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Identification and validation of a prognostic 4 genes signature for hepatocellular carcinoma: Integrated ceRNA network analysis
abstracts
Annals of Oncology Legal entity responsible for the study: The authors. Funding: Ministry of Education, Culture, Sports, Science and Technology, Japan. Disclosure: Y. Ohmori: Full / Part-time employment: Astellas Pharma Inc.
157P
Identification and validation of a prognostic 4 genes signature for hepatocellular carcinoma: Integrated ceRNA network analysis
Background: Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, with a poor long-term prognosis worldwide. The functional deregulations of global transcriptome were associated with the genesis and development of HCC. However, reliable molecular signatures predicting overall survival (OS) lacks of systematic research and validation. Methods: A total of 519 postoperative HCC patients were included. We built an interactive and visual competing endogenous RNA (ceRNA) network from The Cancer Genome Atlas (TCGA) database. The prognostic signature was established with the least absolute shrinkage and selection operator (LASSO) algorithm. Multivariate Cox regression analysis and subgroup analysis was used to screen for independent prognostic factors. A time-dependent ROC curve analysis was performed to compare predictive value of the prognostic signature. The robustness of the prognostic signature was validated in validation cohorts. Results: There were 39 differentially expressed mRNAs (DEmRNAs), 83 differentially expressed lncRNAs and 20 differentially expressed miRNAs involved in the ceRNA network. Twenty DEmRNAs were found to be significantly associated with OS. We identified a 4-gene signature (PBK, CBX2, CLSPN and CPEB3) using LASSO regression in the training set. Patients in the high-score group exhibited worse survival than those in the low-score group (HR ¼ 2.444, P ¼ 0.0004), and median OS was significantly shorter in the high-score group than in the low-score group (1005 days versus 2456 days). The 4-gene signature was an independent prognostic factor in multivariate Cox regression and subgroup analysis, particularly for patients with serum AFP 20 ng/ml. The results were validated in internal validation set (P ¼ 0.0057) and two external validation cohorts (HR ¼ 1.505 and 2.626). The signature (AUCs of one, two, three years were 0.716, 0.726, 0.714, respectively) showed high prognostic accuracy. Conclusions: We constructed a novel lncRNA-miRNA-mRNA ceRNA network for HCC based on genome-wide analysis. Then we identified a 4-gene signature as a new candidate therapeutic decision marker that yields great promise in the prediction of HCC OS. Legal entity responsible for the study: Sun Yat-Sen University. Funding: National Natural Science Foundation of China. Disclosure: All authors have declared no conflicts of interest.
158P
Plasma KIM-1 is associated with clinical outcomes after resection for localized renal cell carcinoma: A trial of the ECOG-ACRIN Research Group (E2805)
W. Xu1, M. Puligandla2, N.B. Haas3, K.T. Flaherty4, R.G. Uzzo5, V. Sabbisetti6, J.J. Dutcher7, R.S. DiPaola8, R.S. Bhatt1 1 Medical Oncology, Beth Israel Deaconess Med. Center, Boston, MA, USA, 2Statistics, ECOG-ACRIN Biostatistics Center, Boston, MA, USA, 3Hematology Oncology, University of Pennsylvania/Abramson Cancer Center, Philadelphia, PA, USA, 4Hematology/ Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 5 Urologic Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA, 6Pathology, Brigham and Women’s Hospital, Boston, MA, USA, 7Renal Sub-committee, Cancer Research Foundation, Chappaqua, NY, USA, 8Medical Oncology, University of Kentucky, Lexington, MA, USA Background: There is currently no circulating biomarker for renal cell carcinoma (RCC). The use of adjuvant sunitinib for RCC after nephrectomy is controversial, and a biomarker could help to select the patients at highest risk for recurrence. Kidney injury molecule-1 (KIM-1) is overexpressed in RCC and its ectodomain can be detected in circulating plasma. We therefore investigated whether KIM-1 is associated with worse outcomes in patients with localized RCC after nephrectomy. Methods: In the ECOG-ACRIN 2805 (ASSURE) trial, 1943 patients with resected highrisk RCC were randomized 1:1:1 to sunitinib, sorafenib, or placebo. Post-nephrectomy baseline samples from 182 randomly selected patients (9.4% of the study population) was available for this post-hoc biomarker analysis. Samples were analyzed using a previously validated microbead-based assay. Kaplan-Meier and Cox proportional hazards
