- Email: [email protected]
Differential expression of various miRNAs in pediatric cytogenetically normal acute myeloid leukemia (CN-AML)
abstracts
Annals of Oncology
160P
Table: 159P Cohort 2: St Andrews
71.64 23.7 - Overall
66 32.57 - Disease Related
16 (41%) 23 (59%)
26 (41%) 37 (59%)
3 (8%) 8 (20%) 28 (72%)
52 (88%) 7 (11%) 0 (0%)
HR 0.93 (0.88 0.98), p ¼ 0.007 ** HR 0.97 (0.94 1.00), p ¼ 0.065 . HR 0.92 (0.87 0.97), p ¼ 0.003 ** HR 0.93 (0.88 0.99), p ¼ 0.025 *
HR 0.90 (0.83 0.97), p ¼ 0.005 ** HR 0.86 (0.75 0.98), p ¼ 0.023 * HR 0.92 (0.87 0.98), p ¼ 0.010 * HR 0.97 (0.93 1.00), p ¼ 0.088 .
Multivariate Cox regression CD8 HR 0.92 (0.88 0.97), p ¼ 0.003 ** PD-L1 HR 0.96 (0.92 1.00), p ¼ 0.053 . CD3 HR 0.90 (0.85 0.95), p ¼ 0.0004** CD68 HR 0.92 (0.86 0.99), p ¼ 0.023 *
HR 0.92 (0.86 0.99), p ¼ 0.029 * HR 0.84 (0.74 0.97), p ¼ 0.015 * HR 0.94 (0.88 1.00), p ¼ 0.060 . HR 0.98 (0.94 1.02), p ¼ 0.294
Median age Median survival time (months) T stage T2 T3 N stage N1 N2 N3 Univariate Cox regression CD8 PD-L1 CD3 CD68
Conclusions: Our multicentre and multi-assay study suggests that the density of CD8 positive cells in the tumour core is a robust prognostic factor in MIBC. Further investigation of PD-L1 and CD3 cell density is warranted. Legal entity responsible for the study: Definiens AG; The Walter and Eliza Hall Institute of Medical Research; University of St Andrews. Funding: Definiens AG. Disclosure: K. Nekolla: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. N. Brieu: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. C.G. Gavriel: Research grant / Funding (self), Definiens is a full subsidiary of AstraZeneca: Definiens AG. M. Widmaier: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. A. Budco: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. D. Medrikova: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. I. Kanchev: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. M. Testori: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. J. Chan: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. D.J. Harrison: Advisory / Consultancy, Member: Scientific Advisory Board: Definiens AG; Full / Part-time employment: NuCana plc; Leadership role, Director: Industrial Centre for AI Research in Digital Diagnostics. M. Baehner: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. P.D. Caie: Research grant / Funding (institution): Definiens AG. B. Tran: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Non-remunerated activity/ies: Janssen-Cilag; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy: Tolmar; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ipsen; Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self): Pfizer; Research grant / Funding (self), Research grant / Funding (institution): Servier; Research grant / Funding (institution): Aslan; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Akeso; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Aptevo; Leadership role, Chair - GU Tumour Group: Cancer Trials Australia; Leadership role, Chair - Germ Cell Tumour Subcommittee, Member - Scientific Advisory Committee: ANZUP; Leadership role, Member - Scientific Advisory Committee: Biogrid; Leadership role, Member - Scientific Advisory Committee: Parkville Cancer Clinical Trials Unit; Leadership role, CoChair - Molecular Tumour Board: Victorian Comprehensive Cancer Centre. G. Schmidt: Full / Parttime employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG; Shareholder / Stockholder / Stock options: AstraZeneca; Licensing / Royalties, Royalities "Tissue Phenomics" ISBN 9789814774888: Pan Stanford Publishing. All other authors have declared no conflicts of interest.
