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Predictive biomarkers for Muscle Invasive Bladder Cancer; the search for the holy grail continues.A Choudhury, P HoskinPatients diagnosed with muscle invasive bladder cancer (MIBC) suitable for radical treatment have an unenviable choice between radical cystectomy with a neobladder or urostomy, or trimodality therapy (TMT) based on maximal TURBT followed by radical radiotherapy given with a radiosensitiser, usually chemotherapy, and cystoscopic surveillance. The available evidence shows no advantage for one or other approach in terms of survival outcomes ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1200/JCO.2016.69.2327","ISSN":"15277755","PMID":"28410011","abstract":"Purpose Multidisciplinary management improves complex treatment decision making in cancer care, but its impact for bladder cancer (BC) has not been documented. Although radical cystectomy (RC) currently is viewed as the standard of care for muscle-invasive bladder cancer (MIBC), radiotherapy-based, bladder-sparing trimodal therapy (TMT) that combines transurethral resection of bladder tumor, chemotherapy for radiation sensitization, and external beam radiotherapy has emerged as a valid treatment option. In the absence of randomized studies, this study compared the oncologic outcomes between patients treated with RC or TMT by using a propensity score matched-cohort analysis. Methods Data from patients treated in a multidisciplinary bladder cancer clinic (MDBCC) from 2008 to 2013 were reviewed retrospectively. Those who received TMT for MIBC were identified and matched (for sex, cT and cN stage, Eastern Cooperative Oncology Group status, Charlson comorbidity score, treatment date, age, carcinoma in situ status, and hydronephrosis) with propensity scores to patients who underwent RC. Overall survival and disease-specific survival (DSS) were assessed with Cox proportional hazards modeling and a competing risk analysis, respectively. Results A total of 112 patients with MIBC were included after matching (56 who had been treated with TMT, and 56 who underwent RC). The median age was 68.0 years, and 29.5% had stage cT3/cT4 disease. At a median follow-up of 4.51 years, there were 20 deaths (35.7%) in the RC group (13 as a result of BC) and 22 deaths (39.3%) in the TMT group (13 as a result of BC). The 5-year DSS rate was 73.2% and 76.6% in the RC and TMT groups, respectively ( P = .49). Salvage cystectomy was performed in 6 (10.7%) of 56 patients who received TMT. Conclusion In the setting of a MDBCC, TMT yielded survival outcomes similar to those of matched patients who underwent RC. Appropriately selected patients with MIBC should be offered the opportunity to discuss various treatment options, including organ-sparing TMT.","author":[{"dropping-particle":"","family":"Kulkarni","given":"Girish S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hermanns","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Wei","given":"Yanliang","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bhindi","given":"Bimal","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Satkunasivam","given":"Raj","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Athanasopoulos","given":"Paul","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bostrom","given":"Peter J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Li","given":"Kathy","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Templeton","given":"Arnoud J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sridhar","given":"Srikala S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chung","given":"Peter","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bristow","given":"Robert G.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Milosevic","given":"Michael","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Warde","given":"Padraig","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Fleshner","given":"Neil E.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Jewett","given":"Michael A.S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bashir","given":"Shaheena","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zlotta","given":"Alexandre R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kuk","given":"Cynthia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zlotta","given":"Alexandre R.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kwast","given":"Theodorus H.","non-dropping-particle":"Van Der","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-1","issue":"20","issued":{"date-parts":[["2017"]]},"page":"2299-2305","title":"Propensity score analysis of radical cystectomy versus bladder-sparing trimodal therapy in the setting of a multidisciplinary bladder cancer clinic","type":"paper-conference","volume":"35"},"uris":[""]},{"id":"ITEM-2","itemData":{"DOI":"10.1200/JCO.2014.57.5548","ISBN":"0732-183X","ISSN":"15277755","PMID":"25366678","abstract":"PURPOSE: Multiple prospective Radiation Therapy Oncology Group (RTOG) protocols have evaluated bladder-preserving combined-modality therapy (CMT) for muscle-invasive bladder cancer (MIBC), reserving cystectomy for salvage treatment. We performed a pooled analysis of long-term outcomes in patients with MIBC enrolled across multiple studies.\\n\\nPATIENTS AND METHODS: Four hundred sixty-eight patients with MIBC were enrolled onto six RTOG bladder-preservation studies, including five phase II studies (RTOG 8802, 9506, 9706, 9906, and 0233) and one phase III study (RTOG 8903). Overall survival (OS) was estimated using the Kaplan-Meier method, and disease-specific survival (DSS), muscle-invasive and non-muscle-invasive local failure (LF), and distant metastasis (DM) were estimated by the cumulative incidence method.\\n\\nRESULTS: The median age of patients was 66 years (range, 34 to 93 years), and clinical T stage was T2 in 61%, T3 in 35%, and T4a in 4% of patients. Complete response to CMT was documented in 69% of patients. With a median follow-up of 4.3 years among all patients and 7.8 years among survivors (n = 205), the 5- and 10-year OS rates were 57% and 36%, respectively, and the 5- and 10-year DSS rates were 71% and 65%, respectively. The 5- and 10-year estimates of muscle-invasive LF, non-muscle-invasive LF, and DM were 13% and 14%, 31% and 36%, and 31% and 35%, respectively.\\n\\nCONCLUSION: This pooled analysis of multicenter, prospective RTOG bladder-preserving CMT protocols demonstrates long-term DSS comparable to modern immediate cystectomy studies, for patients with similarly staged MIBC. Given the low incidence of late recurrences with long-term follow-up, CMT can be considered as an alternative to radical cystectomy, especially in elderly patients not well suited for surgery.","author":[{"dropping-particle":"","family":"Mak","given":"Raymond H.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hunt","given":"Daniel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Shipley","given":"William U.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Efstathiou","given":"Jason A.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Tester","given":"William J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hagan","given":"Michael P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kaufman","given":"Donald S.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Heney","given":"Niall M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zietman","given":"Anthony L.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Journal of Clinical Oncology","id":"ITEM-2","issue":"34","issued":{"date-parts":[["2014"]]},"page":"3801-3809","title":"Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: A pooled analysis of radiation therapy oncology group protocols 8802, 8903, 9506, 9706, 9906, and 0233","type":"article-journal","volume":"32"},"uris":[""]}],"mendeley":{"formattedCitation":"^1,2","plainTextFormattedCitation":"1,2","previouslyFormattedCitation":"^1,2"},"properties":{"noteIndex":0},"schema":""}1,2. Toxicity and patient experience differ greatly and the choice is currently made on patient and clinician perception and preference, with many still regarding non-surgical treatment as less effective in the face of contrary evidence. Against this background the prospect of a robust, readily available biomarker to aid patient selection is a highly attractive proposition. Biomarkers for bladder cancer have a long history with decades of publications of small retrospective cohorts identifying yet another biomarker. Few have undergone rigorous clinical validation and there is no biomarker in routine clinical practice to stratify patients for TMT or surgery. The paper by the Boston group published in this issue of European Urology ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"author":[{"dropping-particle":"du","family":"J.A. Efstathiou, K.W. Mouw, E.A. Gibb, Y. Liu, C.-L. Wu, M.R. Drumm, J.B. da Costa","given":"M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Plessis, N.Q. Wang, E. Davicioni, F.Y. Feng, R. Seiler, P.C. Black, W.U. Shipley","given":"D.T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Miyamoto","given":"","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"European Urology","id":"ITEM-1","issued":{"date-parts":[["2019"]]},"title":"Impact of Immune and Stromal Infiltration on Outcomes Following Bladder-sparing Trimodality Therapy for Muscle-invasive Bladder Cancer","type":"article-journal"},"uris":[""]}],"mendeley":{"formattedCitation":"³","plainTextFormattedCitation":"3","previouslyFormattedCitation":"⁴"},"properties":{"noteIndex":0},"schema":""}3 describes yet another approach by identifying differing immune profiles predicting for prognosis in MIBC. Immunotherapy has long been important in the management of high grade non-muscle invasive bladder cancer (NIMBC) and carcinoma in situ (CIS) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ctrv.2017.01.007","ISSN":"03057372","PMID":"28214651","abstract":"The treatment of bladder cancer has evolved over time to encompass not only the traditional modalities of chemotherapy and surgery, but has been particularly impacted by the use of immunotherapy. The first immunotherapy was the live, attenuated bacterial Bacillus Calmette-Guérin vaccine, which has been the standard of care non-muscle-invasive bladder cancer since 1990. Modern immunotherapy has focused on inhibitors of checkpoint proteins, which are molecules that impede immune function, thereby allowing tumor cells to grow and proliferate unregulated. Several checkpoint targets (programmed death ligand-1 [PD-L1] programmed cell death protien-1 [PD-1], and cytotoxic T-lymphocyte associated protein 4 [CTLA4]) have received the most attention in the treatment of bladder cancer, and have inhibitor agents either approved or in late-stage development. This review describes the most recent data on agents that inhibit PD-L1, found on the surface of tumor cells, and PD-1 found on activated T and B cells and macrophages. Atezolizumab is the only member of this class currently approved for the treatment of bladder cancer, but nivolumab, pembrolizumab, durvalumab, and avelumab all have positive results for this indication, and approvals are anticipated in the near future. The checkpoint inhibitors offer an effective alternative for patients for whom previously there were few options for durable responses, including those who are ineligible for cisplatin-based regimens or who are at risk of significant toxicity. Research is ongoing to further categorize responses, define ideal patient populations, and investigate combinations of checkpoint inhibitors to address multiple pathways in immune system functioning.","author":[{"dropping-particle":"","family":"Bellmunt","given":"Joaquin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Powles","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vogelzang","given":"Nicholas J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer Treatment Reviews","id":"ITEM-1","issued":{"date-parts":[["2017","3"]]},"page":"58-67","title":"A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now","type":"article-journal","volume":"54"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴","plainTextFormattedCitation":"4","previouslyFormattedCitation":"⁵"},"properties":{"noteIndex":0},"schema":""}4. However, the last few years have seen a revolution in the management of metastatic solid tumours with the recognition that checkpoint inhibitors, molecules that themselves inhibit immune function enabling proliferation of tumour cells, have significant activity. In bladder cancer the most promising results are with drugs targeting the programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PDL-1). Proof of principle has been demonstrated in trials showing significant gains in metastatic bladder cancer with atezolizumab, nivolumab and pembrolizumab ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1016/j.ctrv.2017.01.007","ISSN":"03057372","PMID":"28214651","abstract":"The treatment of bladder cancer has evolved over time to encompass not only the traditional modalities of chemotherapy and surgery, but has been particularly impacted by the use of immunotherapy. The first immunotherapy was the live, attenuated bacterial Bacillus Calmette-Guérin vaccine, which has been the standard of care non-muscle-invasive bladder cancer since 1990. Modern immunotherapy has focused on inhibitors of checkpoint proteins, which are molecules that impede immune function, thereby allowing tumor cells to grow and proliferate unregulated. Several checkpoint targets (programmed death ligand-1 [PD-L1] programmed cell death protien-1 [PD-1], and cytotoxic T-lymphocyte associated protein 4 [CTLA4]) have received the most attention in the treatment of bladder cancer, and have inhibitor agents either approved or in late-stage development. This review describes the most recent data on agents that inhibit PD-L1, found on the surface of tumor cells, and PD-1 found on activated T and B cells and macrophages. Atezolizumab is the only member of this class currently approved for the treatment of bladder cancer, but nivolumab, pembrolizumab, durvalumab, and avelumab all have positive results for this indication, and approvals are anticipated in the near future. The checkpoint inhibitors offer an effective alternative for patients for whom previously there were few options for durable responses, including those who are ineligible for cisplatin-based regimens or who are at risk of significant toxicity. Research is ongoing to further categorize responses, define ideal patient populations, and investigate combinations of checkpoint inhibitors to address multiple pathways in immune system functioning.","author":[{"dropping-particle":"","family":"Bellmunt","given":"Joaquin","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Powles","given":"Thomas","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Vogelzang","given":"Nicholas J.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Cancer Treatment Reviews","id":"ITEM-1","issued":{"date-parts":[["2017","3"]]},"page":"58-67","title":"A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now","type":"article-journal","volume":"54"},"uris":[""]}],"mendeley":{"formattedCitation":"⁴","plainTextFormattedCitation":"4","previouslyFormattedCitation":"⁵"},"properties":{"noteIndex":0},"schema":""}4. Attempts to relate the activity of the immune system to prognosis in MIBC are not new. Absolute lymphocyte count, a simple surrogate for immune response, has been shown to associate with survival in a cohort of patients receiving bladder conserving therapy ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1093/annonc/mdv546","ISSN":"0923-7534","PMID":"26578732","abstract":"BACKGROUND Pre-treatment lymphocytopaenia may result from cytokines secreted by the tumour microenvironment in association with aggressive tumour biology. We sought to establish the prognostic significance of lymphocytopaenia in muscle-invasive and advanced bladder cancer. PATIENTS AND METHODS Seventy-four patients with muscle-invasive bladder cancer treated with radical chemoradiotherapy and 131 patients with advanced bladder cancer treated with palliative chemotherapy were included in the study. The absolute lymphocyte count on the first day of treatment was recorded. Invasive local or systemic recurrence in the muscle-invasive bladder cancer cohort and all-cause mortality in the advanced bladder cancer cohort were defined as survival end points. Receiver operating characteristic (ROC) curve analysis was utilized to determine the cut-off for defining lymphocytopaenia in the muscle-invasive bladder cancer cohort followed by multivariable analysis in a model evaluating the following variables: anaemia, neutrophilia, tumour stage, hydronephrosis and neoadjuvant chemotherapy. Subsequently, lymphocytopaenia was assessed in a multivariable model of the advanced bladder cancer cohort analysing the following prognostic variables: neutrophilia, anaemia, performance status and presence of bone or visceral metastases. A further analysis was carried out evaluating absolute lymphocyte count as a continuous variable. RESULTS An absolute lymphocyte count of 1.5 × 10(9)/l was determined as the cut-off on ROC curve analysis in the muscle-invasive bladder cancer cohort, and multivariate analysis revealed that only lymphocytopaenia was predictive for inferior outcome in this cohort. In the advanced bladder cancer cohort, lymphocytopaenia [hazard ratio (HR) 1.6, 95% confidence interval (CI) 1.1-2.4; P = 0.02] and performance status (HR 1.7, 95% CI 1.0-2.7; P = 0.047) were adverse prognostic factors in the binary variable multivariate model. Absolute lymphocyte count was the sole significant factor when analysed as a continuous variable (HR 0.66, 95% CI 0.5-0.87; P = 0.003). CONCLUSION Pre-treatment lymphocytopaenia is an independent adverse prognostic factor in both muscle-invasive and advanced bladder cancer. It may be a manifestation of cancer-induced immune suppression driving tumour progression.","author":[{"dropping-particle":"","family":"Joseph","given":"N.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dovedi","given":"S. J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Thompson","given":"C.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lyons","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Kennedy","given":"J.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Elliott","given":"T.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"West","given":"C. M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Choudhury","given":"A.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Annals of Oncology","id":"ITEM-1","issue":"2","issued":{"date-parts":[["2016","2"]]},"page":"294-299","title":"Pre-treatment lymphocytopaenia is an adverse prognostic biomarker in muscle-invasive and advanced bladder cancer","type":"article-journal","volume":"27"},"uris":[""]}],"mendeley":{"formattedCitation":"⁵","plainTextFormattedCitation":"5","previouslyFormattedCitation":"⁶"},"properties":{"noteIndex":0},"schema":""}5. In a series of 72 patients treated with TMT, overexpression of PD-L1 was both independently associated with loco-regional relapse and prognostic for both disease-specific (DSS) and overall survival (OS) ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/srep19740","ISSN":"2045-2322","PMID":"26804478","abstract":"Identification of potential factors that can stratify a tumor's response to specific therapies will aid in the selection of cancer therapy. The aim was to highlight the role of programmed cell death 1 ligand 1 (PD-L1) in bladder cancer. In this study, 92 of muscle-invasive bladder cancers and 28 of non-muscle invasive bladder cancers were selected for immunohistochemical staining analysis. Furthermore, human and murine bladder cancer cell lines were used to examine the correlation between PD-L1 and radiation response. Our data revealed that PD-L1 was overexpressed in the bladder tumor specimens compared with adjacent non-malignant specimens. Furthermore, the staining of PD-L1 was significantly linked to higher clinical stage, lower complete response rates and reduced disease-free survival rates. By in vitro and in vivo experiments, irradiation up-regulated the expression of PD-L1 in tumor cells, and its increase correlated with the irradiation dose. In immunocompetent mouse models, blocking PD-L1 induced a longer tumour growth delay following irradiation. The inhibition of T cell functions including proliferation and cytotoxicity against tumor cells was responsible to the effects of PD-L1 on radiation response. In conclusion, PD-L1 could be a significant clinical predictor for clinical stage and treatment response of bladder cancer.","author":[{"dropping-particle":"","family":"Wu","given":"Chun-Te","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Wen-Cheng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Ying-Hsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lin","given":"Wei-Yu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Miao-Fen","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016","4","25"]]},"page":"19740","title":"The role of PD-L1 in the radiation response and clinical outcome for bladder cancer","type":"article-journal","volume":"6"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁷"},"properties":{"noteIndex":0},"schema":""}6. Preclinical data showed that in vitro irradiation of urothelial cancer cells increased PD-L1 expression whilst radioresistance of in vivo bladder cancer models could be reversed by anti-PD-L1 drugs ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/srep19740","ISSN":"2045-2322","PMID":"26804478","abstract":"Identification of potential factors that can stratify a tumor's response to specific therapies will aid in the selection of cancer therapy. The aim was to highlight the role of programmed cell death 1 ligand 1 (PD-L1) in bladder cancer. In this study, 92 of muscle-invasive bladder cancers and 28 of non-muscle invasive bladder cancers were selected for immunohistochemical staining analysis. Furthermore, human and murine bladder cancer cell lines were used to examine the correlation between PD-L1 and radiation response. Our data revealed that PD-L1 was overexpressed in the bladder tumor specimens compared with adjacent non-malignant specimens. Furthermore, the staining of PD-L1 was significantly linked to higher clinical stage, lower complete response rates and reduced disease-free survival rates. By in vitro and in vivo experiments, irradiation up-regulated the expression of PD-L1 in tumor cells, and its increase correlated with the irradiation dose. In immunocompetent mouse models, blocking PD-L1 induced a longer tumour growth delay following irradiation. The inhibition of T cell functions including proliferation and cytotoxicity against tumor cells was responsible to the effects of PD-L1 on radiation response. In conclusion, PD-L1 could be a significant clinical predictor for clinical stage and treatment response of bladder cancer.","author":[{"dropping-particle":"","family":"Wu","given":"Chun-Te","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Wen-Cheng","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chang","given":"Ying-Hsu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Lin","given":"Wei-Yu","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chen","given":"Miao-Fen","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Scientific Reports","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2016","4","25"]]},"page":"19740","title":"The role of PD-L1 in the radiation response and clinical outcome for bladder cancer","type":"article-journal","volume":"6"},"uris":[""]}],"mendeley":{"formattedCitation":"⁶","plainTextFormattedCitation":"6","previouslyFormattedCitation":"⁷"},"properties":{"noteIndex":0},"schema":""}6. It is therefore rational to explore potential biomarkers of immune response in bladder cancer based on the preclinical evidence of association between radiation response and immune activity within the tumour. Efstathiou and colleagues have chosen to evaluate tumour and stromal infiltrates by measuring whole transcriptome gene expression profiling in two retrospective cohorts, the first comprising 475 patients receiving TMT from a single institution and the second 223 patients undergoing radical cystectomy (RC) with neoadjuvant chemotherapy (NAC). Mature follow up data was available censored for both cohorts at five years. Ultimately whole transcriptome expression profiles were available for only 136 TMT patients and 223NAC:RC patients. The reasons for the substantial drop out rate from the TMT cohort are not given but raise concern over selection bias, conscious or unconscious. The authors acknowledge that the TMT and NAC:RC cohorts are unbalanced with a higher median age, a larger proportion of males, and lower T stages in the TMT cohort. Gene profiling allowed classification by molecular subtypes: luminal, luminal-infiltrated, basal, and claudin-low. Whilst others have shown worse outcome with luminal subtype this was not seen in the TMT cohort. In the NAC:RC cohort, DSS was worse in the claudin-low tumours. This subgroup has been shown to have an inferior response to NAC:RC which may be of relevance. Two signatures exploring immune infiltration were analysed reflecting CD8 T-cell infiltrate and interferon (IFN) gene expression. Both showed a positive association with DSS in the TMT group, independent of molecular subtype but no association was seen in the NAC:RC cohort. However when a multivariate model including clinical prognostic factors was undertaken only IFN gene expression remained an independent factor for DSS in the TMT cohort. This analysis divided gene expression into quartiles and compared the lower quartile with the rest rather than a simple dichotomisation of the data. It is not clear what exploratory analyses were undertaken with regard to the chosen cut off or whether this was defined a priori.Stromal infiltration was assessed using a predefined gene signature comprising nine genes commonly expressed in fibroblasts or myofibroblasts. Once again the expression levels were divided into quartiles but on this occasion the upper quartile is compared with the rest. The reasons for this difference compared to the immune profiles is not clear. Stromal infiltration expression was not associated with outcome in the TMT cohort but a high stromal infiltration expression was associated with worse DSS and OS in the NAC:RC group (N = 16).This is not the first report of a relationship between T-cell infiltration, stromal cell activity and outcome in MIBC. A study using The Cancer Genome Atlas (TCGA) urothelial cancer dataset comprising 408 samples from radical cystectomy explored the association between tumour-infiltrating T-cell abundance (ITA) and epithelial–mesenchymal transition (EMT)-related gene expression and outcome ADDIN CSL_CITATION {"citationItems":[{"id":"ITEM-1","itemData":{"DOI":"10.1038/s41467-018-05992-x","ISSN":"2041-1723","PMID":"30158554","abstract":"Cancers infiltrated with T-cells are associated with a higher likelihood of response to PD-1/PD-L1 blockade. Counterintuitively, a correlation between epithelial-mesenchymal transition (EMT)-related gene expression and T-cell infiltration has been observed across tumor types. Here we demonstrate, using The Cancer Genome Atlas (TCGA)?urothelial cancer dataset, that although a gene expression-based measure of infiltrating T-cell abundance and EMT-related gene expression are positively correlated, these signatures convey disparate prognostic information. We further demonstrate that non-hematopoietic stromal cells are a major source of EMT-related gene expression in bulk urothelial cancer transcriptomes. Finally, using a cohort of patients with metastatic urothelial cancer treated with a PD-1 inhibitor, nivolumab, we demonstrate that in patients with T-cell infiltrated tumors, higher EMT/stroma-related gene expression is associated with lower response rates and shorter progression-free and overall survival. Together, our findings suggest a stroma-mediated source of immune resistance in urothelial cancer and provide rationale for co-targeting PD-1 and stromal elements.","author":[{"dropping-particle":"","family":"Wang","given":"Li","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Saci","given":"Abdel","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Szabo","given":"Peter M.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Chasalow","given":"Scott D.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Castillo-Martin","given":"Mireia","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Domingo-Domenech","given":"Josep","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Siefker-Radtke","given":"Arlene","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sharma","given":"Padmanee","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Sfakianos","given":"John P.