Volume 30 | Supplement 5 | October 2019
Clovis Oncology; Officer / Board of Directors: Strata Oncology; Officer / Board of Directors: Vivid Biosciences; Advisory / Consultancy, Corporate Advisory Board: X4 Pharmaceuticals; Advisory / Consultancy, Corporate Advisory Board: PIC Therapeutics; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Amgen; Advisory / Consultancy: Asana; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Fount; Advisory / Consultancy: Aeglea; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: Shattuck Labs; Advisory / Consultancy: Arch Oncology; Advisory / Consultancy: Tolero; Advisory / Consultancy: Apricity; Advisory / Consultancy: Oncoceutics; Advisory / Consultancy: Fog Pharma; Advisory / Consultancy, Checkmate, Boston Biomedical, Pierre Fabre, Cell Medica, and Debiopharm.: Others; Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy: Tvardi; Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck; Advisory / Consultancy: Takeda; Advisory / Consultancy: Verastem. V. Sabbisetti: Non-remunerated activity/ies, Patents on blood KIM-1 is a diagnostic, prognostic and predictive biomarker of RCC: Other. All other authors have declared no conflicts of interest.
159P
Prognostic immunoprofiling of muscle invasive bladder cancer (MIBC) patients in a multicentre setting
K. Nekolla1, N. Brieu1, C.G. Gavriel2, M. Widmaier1, A. Budco1, D. Medrikova1, I. Kanchev1, M. Testori1, J. Chan1, P. Dundee3, P. Anderson3, N. Lawrentschuk4, L.-M. Wong5, P. Phan6, P. Gibbs6, D.J. Harrison2, M. Baehner1, P.D. Caie2, B. Tran6, G. Schmidt1 1 R&D, Definiens AG, Munich, Germany, 2School of Medicine, University of St Andrews, St Andrews, UK, 3Department of Urology, Royal Melbourne Hospital, Parkville, Australia, 4 Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia, 5Department of Urology, St Vincent’s Hospital Melbourne, Fitzroy, Australia, 6 Division of Personalised Oncology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia Background: Introduction of checkpoint inhibitors (anti PD-1/PD-L1) have resulted in improved survival for bladder cancer patients, however, only a subset will benefit. The utility of PD-L1 expression as a prognostic or predictive biomarker is limited, motivating the search for more robust biomarkers. Here, we examined the prognostic value of densities of PD-L1, CD3, CD8 or CD68 positive cells and studied the reproducibility of the findings across two patient cohorts in a multi-assay and multicentre setting. Methods: MIBC specimens (T stage 2/3) from two patient cohorts collected at Melbourne, Australia (n ¼ 39) and University of St Andrews, UK (n ¼ 63) were studied. Two consecutive slides were stained with a brightfield immunohistochemistry or an immunofluorescence assay in the first and second cohorts, respectively. The densities of positive cells within the tumour core were determined using assay-specific image analysis algorithms. Within each cohort, the prognostic value of each cell density was assessed using univariate and multivariate Cox regression including age, T stage, N stage and adjuvant chemotherapy as covariates. Results: The Melbourne cohort is slightly older, with a poorer prognosis and a higher proportion of N2/N3 disease compared to the St Andrews cohort. Univariate and multivariate analyses identified the density of CD8 positive cells as an important prognostic factor across both cohorts (p < 0.05). PD-L1 is significant in the St Andrews cohort and trends towards significance (p < 0.1) in the Melbourne cohort, whilst the reverse is seen with CD3. The significance level of CD68 cannot be reproduced across cohorts. Cohort statistics, hazard ratios and p values from univariate and multivariate survival analysis. .p < 0.1, *p<0.05, **p<0.01
doi:10.1093/annonc/mdz239 | v49
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz239.065/5577709 by guest on 24 October 2019
Y. Yan, K. Mao, P. Huang, J. Wang, Z. Xiao Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
