Association of positive Ki-67 and PD-L1 expressions in post neoadjvuant chemotherapy (NAC) radical cystectomy samples with lack of tumor downstaging (TD) and shorter overall survival (OS) in patients with muscle-invasive bladder cancer (MIBC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 554-554
Author(s):  
Selene Rubino ◽  
Wade J. Sexton ◽  
Youngchul Kim ◽  
Junmin Zhou ◽  
Jasreman Dhilon ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Cox Regression ◽  
Unmet Need ◽  
Predictive Biomarker ◽  
Complete Response ◽  
Tissue Microarrays ◽  
Rank Test ◽  
Cancer Center ◽  
Ki 67

554 Background: Previous chart review studies have reported that adjuvant chemotherapy after NAC did not clearly increase OS in MIBC cases characterized by a lack of TD. There is an unmet need to develop biomarkers to guide adjuvant therapy for this patient population. High levels of expression of cell proliferation marker Ki-67 are associated with poor outcome in chemotherapy naïve bladder cancer. Expression of PD-L1 has been studied as a potential predictive biomarker for anti-PD1 or PD-L1 therapies in metastatic MIBC. We therefore studied Ki-67 and PD-L1 expression in post NAC radical cystectomy samples at Moffitt Cancer Center and correlate them with TD and OS. Methods: Tissue microarrays (TMAs) were constructed from 116 post NAC cystectomy samples. The expressions of Ki-67 were evaluated with immunohistochemistry (IHC) and considered positive if any of the cores per sample were stained positive for Ki-67. The Dako 22C3 assay was used for PD-L1 IHC and the combined positive score of 10 or above was considered positive for PD-L1. Results: The median survival of this cohort of 116 patients was 33.4 months (range: 1.13 -127 months). 40 patients (35%) had TD and 21 patients (18%) achieved pathological complete response. Using Cox regression for OS, positive Ki-67 expression in post NAC radical cystectomy sample was associated with poorer OS (hazard ratio=2.412, 95% CI:1.076-5.408, p=0.033), independent of the pathological N stage. Patients with Ki67/PD-L1 double-negative tumors had a significantly longer median OS of 98.2 months versus 29.9 and 26.9 months in PD-L1-/Ki67+ and PD-L1+/Ki67+ tumors respectively (Log-rank test, p=0.0361). Lack of TD was significantly associated with positive Ki-67 (P<0.001) and positive PD-L1 (p=0.003) in the post NAC samples with a multi-variable logistic regression model. Conclusions: Positive Ki-67 and PD-L1 expressions in post NAC radical cystectomy samples were associated with inferior OS and absence of TD. Adjuvant anti-PD1 therapy either alone or in combination with chemotherapy would be indicated for this subset of patients.

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

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1784 ◽  
Author(s):  
Albert Font ◽  
Montserrat Domènech ◽  
Raquel Benítez ◽  
Marta Rava ◽  
Miriam Marqués ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Cox Regression ◽  
Progression Free Survival ◽  
Complete Response ◽  
Tissue Microarrays ◽  
Tumor Subtypes ◽  
Significant Survival ◽  
Taxonomical Classification ◽  
Muscle Invasive

Background: Platinum-based neoadjuvant chemotherapy (NAC) increases the survival of patients with organ-confined urothelial bladder cancer (UBC). In retrospective studies, patients with basal/squamous (BASQ)-like tumors present with more advanced disease and have worse prognosis. Transcriptomics-defined tumor subtypes are associated with response to NAC. Aim: To investigate whether immunohistochemical (IHC) subtyping predicts NAC response. Methods: Patients with muscle-invasive UBC having received platinum-based NAC were identified. Tissue microarrays were used to type tumors for KRT5/6, KRT14, GATA3, and FOXA1. Outcomes: progression-free survival and disease-specific survival; univariable and multivariate Cox regression models were applied. Results: We found a very high concordance between mRNA and protein expression. Using IHC-based hierarchical clustering, we classified 126 tumors in three subgroups: 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). Applying multivariable analyses, patients with BASQ-like tumors were more likely to achieve a pathological response to NAC (OR 3.96; p = 0.017). The clinical benefit appeared reflected in the lack of significant survival differences between patients with BASQ-like and luminal tumors. Conclusions: Patients with BASQ-like tumors—identified through simple and robust IHC—have a higher likelihood of undergoing a pathological complete response to NAC. Prospective validation is required.