v50 | Biomarkers
Y-K. Shi1, S. Jiang1, Y. Qin1, H. Jiang2, B. Liu3, J. Shi2, F. Meng4, P. Liu1, J. Yang1, S. Yang1, X. He1, S. Zhou1, L. Gui1, H. Liu5, J. Lin5 1 Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China, 2Department of Medical Oncology, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China, 3Department of Pathology, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China, 4Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, China, 5Medicine, Burning Rock Biotech, Guangzhou, China Background: Diffuse large B-cell lymphoma (DLBCL) is heterogenous morphologically, clinically and genetically. Although half of patients could be cured by frontline RCHOP, approximately 10%-15% are refractory or relapse within the 1st year. Here, we investigated the molecular landscapes of patients with diverse responses to R-CHOP. Methods: Targeted sequencing was performed on baseline samples of 105 DLBCL patients. After a median follow-up of 67 months, 63 (60.0%) patients had refractory or relapsed disease. All patients received R-CHOP(-like) regimen as the first-line treatment. After excluding double-hit and primary central system lymphoma, 81 patients with measurable disease before initial treatment and followed over 1 year were included for survival analysis. Patients who received less than a partial remission in the first-line setting or those relapsed within the first 12 months since the initiation of the treatment were defined as having primary refractory. Results: Collectively, we identified 1162 mutations spanning 103 genes from this cohort. The most commonly seen mutations included PIM1(33%), MYD88 (29%), BCL2 (29%), TP53 (29%), CD79B (25%) and KMT2D (24%). Patients with TP53 mutations were more likely to have primary refractory disease (41.7% vs 7.4%, p ¼ 0.002). For those with TP53 disruptive mutations, primary refractory is also more common (22.9% vs. 0%, p ¼ 0.006). Interestingly, BCL-2 somatic hypermutation (SHM) was only seen in patients without primary refractory disease (p ¼ 0.014). The International prognostic index (IPI) score and other clinical characteristics were comparable between the 2 groups. Furthermore, TP53 mutations were correlated with shorter PFS (p ¼ 0.001) and OS (p ¼ 0.049). Next, we investigated mutation landscape in patients with WT TP53 (n ¼ 58) and found that patients harboring MYD88 L265P had significantly inferior PFS than those with WT or non-265P (p ¼ 0.046). Conclusions: We revealed that patients with TP53 mutation are more likely to have primary refractory to standard R-CHOP. This study also showed the prognostic potential of MYD88 L265P in those with WT TP53 and indicated that distinct subgroups could be identified by TP53 and MYD88 L265P mutations. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
161P
Differential expression of various miRNAs in pediatric cytogenetically normal acute myeloid leukemia (CN-AML)
V. Gaur1, S. Chaudhary2, A. Tyagi2, S. Bakhshi2, P. Sharma1, S. Kumar2 Amity Institute Of Biotechnology, Amity University, Noida, India, 2Medical Oncology, All India Institute of Medical Sciences, Delhi, India
1
Background: Dysregulation of various miRNAs has been linked to the initiation and progression of several cancers including acute myeloid leukemia (AML). However, their role in pediatric cytogenetically normal AML (CN-AML) is still unclear. The objective of the present study was to identify deregulated miRNA expression patterns and their correlation with survival outcome in pediatric CN-AML. Methods: The study was approved by Institutional Ethical Committee. Informed written consent was taken from all the subjects. Bone marrow (BM) samples from 36 pediatric CN-AML patients and 20 pediatric controls (with solid tumors without BM involvement) were collected and used for isolation of mononuclear cells, genomic DNA and total RNA. Various clinical parameters were accessed and mutation status (NPM1 and FLT3-ITD) determined by PCR. Total RNA from 10 samples (5 CN-AML and 5 controls) was used for global miRNA profiling on Illumina HiSeq2500 platform and data were analysed using bioinformatic pipeline. For all 36 CN-AML patients, cDNA was prepared using TaqMan advanced miRNA cDNA synthesis kit followed by qPCR using TaqMan advanced miRNA assay for selected miRNAs. Results: Global miRNA profiling revealed differential expression of 168 miRNAs of which 66 were upregulated and 102 were downregulated (fold change>1.5, p 0.05) in pediatric CN-AML patients. Interestingly, 40 miRNAs belonging to human 14q32 miRNA cluster were significantly downregulated in CN-AML patients. The expression of 11 miRNAs selected for qPCR-based validation based on their involvement in signalling pathways in AML (and other cancers), were found to be dysregulated in 36 patients. Most of these miRNAs were found to target genes involved in the initiation and progression of AML. Importantly, there was a significant correlation between expression levels of miR-75, miR-589, miR-4446, miR-889, and miR-654 and survival outcomes like Event-free, Disease-free, and Overall survival. Clinical parameters like
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz239.069/5577743 by guest on 26 October 2019
Cohort 1: Melbourne
Molecular profiling and prognostic significance of TP53 mutations in diffuse large b cell lymphoma: Identifying a high-risk subgroup
abstracts
Annals of Oncology TLC, ANC, LDH, Blast percentage were also significantly correlated with survival outcomes. Conclusions: Along with various genetic abnormalities, deregulation in the expression of miRNAs might be an important contributor to the development of pediatric CNAML. Legal entity responsible for the study: The authors. Funding: Department of Biotechnology, Government of India. Disclosure: All authors have declared no conflicts of interest.
