. To address this issue, a multi-methods analysis approach of machine learning and differential gene expression analysis was undertaken on a cohort of 30 MIBC cases highly selected for an exquisitely strong response to NAC or marked resistance and/or progression (discovery cohort). RGIFE (ranked guided iterative feature elimination) machine learning algorithm, previously demonstrated to have the ability to select biomarkers with high predictive power, identified a 9-gene signature (CNGB1, GGH, HIST1H4F, IDO1, KIF5A, MRPL4, NCDN, PRRT3, SLC35B3) able to select responders from non-responders with 100% predictive accuracy. This novel signature correlated with overall survival in meta-analysis performed using published NAC treated-MIBC microarray data (validation cohort 1, n = 26, Log rank test, p = 0.02). Corroboration with differential gene expression analysis revealed cyclic nucleotide-gated channel, CNGB1, as the top ranked upregulated gene in non-responders to NAC. A higher CNGB1 immunostaining score was seen in non-responders in tissue microarray analysis of the discovery cohort (n = 30, p = 0.02). Kaplan-Meier analysis of a further cohort of MIBC patients (validation cohort 2, n = 99) demonstrated that a high level of CNGB1 expression associated with shorter cancer specific survival (p < 0.001). Finally, in vitro studies showed siRNA-mediated CNGB1 knockdown enhanced cisplatin sensitivity of MIBC cell lines, J82 and 253JB-V. Overall, these data reveal a novel signature gene set and CNGB1 as a simpler proxy as a promising biomarker to predict chemoresponsiveness of MIBC patients.

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Immunohistochemistry-Based Taxonomical Classification of Bladder Cancer Predicts Response to Neoadjuvant Chemotherapy

Cited by 33 publications

References 36 publications

Moving towards Personalized Medicine in Muscle-Invasive Bladder Cancer: Where Are We Now and Where Are We Going?

Moving towards Personalized Medicine in Muscle-Invasive Bladder Cancer: Where Are We Now and Where Are We Going?

Different responses to neoadjuvant chemotherapy in urothelial carcinoma molecular subtypes

Identification of CNGB1 as a Predictor of Response to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

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