Usefulness of assessment of circulating tumor DNA(ctDNA) of cerebrospinal fluid(CSF) samples for early detection of brain metastasis (BrM) in patients with triple-negative breast cancer (TNBC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 507-507
Author(s):  
Lucrezia Raimondi ◽  
Giuseppe Naso ◽  
Rachele Lazzeroni ◽  
Laura Di Benedetto ◽  
Filippo Maria Raimondi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cox Regression ◽  
Predictive Biomarker ◽  
Complete Response ◽  
Circulating Tumor Dna ◽  
Additional Treatment ◽  
Rank Test ◽  
Exact Test ◽  
Log Rank Test ◽  
Response To Chemotherapy

507 Background: Despite improvements in treatments, patients diagnosed with TNBC still have poor prognosis for a higher tendency of developing BrM. Identifying patients at high risk of BrM, enabling to predict who will take advantage from appropriate additional treatment, remains a critical problem. ctDNA represents a valuable tool associated with the outcome and the aggressiveness of breast cancer but no prognostic and predictive biomarker has been identified to predict the development of BrM in TNBC. We studied the usefulness of assessment of CSF-ctDNA for early identification of the risk of BrM in TNBC. Methods: Between January 2016 and December 2020, 323 newly diagnosed non-metastatic TNBC patients who underwent neoadjuvant therapy+surgery(NACT) with complete response(CR)were prospectively enrolled. After surgery, samples of CSF measuring ctDNA were obtained from all patients: CSF-ctDNA was extracted with the QIAamp Circulating Nucleic Acid Kit (Qiagen, Valencia, CA, USA) and ctDNA levels were measured. Survival curves were estimated using the Kaplan-Meier method and compared with the Log-rank test. Multivariate Cox regression was used to identify the risk of mortality at three years. Results: After NACT, CSF-ctDNA was detectable in 126/323 (39%) patients, 101/126 (80%) were diagnosed at III stage. 124 of 126 (98.4%) ctDNA+ patients subsequently developed BrM. In contrast, only 2 (2/197, 1%) ctDNA- patients subsequently developed BrM and the 195 other patients remain in a CR (p < 0.001, Fisher's exact test). CSF-ctDNA did associate with PFS and OS: undetectable ctDNA was associated with superior PFS (HR 0.3; p = 0.002) and OS (HR 0.2; p < 0.01), indicating survival is largely determined by the onset of BrM. With a median follow-up of 3 years, median PFS of ctDNA+ vs ctDNA- patients was 13 months vs not reach, p = 0.004 (by Log-rank test). Median OS for ctDNA+ vs ctDNA- patients was 16 months after NACT vs not reach, p = 0.0016 (by Log-rank test). At multivariate analysis detectable CSF-ctDNA emerged as the best predictor of the develop of BrM and 24-month mortality (HR:3.62; p < 0.0001). Age, stage, Ki67% and response to chemotherapy were not significantly associated with the prognosis. Conclusions: After NACT, detectable CSF-ctDNA significantly associates with PFS and OS, identifying early at-risk patients to develop BrM in TNBC.

scholarly journals Expression of E-cadherin, Ki-67, and p53 in urinary bladder cancer in relation to progression, survival, and recurrence

2020 ◽  
Vol 64 (2) ◽  
Author(s):  
Stanislav Ziaran ◽  
Stefan Harsanyi ◽  
Katarina Bevizova ◽  
Zuzana Varchulova Novakova ◽  
Branislav Trebaticky ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Urinary Bladder ◽  
Cox Regression ◽  
Urinary Bladder Cancer ◽  
Rank Test ◽  
Ki 67 ◽  
Free Survival ◽  
Log Rank Test ◽  
Kaplan Meier ◽  
E Cadherin

Although the incidence varies with age and gender, urothelial bladder cancer is a relatively frequently occurring malignancy with variable clinical behavior that often has high recurrence rates. In this study, we analyzed the tumor tissues of 224 patients with pTa, pT1, and pT2 urinary bladder cancer. We performed a histomorphologic analysis and immunohistochemistry for p53, Ki-67, and E-cadherin, which were selected as markers of the malignant process. For pTa and pT1, univariate analyses of cancer-specific survival (CSS), progression-free survival (PFS), and recurrence-free survival (RFS) were calculated using the Kaplan-Meier method, the log-rank test and Cox regression. Multivariate analysis was performed by a Cox regression analysis. Ki-67 (P<0.001) was significantly associated with CSS, but the highest association was shown for E-cadherin (P<0.001). For pT1 and pTa, the Kaplan-Meier analysis and the log-rank test revealed significantly worse PFS for patients with higher levels of Ki-67 (P<0.001) and lower levels of E-cadherin (P<0.001). Based on these obtained results, it can be clearly stated that Ki-67 and E-cadherin expression levels are associated with CSS, PFS and RFS. The clinical utility of these markers is valuable for pTa and pT1 urinary bladder cancer and should be further verified with prospective multi-center trials.

Perioperative blood transfusion and postoperative outcomes in patients undergoing radical cystectomy for bladder cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17012-e17012
Author(s):  
Leonidas Nikolaos Diamantopoulos ◽  
Rishi Robert Sekar ◽  
Ali Raza Khaki ◽  
Natalie Miller ◽  
Adam John Gadzinski ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Blood Transfusion ◽  
Radical Cystectomy ◽  
Cox Regression ◽  
Performance Status ◽  
Length Of Hospital Stay ◽  
Postoperative Outcomes ◽  
Red Blood Cell Transfusion ◽  
Rank Test ◽  
Perioperative Blood Transfusion

e17012 Background: Perioperative blood transfusion (PBT) has been associated with worse outcomes in surgical oncology across tumor types. We report our institutional experience of postoperative outcomes related to PBT utilization, in patients (pts) with bladder cancer (BC) treated with radical cystectomy (RC). We hypothesized that PBT is associated with worse clinical outcomes. Methods: Pts with BC treated with RC were retrospectively identified. Clinicopathologic and peri/post-operative data were extracted. PBT was defined as red blood cell transfusion during RC or postoperative hospitalization. Overall survival (OS, diagnosis to death) and recurrence free survival (RFS, RC to recurrence/death) were estimated with the KM method. T-test, χ2 and log-rank test were used for group comparison analysis. Univariate/multivariate logistic (LR) and Cox regression (CR) were used to identify variables associated with dependent dichotomous outcomes and OS/RFS, respectively. Results: 784 consecutive pts (78% men; median age 67) were identified. At least one post-operative complication (POC) occurred in 407 (52%) pts; most common were pyelonephritis and sepsis (11% each). PBT was administered to 238 pts (30%). Those with PBT had a higher proportion of POCs (35% vs 28%, p = .02). Median follow-up, OS and RFS were 66 (95% CI: 60 - 72), 94 (95% CI: 79 - 109) and 66 months (95% CI: 50 – 82), respectively. Pts who received PBT had shorter OS (51 vs 130 months, p < .001) and RFS (27 vs 86 months, p < .001). In multivariate LR and CR, PBT was independently associated with higher odds of POCs (OR 1.5, 95% CI: 1.03 – 2.2, p = .03), length of hospital stay (LOS) > 10 days (OR 2.0, 95% CI 1.1 – 3.5, p = .02), shorter OS (HR 1.6, 95% CI 1.2-2.0, p = .001), and RFS (HR 1.5, 95% CI 1.2 - 1.9, p = .001), after adjustment for other relevant clinicopathologic variables (age, gender, performance status, neoadjuvant chemotherapy, baseline hemoglobin, open/robotic approach, pT/N stage, surgical margins, lymphovascular invasion at RC, variant histologies). Conclusions: Pts who received PBT had higher odds of POC, longer LOS and poor outcomes after RC. This is hypothesis-generating due to inherent study limitations. Further studies are needed to validate this finding, explain underlying mechanisms and explore putative interventions to improve outcomes.

scholarly journals Myosteatosis as a novel prognostic biomarker after radical cystectomy for bladder cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Shimpei Yamashita ◽  
Yuya Iwahashi ◽  
Haruka Miyai ◽  
Takashi Iguchi ◽  
Hiroyuki Koike ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Cox Regression ◽  
Group Performance ◽  
Performance Status ◽  
Eastern Cooperative Oncology Group ◽  
Psoas Muscle ◽  
Hounsfield Units ◽  
Computed Tomography Images ◽  
Psoas Muscles