models were used to test for association between circulating KIM-1 and disease free survival (DFS) as well as overall survival (OS). ROC analysis was performed to evaluate test characteristics for KIM-1 in predicting RCC recurrence within 6 months after nephrectomy. Results: Higher KIM-1 levels were associated with worse DFS and OS after nephrectomy. This association remained independently significant after controlling for pathologic stage, sarcomatoid features, and Fuhrman grade (DFS: HR 1.20 per log increase in KIM-1, 95% CI 1.09-1.33, p < 0.001; OS: HR 1.27 per log increase in KIM-1, 95% CI 1.11-1.45, p < 0.001). These associations were independent of treatment arm. In Kaplan-Meier analysis using KIM-1 quartiles, higher quartiles of KIM-1 were associated with worse DFS and OS (log-rank p ¼ 0.02 for both). Post-nephrectomy KIM-1 was a prognostic marker for disease recurrence within 6 months after nephrectomy (AUC 0.85). Conclusions: Elevated plasma KIM-1 is associated with worse DFS and OS in patients with resected RCC, and therefore has potential as an adjuvant biomarker. Analysis of larger cohorts to confirm this association is underway. Clinical trial identification: NCT00326898. Legal entity responsible for the study: ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs). Funding: National Cancer Institute of the National Institutes of Health under the following award numbers: CA180820, CA180794, CA180867, CA189859. Disclosure: K.T. Flaherty: Officer / Board of Directors: Loxo Oncology; Officer / Board of Directors:
Annals of Oncology Legal entity responsible for the study: The authors. Funding: Ministry of Education, Culture, Sports, Science and Technology, Japan. Disclosure: Y. Ohmori: Full / Part-time employment: Astellas Pharma Inc.
157P
Identification and validation of a prognostic 4 genes signature for hepatocellular carcinoma: Integrated ceRNA network analysis
Background: Hepatocellular carcinoma (HCC) is one of the most aggressive malignant tumors, with a poor long-term prognosis worldwide. The functional deregulations of global transcriptome were associated with the genesis and development of HCC. However, reliable molecular signatures predicting overall survival (OS) lacks of systematic research and validation. Methods: A total of 519 postoperative HCC patients were included. We built an interactive and visual competing endogenous RNA (ceRNA) network from The Cancer Genome Atlas (TCGA) database. The prognostic signature was established with the least absolute shrinkage and selection operator (LASSO) algorithm. Multivariate Cox regression analysis and subgroup analysis was used to screen for independent prognostic factors. A time-dependent ROC curve analysis was performed to compare predictive value of the prognostic signature. The robustness of the prognostic signature was validated in validation cohorts. Results: There were 39 differentially expressed mRNAs (DEmRNAs), 83 differentially expressed lncRNAs and 20 differentially expressed miRNAs involved in the ceRNA network. Twenty DEmRNAs were found to be significantly associated with OS. We identified a 4-gene signature (PBK, CBX2, CLSPN and CPEB3) using LASSO regression in the training set. Patients in the high-score group exhibited worse survival than those in the low-score group (HR ¼ 2.444, P ¼ 0.0004), and median OS was significantly shorter in the high-score group than in the low-score group (1005 days versus 2456 days). The 4-gene signature was an independent prognostic factor in multivariate Cox regression and subgroup analysis, particularly for patients with serum AFP 20 ng/ml. The results were validated in internal validation set (P ¼ 0.0057) and two external validation cohorts (HR ¼ 1.505 and 2.626). The signature (AUCs of one, two, three years were 0.716, 0.726, 0.714, respectively) showed high prognostic accuracy. Conclusions: We constructed a novel lncRNA-miRNA-mRNA ceRNA network for HCC based on genome-wide analysis. Then we identified a 4-gene signature as a new candidate therapeutic decision marker that yields great promise in the prediction of HCC OS. Legal entity responsible for the study: Sun Yat-Sen University. Funding: National Natural Science Foundation of China. Disclosure: All authors have declared no conflicts of interest.
