Impact of Immunohistochemistry-Based Subtypes in Muscle-Invasive Bladder Cancer on Response to Chemoradiation Therapy

Tanaka, Hajime; Yoshida, Soichiro; Koga, Fumitaka; Toda, Kazuma; Yoshimura, Ryoichi; Nakajima, Yoshiki; Sugawara, Etsuko; Akashi, Takumi; Waseda, Yuma; Inoue, Masaharu; Kijima, Toshiki; Yokoyama, Minato; Ishioka, Junichiro; Matsuoka, Yoh; Saito, Kazutaka; Kihara, Kazunori; Fujii, Yasuhisa

doi:10.1016/j.ijrobp.2018.06.030

Cited by 22 publications

(27 citation statements)

References 23 publications

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“…43 This could partially explain why luminal variants appear to be insensitive to standard chemotherapy or chemoradiation. 2,44,45 Shortlisting of proteins discriminating the two apparently "extreme" (based on both pathological and molecular characteristics) NMIBC subtypes (NPS1 and NPS3), showing also concordant expression patterns in the MIBC vs. NMIBC proteomic comparison but also, at the mRNA levels, in the high vs. low risk subtype comparisons in the UROMOL 8 and LUND 3 cohorts, highlighted a set of 77 features of high consistency in all tested datasets and molecular levels. Features overexpressed consistently in the aggressive NMIBC phenotypes represented predominantly inflammation and immune recognition, unfolded protein response, oncogenic signaling and RNA processing.…”

Section: Discussionmentioning

confidence: 94%

“…Analysis for subtype‐specific pathways indicated that NPS3 was selectively enriched in detoxification activity by glutathione, which is considered to inactivate cisplatin, offering chemoresistant properties to tumor cells . This could partially explain why luminal variants appear to be insensitive to standard chemotherapy or chemoradiation …”

Section: Discussionmentioning

confidence: 99%

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Proteome‐based classification of Nonmuscle Invasive Bladder Cancer

Stroggilos

Mokou

Latosinska

et al. 2019

Intl Journal of Cancer

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DNA/RNA‐based classification of bladder cancer (BC) supports the existence of multiple molecular subtypes, while investigations at the protein level are scarce. Here, we aimed to investigate if Nonmuscle Invasive Bladder Cancer (NMIBC) can be stratified to biologically meaningful groups based on the proteome. Tissue specimens from 117 patients at primary diagnosis (98 with NMIBC and 19 with MIBC), were processed for high‐resolution proteomics analysis by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). The proteomics output was subjected to unsupervised consensus clustering, principal component analysis (PCA) and investigation of subtype‐specific features, pathways, and gene sets. NMIBC patients were optimally stratified to three NMIBC proteomic subtypes (NPS), differing in size, clinicopathologic and molecular backgrounds: NPS1 (mostly high stage/grade/risk samples) was the smallest in size (17/98) and overexpressed proteins reflective of an immune/inflammatory phenotype, involved in cell proliferation, unfolded protein response and DNA damage response, whereas NPS2 (mixed stage/grade/risk composition) presented with an infiltrated/mesenchymal profile. NPS3 was rich in luminal/differentiation markers, in line with its pathological composition (mostly low stage/grade/risk samples). PCA revealed a close proximity of NPS1 and conversely, remoteness of NPS3 to the proteome of MIBC. Proteins distinguishing these two extreme subtypes were also found to consistently differ at the mRNA levels between high and low‐risk subtypes of the UROMOL and LUND cohorts. Collectively, our study identifies three proteomic NMIBC subtypes and following a cross‐omics validation in two independent cohorts, shortlists molecular features meriting further investigation for their biomarker or potentially therapeutic value.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Proteome‐based classification of Nonmuscle Invasive Bladder Cancer

Stroggilos

Mokou

Latosinska

et al. 2019

Intl Journal of Cancer

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“…Molecular subtypes of bladder cancer can characterize their clinical behaviors and can help predict therapeutic responses to neoadjuvant chemotherapy prior to RC [ 52 , 53 ]. Tanaka et al demonstrated that molecular subtypes may be used to predict chemoradiation response in 118 MIBC patients [ 30 ]. The subtyping model used was the Lund University model, which characterizes three subtypes based on immunohistochemical expression patterns of cyclin B1 and keratin 5: Urobasal (Uro), genomically unstable (GU), and squamous cell cancer-like (SCC-like) [ 54 ].…”

Section: Biomarkers Associated With Chemoradiation Response and Prmentioning

confidence: 99%

“…CR rates after chemoradiation (40 Gy + cisplatin) were 52%, 45%, and 15% for GU, SCC-like, and Uro, respectively ( p < 0.001). Molecular subtypes were not associated with CSS probably because most non-CR patients underwent salvage cystectomy [ 30 ].…”

Section: Biomarkers Associated With Chemoradiation Response and Prmentioning

confidence: 99%

Biomarkers for Predicting Clinical Outcomes of Chemoradiation-Based Bladder Preservation Therapy for Muscle-Invasive Bladder Cancer

Koga

Takemura

Fukushima

2018

IJMS

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Chemoradiation-based bladder preservation therapy (BPT) is currently a curative option for non-metastatic muscle-invasive bladder cancer (MIBC) patients at favorable risk or an alternative to radical cystectomy (RC) for those who are unfit for RC. In BPT, only patients who achieve complete response (CR) after chemoradiation have a favorable prognosis and quality of life with a preserved functional bladder. Thus, predicting CR and favorable prognosis is important for optimal patient selection for BPT. We reviewed biomarkers for predicting the clinical outcomes of chemoradiation-based BPT. The biomarkers studied were categorized into those related to apoptosis, cell proliferation, receptor tyrosine kinases, DNA damage response genes, hypoxia, molecular subtype, and others. Among these biomarkers, the Ki-67 labeling index (Ki-67 LI) and meiotic recombination 11 may be used for selecting BPT or RC. Ki-67 LI and erythroblastic leukemia viral oncogene homolog 2 (erbB2) may be used for predicting both the chemoradiation response and the prognosis of patients on BPT. Concurrent use of trastuzumab and a combination of carbogen and nicotinamide can overcome chemoradiation resistance conferred by erbB2 overexpression and tumor hypoxia. Further studies are needed to confirm the practical utility of these biomarkers for progress on biomarker-directed personalized management of MIBC patients.

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“…With respect to local definitive therapy, low expression of MRE11 (a protein involved in double-stranded DNA damage repair and cell cycle checkpoint) and high expression of TIP60 (tat-interactive protein 60 kDa) have been associated with improved outcomes with RC [288,289]. Molecular determinants of response to radiotherapy may include miR-23a and miR-27a [290], genomically unstable and squamous cell cancer-like tumor subtypes [291], and tumors with higher immune infiltration [292].…”

Section: Biomarkersmentioning

confidence: 99%

Current Management of Localized Muscle-Invasive Bladder Cancer: A Consensus Guideline from the Genitourinary Medical Oncologists of Canada

Jiang

North

Canil

et al. 2020

BLC

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BACKGROUND: Despite recent advances in the management of muscle-invasive bladder cancer (MIBC), treatment outcomes remain suboptimal, and variability exists across current practice patterns. OBJECTIVE: To promote standardization of care for MIBC in Canada by developing a consensus guidelines using a multidisciplinary, evidence-based, patient-centered approach who specialize in bladder cancer. METHODS: A comprehensive literature search of PubMed, Medline, and Embase was performed; and most recent guidelines from national and international organizations were reviewed. Recommendations were made based on best available evidence, and strength of recommendations were graded based on quality of the evidence. RESULTS: Overall, 17 recommendations were made covering a broad range of topics including pathology review, staging investigations, systemic therapy, local definitive therapy and surveillance. Of these, 10 (59% ) were level 1 or 2, 7 (41% ) were level 3 or 4 recommendations. There were 2 recommendations which did not reach full consensus, and were based on majority opinion. This guideline also provides guidance for the management of cisplatin-ineligible patients, variant histologies, and bladder-sparing trimodality therapy. Potential biomarkers, ongoing clinical trials, and future directions are highlighted. CONCLUSIONS: This guideline embodies the collaborative expertise from all disciplines involved, and provides guidance to further optimize and standardize the management of MIBC.

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Impact of Immunohistochemistry-Based Subtypes in Muscle-Invasive Bladder Cancer on Response to Chemoradiation Therapy

Cited by 22 publications

References 23 publications

Proteome‐based classification of Nonmuscle Invasive Bladder Cancer

Proteome‐based classification of Nonmuscle Invasive Bladder Cancer

Biomarkers for Predicting Clinical Outcomes of Chemoradiation-Based Bladder Preservation Therapy for Muscle-Invasive Bladder Cancer

Current Management of Localized Muscle-Invasive Bladder Cancer: A Consensus Guideline from the Genitourinary Medical Oncologists of Canada

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