AbstractThis study aims to evaluate the influence of myosteatosis on survival of patients after radical cystectomy (RC) for bladder cancer. We retrospectively identified 230 patients who underwent RC for bladder cancer at our three institutions between 2009 and 2018. Digitized free-hand outlines of the left and right psoas muscles were made on axial non-contrast computed tomography images at level L3. To assess myosteatosis, average total psoas density (ATPD) in Hounsfield Units (HU) was also calculated as an average of bilateral psoas muscle density. We compared cancer-specific survival (CSS) between high ATPD and low ATPD groups and performed cox regression hazard analyses to identify the predictors of CSS. Median ATPD was 44 HU (quartile: 39–47 Hounsfield Units). Two-year CSS rate in overall patients was 76.6%. Patients with low ATPD (< 44 HU) had significantly lower CSS rate (P = 0.01) than patients with high ATPD (≥ 44 HU). According to multivariate analysis, significant independent predictors of poor CSS were: Eastern Cooperative Oncology Group performance status ≥ 1 (P = 0.03), decreasing ATPD (P = 0.03), non-urothelial carcinoma (P = 0.01), pT ≥ 3 (P < 0.01), and pN positive (P < 0.01). In conclusion, myosteatosis (low ATPD) could be a novel predictor of prognosis after RC for bladder cancer.

Exploratory circulating biomarker analyses: lenvatinib + pembrolizumab (L + P) in a phase 1b trial in unresectable hepatocellular carcinoma (uHCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4084-4084
Author(s):  
Andrew X. Zhu ◽  
Josep M Llovet ◽  
Masahiro Kobayashi ◽  
Masafumi Ikeda ◽  
Marc Pracht ◽  
...  
Keyword(s):  
Cox Regression ◽  
Objective Response ◽  
Rank Correlation ◽  
Study Drug ◽  
Complete Response ◽  
Rank Test ◽  
Cox Regression Analysis ◽  
Clinical Endpoints ◽  
Spearman’S Rank Correlation ◽  
Phase 1B

4084 Background: In a phase 1b trial (NCT03006926), L + P had promising antitumor activity as first-line (1L) therapy in uHCC. We present exploratory biomarker analyses of circulating angiogenic factors and cytokines/chemokines related to the mechanism of action of L + P (ie, pharmacodynamic [PD] biomarkers), as well as biomarker correlations with clinical outcomes in patients (pts) with uHCC, from this trial. Methods: Pts received lenvatinib 12 mg/d (bodyweight [BW] >60 kg) or 8 mg/d (BW < 60 kg) PO + pembrolizumab 200 mg IV Q3W. Tumors were assessed using mRECIST or RECIST v1.1 per independent imaging review. Peripheral blood samples were collected before administration of study drug at baseline, cycle (C) 2, day (D) 1, C3D1, C4D1, and off-treatment. 43 Biomarkers were assayed in serum from 100 1L uHCC pts (excluding 4 pts from the dose-limiting toxicity part of the trial with prior sorafenib). Of these 43, 31 biomarkers (for which ≤20% of samples had measurements above/below the quantification limit of the assay) were included in the analyses. Changes in biomarker levels from baseline were evaluated via 1-sample Wilcoxon signed-rank test. Associations were explored between changes in biomarker levels and maximum tumor shrinkage (MTS) via the Spearman’s rank correlation test, objective response (OR; complete response + partial response) via the Wilcoxon rank sum test, and PFS via Cox regression analysis and log rank test. Data cutoff date for clinical endpoints was 7 August 2020. Results: Levels of PD biomarkers related to angiogenic signaling (VEGF increase/ANG2 decrease), FGF signaling (increase in FGF23/FGF19), and IFNγ signaling (increase in IFNγ, CXCL9/10/11) were changed significantly (adjusted P< 0.05) with L + P (C2D1–C4D1; except for FGF19 at C3D1). Significant decreases of TIMP1 and increases of MCP1 were observed at C4D1 during treatment; these were associated with greater MTS. Greater decreases in TIMP1 and greater increases in MCP1 were observed in pts with OR vs others. Changes in levels of the PD biomarkers ANG2, IL10, and VEGFR2 were found to be associated with PFS by dichotomized analysis. With tertile 2 cutoff, median PFS for pts in the group with greater decreases of ANG2 was 13.9 months vs 9.6 months for pts in the group with lesser decreases of ANG2 (unadjusted P= 0.002; HR 2.65, 95% CI 1.39–5.08). Conclusions: These are the first exploratory biomarker analyses for the single-arm study of L + P in pts with uHCC. Changes in serum biomarkers associated with angiogenic-, FGF-, and IFNγ-signaling pathways indicated target engagement of L + P. Decreases in TIMP1 and increases in MCP1 were associated with MTS and OR. Associations were found between longer PFS and a greater decrease in levels of ANG2. Angiogenesis inhibition and modulation of cancer immune response were observed with L + P. Further validation from independent studies is warranted. Clinical trial information: NCT03006926.