158P
Plasma KIM-1 is associated with clinical outcomes after resection for localized renal cell carcinoma: A trial of the ECOG-ACRIN Research Group (E2805)
W. Xu1, M. Puligandla2, N.B. Haas3, K.T. Flaherty4, R.G. Uzzo5, V. Sabbisetti6, J.J. Dutcher7, R.S. DiPaola8, R.S. Bhatt1 1 Medical Oncology, Beth Israel Deaconess Med. Center, Boston, MA, USA, 2Statistics, ECOG-ACRIN Biostatistics Center, Boston, MA, USA, 3Hematology Oncology, University of Pennsylvania/Abramson Cancer Center, Philadelphia, PA, USA, 4Hematology/ Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA, 5 Urologic Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA, 6Pathology, Brigham and Women’s Hospital, Boston, MA, USA, 7Renal Sub-committee, Cancer Research Foundation, Chappaqua, NY, USA, 8Medical Oncology, University of Kentucky, Lexington, MA, USA Background: There is currently no circulating biomarker for renal cell carcinoma (RCC). The use of adjuvant sunitinib for RCC after nephrectomy is controversial, and a biomarker could help to select the patients at highest risk for recurrence. Kidney injury molecule-1 (KIM-1) is overexpressed in RCC and its ectodomain can be detected in circulating plasma. We therefore investigated whether KIM-1 is associated with worse outcomes in patients with localized RCC after nephrectomy. Methods: In the ECOG-ACRIN 2805 (ASSURE) trial, 1943 patients with resected highrisk RCC were randomized 1:1:1 to sunitinib, sorafenib, or placebo. Post-nephrectomy baseline samples from 182 randomly selected patients (9.4% of the study population) was available for this post-hoc biomarker analysis. Samples were analyzed using a previously validated microbead-based assay. Kaplan-Meier and Cox proportional hazards
Volume 30 | Supplement 5 | October 2019
Clovis Oncology; Officer / Board of Directors: Strata Oncology; Officer / Board of Directors: Vivid Biosciences; Advisory / Consultancy, Corporate Advisory Board: X4 Pharmaceuticals; Advisory / Consultancy, Corporate Advisory Board: PIC Therapeutics; Advisory / Consultancy: Sanofi; Advisory / Consultancy: Amgen; Advisory / Consultancy: Asana; Advisory / Consultancy: Adaptimmune; Advisory / Consultancy: Fount; Advisory / Consultancy: Aeglea; Advisory / Consultancy: Array BioPharma; Advisory / Consultancy: Shattuck Labs; Advisory / Consultancy: Arch Oncology; Advisory / Consultancy: Tolero; Advisory / Consultancy: Apricity; Advisory / Consultancy: Oncoceutics; Advisory / Consultancy: Fog Pharma; Advisory / Consultancy, Checkmate, Boston Biomedical, Pierre Fabre, Cell Medica, and Debiopharm.: Others; Advisory / Consultancy: Neon Therapeutics; Advisory / Consultancy: Tvardi; Advisory / Consultancy: Novartis; Advisory / Consultancy: Genentech; Advisory / Consultancy: BMS; Advisory / Consultancy: Merck; Advisory / Consultancy: Takeda; Advisory / Consultancy: Verastem. V. Sabbisetti: Non-remunerated activity/ies, Patents on blood KIM-1 is a diagnostic, prognostic and predictive biomarker of RCC: Other. All other authors have declared no conflicts of interest.