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Gong","given":"Yixuan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Dominguez-Andres","given":"Ana","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Oh","given":"William K.","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Mulholland","given":"David","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Azrilevich","given":"Alex","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Hu","given":"Liangyuan","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Cordon-Cardo","given":"Carlos","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Salmon","given":"Hélène","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Bhardwaj","given":"Nina","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Zhu","given":"Jun","non-dropping-particle":"","parse-names":false,"suffix":""},{"dropping-particle":"","family":"Galsky","given":"Matthew D.","non-dropping-particle":"","parse-names":false,"suffix":""}],"container-title":"Nature Communications","id":"ITEM-1","issue":"1","issued":{"date-parts":[["2018","12","29"]]},"page":"3503","title":"EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer","type":"article-journal","volume":"9"},"uris":[""]}],"mendeley":{"formattedCitation":"⁷","plainTextFormattedCitation":"7","previouslyFormattedCitation":"⁸"},"properties":{"noteIndex":0},"schema":""}7. EMT has been associated with an enhanced capacity for invasion and metastases and, in this study predicted a worse OS. Whilst ITA alone did not predict outcome, when combined with EMT gene expression, a highly significant prognostic biomarker was defined, good prognosis being associated with high ITA, low EMT and poor prognosis with low ITA and high EMT in both the TCGA dataset and a dataset from the CheckMate 275 trial of nivolumab in metastatic bladder cancer.Clearly there is a complex association between immune activity in the tumour microenvironment and prognosis in bladder cancer. In principle immune activation imparts a better outcome whilst stromal gene activity can be adverse. However despite the sophisticated use of gene expression profiles neither the Boston study nor the TCGA study have shown a positive impact of gene expression reflecting T-cell infiltration in either TMT or cystectomy cohorts. It is of course unlikely that a single gene expression parameter will be the biomarker which is so sorely needed in the clinical setting. The TCGA group performed the more rigorous study by moving towards the use of a panel of genes reflecting both good and poor prognosis. It is unfortunate that the Boston group have not analysed by combining T-cell, IFN and stromal signatures. To have validated the TCGA signatures would have been a step forward and would have been a first in patients treated with TMT. Unfortunately as it stands this paper does not move the field forward or change practice, but adds to the number of small retrospective cohort studies awaiting further validation. References ADDIN Mendeley Bibliography CSL_BIBLIOGRAPHY 1. Kulkarni GS, Hermanns T, Wei Y, et al. Propensity score analysis of radical cystectomy versus bladder-sparing trimodal therapy in the setting of a multidisciplinary bladder cancer clinic. In: Journal of Clinical Oncology. Vol 35. ; 2017:2299-2305. doi:10.1200/JCO.2016.69.23272. Mak RH, Hunt D, Shipley WU, et al. Long-term outcomes in patients with muscle-invasive bladder cancer after selective bladder-preserving combined-modality therapy: A pooled analysis of radiation therapy oncology group protocols 8802, 8903, 9506, 9706, 9906, and 0233. J Clin Oncol. 2014;32(34):3801-3809. doi:10.1200/JCO.2014.57.55483. J.A. Efstathiou, K.W. Mouw, E.A. Gibb, Y. Liu, C.-L. Wu, M.R. Drumm, J.B. da Costa M du, Plessis, N.Q. Wang, E. Davicioni, F.Y. Feng, R. Seiler, P.C. Black, W.U. Shipley DT, Miyamoto. Impact of Immune and Stromal Infiltration on Outcomes Following Bladder-sparing Trimodality Therapy for Muscle-invasive Bladder Cancer. Eur Urol. 2019.4. Bellmunt J, Powles T, Vogelzang NJ. A review on the evolution of PD-1/PD-L1 immunotherapy for bladder cancer: The future is now. Cancer Treat Rev. 2017;54:58-67. doi:10.1016/j.ctrv.2017.01.0075. Joseph N, Dovedi SJ, Thompson C, et al. Pre-treatment lymphocytopaenia is an adverse prognostic biomarker in muscle-invasive and advanced bladder cancer. Ann Oncol. 2016;27(2):294-299. doi:10.1093/annonc/mdv5466. Wu C-T, Chen W-C, Chang Y-H, Lin W-Y, Chen M-F. The role of PD-L1 in the radiation response and clinical outcome for bladder cancer. Sci Rep. 2016;6(1):19740. doi:10.1038/srep197407. Wang L, Saci A, Szabo PM, et al. EMT- and stroma-related gene expression and resistance to PD-1 blockade in urothelial cancer. Nat Commun. 2018;9(1):3503. doi:10.1038/s41467-018-05992-x ................
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