scholarly journals Combination of C-Reactive Protein and Neutrophil-to-Lymphocyte Ratio as a Novel Prognostic Index in Patients With Bladder Cancer After Radical Cystectomy

2021 ◽  
Vol 11 ◽  
Author(s):  
Yidi Wang ◽  
Keyi Wang ◽  
Jinliang Ni ◽  
Houliang Zhang ◽  
Lei Yin ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Radical Cystectomy ◽  
Cox Regression ◽  
Roc Curves ◽  
Neutrophil To Lymphocyte Ratio ◽  
Postoperative Survival ◽  
C Reactive Protein ◽  
Lymphocyte Ratio ◽  
Reactive Protein ◽  
T Stage

BackgroundInflammation is widely considered an important hallmark of cancer and associated with poor postoperative survival. The objective of this study is to assess the significance of preoperative C-NLR, a new inflammation-based index that includes preoperative C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR), on therapeutic outcomes for bladder cancer (BC) patients after radical cystectomy (RC).Materials and MethodsBC patients who underwent RC between 2010 and 2019 were retrospectively analyzed from our medical center. The predictive effect of CRP, NLR, and C-NLR on the survival of BC patients were analyzed by the receiver operating characteristic (ROC) curves. The relationship between C-NLR and postoperative survival was investigated by Cox regression. The corresponding nomograms were built based on the Cox regression results of overall survival (OS) and disease-free survival (DFS), which were further validated by ROC curves, decision curve analysis (DCA) curves, and calibration curves.ResultsOf the 199 eligible patients, 83 (41.70%) were classified as high C-NLR group and the remaining 116 (58.30%) were classified as low C-NLR group. ROC analysis showed that C-NLR had the largest area under curve (AUC) compared to CRP and NLR. Multivariate analysis revealed that T-stage and C-NLR [high C-NLR vs. low C-NLR, hazard ratio (HR) = 2.478, 95% confidence interval (CI), 1.538–3.993, p &lt; 0.001] were independent predictors of OS, whereas T-stage, M-stage, and C-NLR (high C-NLR vs. low C-NLR, HR = 2.817, 95% CI, 1.667–4.762, p &lt; 0.001) were independent predictors of DFS. ROC and DCA analysis demonstrated better accuracy and discrimination of 3- and 5-year OS and DFS with C-NLR-based nomogram compared to TNM stage. The calibration curve reconfirmed the accurate predicting performance of nomograms.ConclusionC-NLR is a reliable predictor of long-term prognosis of BC patients after RC and will contribute to the optimization of individual therapy for BC patients.

Prognostic utility of the combination of pretreatment monocyte-to-lymphocyte ratio and neutrophil-to-lymphocyte ratio in patients with NMIBC after transurethral resection

2019 ◽  
Vol 13 (18) ◽  
pp. 1543-1555
Author(s):  
Qinghai Wang ◽  
Tao Huang ◽  
Jianlei Ji ◽  
Hongyang Wang ◽  
Chen Guo ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Transurethral Resection ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Predictive Biomarker ◽  
Neutrophil To Lymphocyte Ratio ◽  
Invasive Bladder Cancer ◽  
Lymphocyte Ratio ◽  
Prognostic Utility ◽  
Nonmuscle Invasive Bladder Cancer

Aim: To investigate and validate predictive value of combination of pretreatment monocyte-to-lymphocyte ratio (MLR) and neutrophil-to-lymphocyte ratio (NLR) for disease free survival (DFS) and overall survival (OS) in nonmuscle invasive bladder cancer after transurethral resection. Materials & methods: Total 358 patients enrolled were assigned into three (MLR-NLR 0, 1 and 2) groups per the cut-off values of MLR and NLR. Results: Kaplan–Meier curves showed MLR, NLR and their combination were statistically associated with DFS (p < 0.001) and OS (p < 0.001). Univariate and multivariate COX regression analyses revealed that combination of MLR with NLR was an independent prognostic predictor for both DFS (HR: 3.080; 95% CI: 1.870–5.074; p < 0.001 for MLR-NLR 2 vs MLR-NLR 0) and OS (HR: 2.815; 95% CI: 1.778–4.456; p < 0.001 for MLR-NLR 2 vs MLR-NLR 0). Calibration plots and decision curve analysis exhibited combination of MLR and NLR had good calibration accuracy with potential clinical usefulness. Conclusion: Combined MLR and NLR is a prognostic predictive biomarker in nonmuscle invasive bladder cancer after transurethral resection.

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