159P
Prognostic immunoprofiling of muscle invasive bladder cancer (MIBC) patients in a multicentre setting
K. Nekolla1, N. Brieu1, C.G. Gavriel2, M. Widmaier1, A. Budco1, D. Medrikova1, I. Kanchev1, M. Testori1, J. Chan1, P. Dundee3, P. Anderson3, N. Lawrentschuk4, L.-M. Wong5, P. Phan6, P. Gibbs6, D.J. Harrison2, M. Baehner1, P.D. Caie2, B. Tran6, G. Schmidt1 1 R&D, Definiens AG, Munich, Germany, 2School of Medicine, University of St Andrews, St Andrews, UK, 3Department of Urology, Royal Melbourne Hospital, Parkville, Australia, 4 Department of Surgical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia, 5Department of Urology, St Vincent’s Hospital Melbourne, Fitzroy, Australia, 6 Division of Personalised Oncology, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia Background: Introduction of checkpoint inhibitors (anti PD-1/PD-L1) have resulted in improved survival for bladder cancer patients, however, only a subset will benefit. The utility of PD-L1 expression as a prognostic or predictive biomarker is limited, motivating the search for more robust biomarkers. Here, we examined the prognostic value of densities of PD-L1, CD3, CD8 or CD68 positive cells and studied the reproducibility of the findings across two patient cohorts in a multi-assay and multicentre setting. Methods: MIBC specimens (T stage 2/3) from two patient cohorts collected at Melbourne, Australia (n ¼ 39) and University of St Andrews, UK (n ¼ 63) were studied. Two consecutive slides were stained with a brightfield immunohistochemistry or an immunofluorescence assay in the first and second cohorts, respectively. The densities of positive cells within the tumour core were determined using assay-specific image analysis algorithms. Within each cohort, the prognostic value of each cell density was assessed using univariate and multivariate Cox regression including age, T stage, N stage and adjuvant chemotherapy as covariates. Results: The Melbourne cohort is slightly older, with a poorer prognosis and a higher proportion of N2/N3 disease compared to the St Andrews cohort. Univariate and multivariate analyses identified the density of CD8 positive cells as an important prognostic factor across both cohorts (p < 0.05). PD-L1 is significant in the St Andrews cohort and trends towards significance (p < 0.1) in the Melbourne cohort, whilst the reverse is seen with CD3. The significance level of CD68 cannot be reproduced across cohorts. Cohort statistics, hazard ratios and p values from univariate and multivariate survival analysis. .p < 0.1, *p<0.05, **p<0.01
doi:10.1093/annonc/mdz239 | v49
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz239.065/5577709 by guest on 24 October 2019
Y. Yan, K. Mao, P. Huang, J. Wang, Z. Xiao Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
models were used to test for association between circulating KIM-1 and disease free survival (DFS) as well as overall survival (OS). ROC analysis was performed to evaluate test characteristics for KIM-1 in predicting RCC recurrence within 6 months after nephrectomy. Results: Higher KIM-1 levels were associated with worse DFS and OS after nephrectomy. This association remained independently significant after controlling for pathologic stage, sarcomatoid features, and Fuhrman grade (DFS: HR 1.20 per log increase in KIM-1, 95% CI 1.09-1.33, p < 0.001; OS: HR 1.27 per log increase in KIM-1, 95% CI 1.11-1.45, p < 0.001). These associations were independent of treatment arm. In Kaplan-Meier analysis using KIM-1 quartiles, higher quartiles of KIM-1 were associated with worse DFS and OS (log-rank p ¼ 0.02 for both). Post-nephrectomy KIM-1 was a prognostic marker for disease recurrence within 6 months after nephrectomy (AUC 0.85). Conclusions: Elevated plasma KIM-1 is associated with worse DFS and OS in patients with resected RCC, and therefore has potential as an adjuvant biomarker. Analysis of larger cohorts to confirm this association is underway. Clinical trial identification: NCT00326898. Legal entity responsible for the study: ECOG-ACRIN Cancer Research Group (Peter J. O’Dwyer, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs). Funding: National Cancer Institute of the National Institutes of Health under the following award numbers: CA180820, CA180794, CA180867, CA189859. Disclosure: K.T. Flaherty: Officer / Board of Directors: Loxo Oncology; Officer / Board of Directors: