Therapeutic Responses to Chemotherapy or Immunotherapy by Molecular Subtype in Bladder Cancer Patients: A Meta-Analysis and Systematic Review

Abstract Background Bladder cancer (BC) is a heterogeneous disease characterized by high recurrence and a poor prognosis. Molecular subtypes of BC portend personalized and precision medicine. However, whether there is a difference in therapeutic response to chemotherapy or immunotherapy between different molecular subtypes of BC has not been systematically evaluated.Methods A comprehensive literature search was performed up to October 2020. Consensus clusters 1 (CC1), CC2 and CC3 molecular subtypes were defined according to the heterogeneity and similarity of BC molecular subtypes from published studies to perform meta-analysis. Pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the therapeutic response, and a fixed- or random-effects model was used according to the existence of heterogeneity.Results Eight studies involving 1463 patients were included in this research. For immunotherapy, CC3 showed the highest respond rate (CC3 vs CC1: OR 0.52, CI [0.34–0.78], P = 0.002. CC3 vs CC2: OR 0.42, CI [0.28–0.62], P < 0.0001), which was mainly reflected in the highest response rate to atezolizumab (CC3 vs CC1: OR 0.47, CI [0.29–0.75], P = 0.002. CC3 vs CC2: OR 0.38, CI [0.24–0.59], P < 0.0001), and the response rates to nivolumab showed no advantage over CC1 and CC2. No difference in response to the two immunotherapies between CC1 and CC2. For chemotherapy, CC3 had the lowest response rate to the overall chemotherapy (CC3 vs CC1: OR 2.28, CI [1.39–3.74], P = 0.001. CC3 vs CC2: OR = 2.25, 95% CI 1.34–3.76, P = 0.002). Compared with CC2, CC3 responded poorly to both neo-adjuvant chemotherapy (NAC) (OR 1.93, CI [1.09–3.41], P = 0.02) and chemoradiation therapy (CRT) (OR 4.53, CI [1.26–16.27], P = 0.02). Compared with CC1, CC3 only showed a poorer response to CRT (OR 6.07, CI [1.87–19.71], P = 0.003), and no difference in NAC. No difference between CC1 and CC2 subtypes in the response rates to NAC and CRT.Conclusions Our study suggested that molecular classifications are important predictors of cancer treatment outcomes of BC patients and could identify subgroup patients who are most likely to benefit from specific cancer treatments.

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CGRP-antibodies, topiramate and botulinum toxin type A in episodic and chronic migraine: A systematic review and meta-analysis

Cephalalgia ◽

10.1177/03331024211018137 ◽

2021 ◽

pp. 033310242110181

Author(s):

Florian Frank ◽

Hanno Ulmer ◽

Victoria Sidoroff ◽

Gregor Broessner

Keyword(s):

Systematic Review ◽

Monoclonal Antibodies ◽

Botulinum Toxin ◽

Response Rate ◽

Meta Analysis ◽

Botulinum Toxin Type A ◽

Type A ◽

Response Rates ◽

Botulinum Toxin Type ◽

Odds Ratios

Background The approval of monoclonal antibodies for prevention of migraine has revolutionized treatment for patients. Oral preventatives are still considered first line treatments as head-to-head trials comparing them with antibodies are lacking. Methods The main purpose of this study was to provide a comparative overview of the efficacy of three commonly prescribed migraine preventative medication classes. For this systematic review and meta-analysis, we searched the databases CENTRAL, EMBASE, and MEDLINE until 20 March 2020. We included RCTs reporting the 50% response rates for topiramate, Botulinum Toxin Type A and monoclonal antibodies against CGRP(r). Studies were excluded if response rates were not reported, treatment allocation was unclear, or if study quality was insufficient. Primary outcome measure were the 50% response rates. The pooled odds ratios with 95% confidence intervals were calculated with the random effects model. The study was registered at PROSPERO (CRD42020222880). Findings We identified 6552 reports. Thirty-two were eligible for our review. Studies assessing monoclonal antibodies included 13,302 patients and yielded pooled odds ratios for the 50% response rate of 2.30 (CI: 2.11–2.50). Topiramate had an overall effect estimate of 2.70 (CI: 1.97–3.69) with 1989 included patients and Botulinum Toxin Type A achieved 1.28 (CI: 0.98–1. 67) with 2472 patients included. Interpretation Topiramate, botulinum toxin type A and monoclonal antibodies showed higher odds ratios in achieving a 50% response rate compared to placebo. Topiramate numerically demonstrated the greatest effect size but also the highest drop-out rate.

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Predictive and prognostic role of tumour-infiltrating lymphocytes in breast cancer patients with different molecular subtypes: a meta-analysis

BMC Cancer ◽

10.1186/s12885-020-07654-y ◽

2020 ◽

Vol 20 (1) ◽

Author(s):

Zhao-hua Gao ◽

Cun-xin Li ◽

Ming Liu ◽

Jia-yuan Jiang

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Cancer Patients ◽

Predictive Value ◽

Molecular Subtypes ◽

Molecular Subtype ◽

Meta Analysis ◽

Breast Cancer Patients ◽

Tumour Infiltrating Lymphocytes ◽

Infiltrating Lymphocytes

Abstract Background Whether tumour-infiltrating lymphocytes (TILs) play different roles in different molecular subtypes of breast cancer remains unknown. Additionally, their prognostic and predictive value in different molecular subtypes of breast cancer is still controversial. The aim of our meta-analysis was to assess the prognostic and predictive value of TILs in different molecular subtypes of breast cancer by summarizing all relevant studies performing multivariate analysis. Methods PubMed, Embase, EBSCO, ScienceDirect, the Cochrane Database and Web of Science were comprehensively searched (until March 2020). Hazard ratios (HRs), odds ratios (ORs) and their 95% confidence intervals (CIs) were used as effect measures to perform our meta-analysis. A random effect model was used. Stata software, version 15 (2017) (StataCorp, College Station, TX, USA) was used to perform the statistical analysis. Results Thirty-three studies including 18,170 eligible breast cancer patients were analysed. The meta-analysis showed that high TIL expression was significantly associated with increased pathological complete response (pCR) rates after neoadjuvant chemotherapy in patients with the HER2-enriched molecular subtype (OR = 1.137, 95% CI [1.061 ~ 1.218], p < 0.001) and triple-negative breast cancer (TNBC) subtype (OR = 1.120, 95% CI [1.061 ~ 1.182], p < 0.001). However, high TIL expression was not significantly associated with high pCR rates after neoadjuvant chemotherapy in patients with the luminal molecular subtype of breast cancer (OR = 1.154, 95% CI [0.789 ~ 1.690], p = 0.460). We carried out a meta-analysis on the HRs of overall survival (OS) and disease-free survival (DFS) to assess the prognostic value of TILs in breast cancer with different molecular subtypes more deeply. Our meta-analysis confirmed that high TILs were associated with significantly improved DFS in patients with the HER2-enriched molecular subtype [HR = 0.940, 95% CI (0.903 ~ 0.979), p = 0.003] and TNBC molecular subtype [HR = 0.907, 95% CI (0.862 ~ 0.954), p < 0.001]. However, high TILs were not associated with significantly better DFS in patients with the luminal molecular subtype of breast cancer [HR = 0.998, 95% CI (0.977 ~ 1.019), p = 0.840]. Furthermore, the results confirmed that high TILs were significantly related to better OS in patients with the HER2-enriched molecular subtype [HR = 0.910, 95% CI (0.866 ~ 0.957), p < 0.001] and TNBC molecular subtype [HR = 0.869, 95% CI (0.836 ~ 0.904), p < 0.001]. Conversely, the summarized results indicated that high TILs were significantly associated with poor OS in patients with the luminal molecular subtype of breast cancer [HR = 1.077, 95% CI (1.016 ~ 1.141), p = 0.012]. Conclusions Our meta-analysis confirms that high TILs are associated with favourable survival and predicts pCR in breast cancer patients with the TNBC and HER2-enriched molecular subtypes.

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Efficacy of carboplatin-based chemotherapy regimens in patients with bladder cancer in the neoadjuvant setting.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e17001 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e17001-e17001

Author(s):

Hafiz Aslam ◽

Sumera Bukhari ◽

Muhammad Nadeem ◽

Talha Awwal

Keyword(s):

Bladder Cancer ◽

Clinical Trials ◽

Protocol Analysis ◽

Response Rate ◽

Meta Analysis ◽

Pathologic Complete Response ◽

Complete Response ◽

P Value ◽

Clinical Complete Response ◽

Statistical Heterogeneity

e17001 Background: There is paucity of evidence regarding efficacy of neoadjuvant chemotherapy regimens in bladder cancer patients. Radical cystectomy has been standard of care for patients with T2-T4, N0, M0 bladder cancer. However, recent trials have shown better survival rates in patients who underwent neo-adjuvant chemotherapy. Our meta-analysis is based on the data from non-randomized clinical trials on the efficacy of carboplatin based regimens. Methods: We conducted a systematic search of Medline (Pubmed) and Cochrane (from inception through May, 2018). Only published single arm clinical trials, abstracts of single arm clinical trials and data from one randomized trial on efficacy of neoadjuvant Carboplatin based therapies in patients with bladder cancer were included in our meta-analysis. Total of > 70 studies were identified. Studies which were duplicate, included adjuvant therapy, systematic reviews or meta-analysis, trials not based on neoadjuvant therapy were excluded. A random effect model was used to calculate pooled proportions. Studies based on ITT protocol were analyzed separately as well as studies based on per protocol analysis. Comprehensive Meta-Analysis software version 3.0 was used. Results: The pooled proportion of pCR (pathologic complete response) calculated from trials based on ITT analysis was 0.23 (95% CI 0.19 to 0.28, P= 0.000). Tests for statistical heterogeneity was non-significant heterogeneity p-value = 0.79 (I2 = 0 %). The pooled proportion of pCR calculated from trials based on per-protocol analysis was 0.29 (95% CI 0.19 to 0.42, P= 0.002). Tests for statistical heterogeneity show nonsignificant heterogeneity p-value = 0.95 (I2 = 0 %). The pooled proportion of ORR (objective response rate) calculated from trials based on per-protocol analysis was 0.69 (95% CI 0.57 to 0.78, P= 0.001). Tests for statistical heterogeneity showed heterogeneity p-value = 0.203 (I2 = 37.3). The pooled proportion of cCR (clinical Complete response) calculated from trials based on per-protocol analysis was 0.25 (95% CI 0.18 to 0.34, P= 0.000). Tests for statistical heterogeneity did not show heterogeneity p-value = 0.80 (I2 = 0%). The pooled proportion of cPR (clinical Partial Response) calculated from trials based on per-protocol analysis was 0.47 (95% CI 0.39 to 0.56, P= 0.59). Tests for statistical heterogeneity did not show heterogeneity p-value = 0.93 (I2 = 0%). Conclusions: Carboplatin based chemotherapy has shown significant efficacy in terms of over-all response rate, pathologic complete response and clinical complete response.

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Prognostic Value of Circulating Tumour Cells detected with the CellSearch System in Esophageal Cancer Patients: A Systematic Review and Meta-Analysis

10.21203/rs.3.rs-20428/v3 ◽

2020 ◽

Author(s):

Yiding Li ◽

Guiling Wu ◽

Wanli Yang ◽

Xiaoqian Wang ◽

Lili Duan ◽

...

Keyword(s):

Therapeutic Response ◽

Meta Analysis ◽

Prognostic Significance ◽

Pooled Analysis ◽

Clinicopathological Characteristics ◽

Cochrane Library ◽

Cellsearch System ◽

Poor Overall Survival ◽

Response To Chemotherapy ◽

The Cochrane Library

Abstract Background: Esophageal carcinoma (EC) is the seventh-most prevalent tumor in the world, which is still one of the primary causes of tumor-related death. Identifying noteworthy biomarkers for EC is particularly significant in guiding effective treatment. Recently, circulating tumor cells (CTCs) in peripheral blood (PB) were intensively discussed as prognostic markers in patients with EC. However, an ongoing controversy still exists regarding the prognostic significance of CTCs determined by the CellSearch system in EC sufferers. This meta-analysis was designed to approach this topic. Methods: We systematically conducted searches using PubMed, Medline, Web of Science and the Cochrane Library for relevant studies, which were published through February 20, 2020. Using the random-effects model, our study was performed in Review Manager software, with odds ratios (ORs), risk ratios (RRs), hazard ratios (HRs) and 95% confidence intervals (CIs) as the effect values. Results: Totally 7 articles were finally included in this study. For clinicopathological characteristics, the pooled results on TNM stage indicated that the III/IV group had higher rate of CTCs compared with the I/II group (OR=1.36, 95% CI: 0.68-2.71, I2=0%). Incidence of CTCs was higher in patients with T3/T4 stage (OR=2.92, 95% CI: 1.31-6.51, I2=0%) and distant metastasis group (OR=5.18, 95% CI: 2.38-11.25, I2=0%) compared to patients with T1/T2 stage or non-metastatic group. The pooled analysis revealed that CTC positivity detected in EC patients was correlated with poor overall survival (OS) (HR=2.83, 95% CI:1.99-4.03, I2=0%) and relapse-free survival (RFS) (HR=4.71, 95% CI:2.73-8.13, I2=0%). When pooling the estimated RR, a poor therapeutic response to chemoradiotherapy was discovered in patients with CTC positivity (RR=1.99, 95% CI:1.73-2.29, I2=60%). Conclusions: In summary, our meta-analysis demonstrated that CTCs positivity determined by the CellSearch system are correlated with the prognosis of EC patients and might indicate a poor therapeutic response to chemotherapy in EC patients.

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5mC regulator-mediated molecular subtypes depict the hallmarks of the tumor microenvironment and guide precision medicine in bladder cancer

BMC Medicine ◽

10.1186/s12916-021-02163-6 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Jiao Hu ◽

Belaydi Othmane ◽

Anze Yu ◽

Huihuang Li ◽

Zhiyong Cai ◽

...

Keyword(s):

Bladder Cancer ◽

Tumor Microenvironment ◽

Precision Medicine ◽

Molecular Subtypes ◽

Molecular Subtype ◽

Antiangiogenic Therapy ◽

Principal Component ◽

High Sensitivity ◽

Ppar Γ ◽

Low Sensitivity

Abstract Background Depicting the heterogeneity and functional characteristics of the tumor microenvironment (TME) is necessary to achieve precision medicine for bladder cancer (BLCA). Although classical molecular subtypes effectively reflect TME heterogeneity and characteristics, their clinical application is limited by several issues. Methods In this study, we integrated the Xiangya cohort and multiple external BLCA cohorts to develop a novel 5-methylcytosine (5mC) regulator-mediated molecular subtype system and a corresponding quantitative indicator, the 5mC score. Unsupervised clustering was performed to identify novel 5mC regulator-mediated molecular subtypes. The principal component analysis was applied to calculate the 5mC score. Then, we correlated the 5mC clusters (5mC score) with classical molecular subtypes, immunophenotypes, clinical outcomes, and therapeutic opportunities in BLCA. Finally, we performed pancancer analyses on the 5mC score. Results Two 5mC clusters, including 5mC cluster 1 and cluster 2, were identified. These novel 5mC clusters (5mC score) could accurately predict classical molecular subtypes, immunophenotypes, prognosis, and therapeutic opportunities of BLCA. 5mC cluster 1 (high 5mC score) indicated a luminal subtype and noninflamed phenotype, characterized by lower anticancer immunity but better prognosis. Moreover, 5mC cluster 1 (high 5mC score) predicted low sensitivity to cancer immunotherapy, neoadjuvant chemotherapy, and radiotherapy, but high sensitivity to antiangiogenic therapy and targeted therapies, such as blocking the β-catenin, FGFR3, and PPAR-γ pathways. Conclusions The novel 5mC regulator-based subtype system reflects many aspects of BLCA biology and provides new insights into precision medicine in BLCA. Furthermore, the 5mC score may be a generalizable predictor of immunotherapy response and prognosis in pancancers.

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Prognostic Value of Circulating Tumour Cells detected with the CellSearch System in Esophageal Cancer Patients: A Systematic Review and Meta-Analysis

10.21203/rs.3.rs-20428/v1 ◽

2020 ◽

Author(s):

Yiding Li ◽

Guiling Wu ◽

Wanli Yang ◽

Xiaoqian Wang ◽

Lili Duan ◽

...

Keyword(s):

Therapeutic Response ◽

Meta Analysis ◽

Prognostic Significance ◽

Pooled Analysis ◽

Tumour Cells ◽

Cochrane Library ◽

Circulating Tumour Cells ◽

Cellsearch System ◽

Poor Overall Survival ◽

Response To Chemotherapy

Abstract Background: Esophageal carcinoma (EC) is the seventh-most prevalent tumour in the world, which is still the primary cause of tumour-related death. Identifying noteworthy biomarkers for EC is particularly significant in guiding active and effective treatment. Recently, circulating tumour cells (CTCs) in peripheral blood (PB) were intensively discussed as prognostic markers in patients with EC. However, an ongoing controversy still exists regarding the prognostic significance of CTCs determined using the CellSearch System in EC sufferers. This meta-analysis was designed to approach this topic. Methods: We systematically conducted searches using PubMed, Medline, Web of Science and the Cochrane Library for relevant studies, which were published through February 20, 2020. Using the random-effects model, our study was performed in Review Manager software, with odds ratios (ORs), risk ratios (RRs), hazard ratios (HRs) and 95% confidence intervals (CIs) as effect values. Results: In total, 7 articles were finally included in this study. For clinicopathological characteristics, the pooled results on TNM stage indicated that the III/IV group had higher incidence of CTCs compared with the I/II group (OR=1.36, 95% CI (0.68,2.71), I2=0%). Incidence of CTCs was higher among patients on T3/T4 stage (OR=2.92, 95% CI (1.31,6.51), I2=0%) and distant metastasis group (OR=5.18, 95% CI (2.38,11.25), I2=0%) compared to patients on T1/T2 stage or non-metastatic group. The pooled analysis revealed that CTC positivity detected in EC patients was correlated with poor overall survival (OS) (HR =2.83, 95% CI (1.99,4.03), I2=0%) and relapse-free survival (RFS) (HR =4.71, 95% CI (2.73,8.13), I2=0%). When pooling the estimated RR, a poor therapeutic response to chemoradiotherapy was discovered in patients with CTC positivity (RR =1.99, 95% CI (1.73,2.29), I2=60%). Conclusions: In summary, our meta-analysis demonstrated that CTCs from PB of EC patients determined using the CellSearch System are correlated with the prognosis of EC patients and might indicate a poor therapeutic response to chemotherapy in EC patients.

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Defining muscle-invasive bladder cancer immunotypes by introducing tumor mutation burden, CD8+ T cells, and molecular subtypes

Hereditas ◽

10.1186/s41065-020-00165-7 ◽

2021 ◽

Vol 158 (1) ◽

Author(s):

Zihao Chen ◽

Guojun Liu ◽

Guoqing Liu ◽

Mikhail A. Bolkov ◽

Khyber Shinwari ◽

...

Keyword(s):

Bladder Cancer ◽

T Cells ◽

Signaling Pathway ◽

Cd8 T Cells ◽

Molecular Subtypes ◽

Molecular Subtype ◽

Muscle Invasive Bladder Cancer ◽

Tumor Mutation Burden ◽

Mutation Burden ◽

Muscle Invasive

AbstractImmunotherapy, especially anti-PD-1, is becoming a pillar of modern muscle-invasive bladder cancer (MIBC) treatment. However, the objective response rates (ORR) are relatively low due to the lack of precise biomarkers to select patients. Herein, the molecular subtype, tumor mutation burden (TMB), and CD8+ T cells were calculated by the gene expression and mutation profiles of MIBC patients. MIBC immunotypes were constructed using clustering analysis based on tumor mutation burden, CD8+ T cells, and molecular subtypes. Mutated genes, enriched functional KEGG pathways and GO terms, and co-expressed network-specific hub genes have been identified. We demonstrated that ORR of immunotype A patients identified by molecular subtype, CD8+ T cells, and TMB is about 36% predictable. PIK3CA, RB1, FGFR3, KMT2C, MACF1, RYR2, and EP300 are differentially mutated among three immunotypes. Pathways such as ECM-receptor interaction, PI3K-Akt signaling pathway, and TGF-beta signaling pathway are top-ranked in enrichment analysis. Low expression of ACTA2 was associated with the MIBC survival benefit. The current study constructs a model that could identify suitable MIBC patients for immunotherapy, and it is an important step forward to the personalized treatment of bladder cancers.

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Gene expression subtype and p53 mutational status are correlated among neoadjuvantly treated breast cancers in UNC LCCC9819 and I-SPY1 (CALGB 150007/ACRIN 6657)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.10048 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 10048-10048

Author(s):

L. A. Carey ◽

D. Oh ◽

L. Sawyer ◽

S. Edmiston ◽

D. Tolbert ◽

...

Keyword(s):

Mutation Analysis ◽

Molecular Subtypes ◽

Molecular Subtype ◽

P53 Mutation ◽

Missense Mutations ◽

P53 Mutations ◽

Luminal A ◽

Cell Cycle Protein ◽

Mutational Status ◽

Response To Chemotherapy

10048 Background: LCCC9819 and I-SPY1 are designed to examine multiple potential predictive markers and assays simultaneously in biopsies from neoadjuvantly treated patients. Both p53 mutation status and molecular ‘intrinsic‘ subtype have been associated with chemosensitivity. In this preliminary analysis, we present the p53 mutation spectra by molecular subtype from patients enrolled in the combined LCCC 9819 and I-SPY1 datasets. Methods: Patients received neoadjuvant anthracycline-based chemotherapy with pre-therapy biopsies. p53 mutation analysis was performed by p53 GeneChip assay for point mutations/1 bp deletions followed by SSCP if GeneChip-negative. Abnormal GeneChip or SSCP were confirmed by sequencing. DNA microarrays used Agilent human microarrays and a common reference strategy approach. Results: 51 patients were treated on LCCC9819 and have available molecular analyses; 87 from I-SPY1. 111 patients have completed p53 mutation analysis, revealing a high proportion (42%) with abnormal p53. Of these, several were in known hotspots, including R175H (4 mutations), R248L (1), R273H (3), and R273C (2). Most were missense mutations (81%), however, there were 8 (17%) null and 1 (2%) silent mutations. Most (91%) mutations were in the DNA binding domain. Molecular subtypes are known on 111 tumors: 22% Luminal A, 22% Luminal B, 3% Normal-like, 23% HER2+/ER−, 27% Basal-like, and 3% unclassified. Among those with both assays complete, we found that p53 mutations differed by subtype (Table). Conclusions: P53 mutations are common in these independent neoadjuvant datasets, and differ in frequency between molecular subtypes, which may have implications for predictive factor identification. Future analyses will include aCGH, cell cycle protein analysis, proteomics, and clinical data including response to chemotherapy. (supported by UNC Breast SPORE-CA58223, NIH M01RR00046, DAMD 17–02–1-0521). [Table: see text] No significant financial relationships to disclose.

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Molecular subtyping of colorectal cancer to identify a mesenchymal tumor type that might benefit from TGF-beta pathway inhibition.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.456 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 456-456 ◽

Cited By ~ 2

Author(s):

Ramon Salazar ◽

Paul Roepman ◽

Stefan M. Willems ◽

Diede Brunen ◽

Udo Kellner ◽

...

Keyword(s):

Colorectal Cancer ◽

Cellular Proliferation ◽

Molecular Subtypes ◽

Molecular Subtype ◽

Tumor Type ◽

Tgf Beta ◽

Chemotherapy Treatment ◽

Treatment Benefit ◽

Mesenchymal Transition ◽

Response To Chemotherapy

456 Background: Currently, most colorectal cancer (CRC) patients receive chemotherapy treatment, even though many patients do not benefit. Therefore, a better understanding of the biology is required to identify those patients who will benefit from chemotherapy and to find a more tailored therapy plan for all other patients. Methods: A molecular subtype classification was developed using full genome expression data of 188 stage I-IV CRC patients and validated in 543 stage II and III patients. Subtypes were correlated to clinical factors, prognosis and treatment benefit (stage III). To determine whether TGF-β signaling is elevated in the tumors, 78 patient biopsies were analyzed for p-SMAD2/3 expression using immunohistochemistry. To analyze the effect of TGF-β activation, we studied the effects of MED12 suppression in SKCO-1 CRC cells under treatment with Cisplatin, Oxaliplatin or 5-FU. Results: We developed a diagnostic test that allows the classification of colorectal cancer tumors into different intrinsic molecular subtypes (A-, B-, C-type). The heterogeneity of these subtypes is largely based on 3 biological hallmarks of the tumor: an epithelial-to-mesenchymal transition, deficiency in mismatch repair genes resulting in a high mutation frequency associated with MSI, and cellular proliferation. Especially the C-type (~15% of CRC tumors) is of clinical interest, as C-type patients have the worst outcome, a mesenchymal phenotype and show no benefit from chemotherapy treatment in our patient set or a public dataset. The C-type subgroup has elevated TGF-β signaling, as shown by TGF-beta and TGF-beta receptor over-expression (TGFB1, p=0.0012; TGFBR1, p=0.0005) and increased phopho-SMAD2/3 staining in the tumor cells (1.9-fold, p=0.0002). In cell line experiments, we show that up-regulation of TGF-β signaling by MED12 knockdown resulted in resistance against chemotherapy by preventing apoptosis. Conclusions: The molecular subtypes differ largely in prognosis and response to chemotherapy. A treatment strategy combining standard drugs with agents suppressing TGF-β signaling might benefit C-type patients.

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Muscle invasive bladder cancer (MIBC) demonstrates neoadjuvant cisplatin-based chemotherapy (NAC) related changes in molecular subtype and immune infiltration.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.7_suppl.443 ◽

2019 ◽

Vol 37 (7_suppl) ◽

pp. 443-443

Author(s):

Samuel Aaron Funt ◽

Alexander Solovyov ◽

Bishoy Morris Faltas ◽

Gopa Iyer ◽

Mariel Elena Boyd ◽

...

Keyword(s):

Bladder Cancer ◽

Bladder Tumor ◽

Molecular Subtypes ◽

Molecular Subtype ◽

Expression Patterns ◽

The Cancer Genome Atlas ◽

Rna Expression ◽

Cancer Therapies ◽

Primary Bladder ◽

Muscle Invasive

443 Background: Defining the role of MIBC molecular subtypes and immune expression in determining clinical outcomes is an area of active investigation. However, changes in these transcriptomic profiles pre- and post-NAC have not been well characterized. Methods: This retrospective study reviewed 53 pts with MIBC treated with NAC, of whom 12 pts without complete pathological response had both pre- and post-NAC samples of sufficient quality. Post-NAC staging was > = pT2 in 11 pts and pT1 in 1 pt. We performed RNA expression analysis of matched pre-NAC transurethral resection of bladder tumor specimens and post-treatment radical cystectomy primary bladder tumor specimens. We used a customized NanoString panel incorporating previously reported immune signatures (Ayers, JCI 2017; O’Donnell, ASCO 2017) and additional genes to assign basal ( CD14, CD44, PDGFC, KRT14, KRT5) and luminal ( GATA3, PPARG, SHH, CD24, FOXA1, WNT7B, ERBB2) molecular subtypes. Results: We first classified the bladder cancer cohort of The Cancer Genome Atlas into basal and luminal subtypes using the BASE47 signature (Damrauer, PNAS 2014) and the NanoString panel and there was good agreement (Rand Index = 0.72). We then assigned subtypes using the NanoString panel on matched pre- and post-NAC samples and found marked subtype shift (Table). We identified two robust clusters of samples according to immune expression with a 3-fold change of immune expression between them (FDR = 0.0008). We found that 4 pts switched from the low to the high cluster, while 2 switched from the high to the low cluster after NAC (Table). Conclusions: MIBC molecular subtype membership is dynamic and is influenced by NAC. NAC can induce both enhanced and suppressed immune activity. These findings have implications on future studies exploring the predictive value of RNA expression patterns for bladder cancer therapies as well as post-NAC immunotherapy. [Table: see text]

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