Circulating tumour cells in head and neck and non-small cell lung cancer
K.J. O’Byrne Cancer Services, Princess Alexandra Hospital, Woolloongabba, Australia Background: Metastasis in cancer patients is reflected by measurable levels of circulating tumour cells (CTCs) in the blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumour burden of an individual patient. Methods: Our study was designed to use microfluidic devices for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. Head and Neck cancer (HNC) and non-small cell lung cancer (NSCLC) patients were recruited to investigate the prognostic role of CTCs (n ¼ 400). Results: We demonstrated a higher CTC capture efficiency using microfluidic CTC platforms. Molecular alterations present in the primary tissue were confirmed in the CTCs by DNA FISH (EGFR-amplification, ALK-translocations). The presence of CTC clusters was associated with the development of distant metastatic disease (P ¼ 0.0313). In a proof of principle study, we were able to demonstrate for the first time, short-term patient derived CTC cultures outside the patient’s body from 7/18 HNC samples (4/7 HPV-positive). Likewise CTC cultures were established from 6/40 NSCLC samples. Exome sequencing of CTC and white blood cells (as germline control) confirmed the presence of somatic mutations in the CTC culture with mutational signatures consistent with NSCLC. Additionally our preliminary data indicate that PD-L1 is frequently expressed on CTCs in HNC and lung cancer and an immunoscore may be able to identify patients likely to benefit from immunotherapy. Conclusions: Expanding CTCs outside the patient’s body allows for the recapitulation of the molecular diversity present within the tumour, understanding of the disease progression and testing of therapies. Legal entity responsible for the study: The author. Funding: Has not received any funding. Disclosure: The author has declared no conflicts of interest.
163P
OX40/OX40L protein expression in non-small cell lung cancer and its role in clinical outcome and relationships with other immune biomarkers
X. Zhang1, Y. He1, F.R. Hirsch2, C. Zhou3 1 Oncology, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China, 2 Department of Medicine, Division of Medical Oncology, Mount Sinai New York, USA, 3Shanghai Pulmonary Hospital, Tongji University, Shanghai, China Background: Anti-tumoral immunotherapy of anti- programmed cell death (PD-1)/programmed cell death protein-ligand 1 (PD-L1) immune checkpoint demonstrated the efficacy and tolerability in patients with lung cancer. Apart inhibitory checkpoints, OX40, the co-stimulatory receptor related to T cell and proliferation, was valued identically. In this study, the relationship between OX40L among PD-1/PD-L1 and other immunological factors, as well as its role as the potential prognostic biomarker were analyzed in NSCLC. Methods: We investigated the relationship between OX40/OX40L, PD-1/PD-L1 and in surgical samples from 139 patients with NSCLC by immunohistochemistry (IHC). Factors related to OX40/OX40L expression were analyzed by logistic regression and linear regression. Cox analysis was also performed to find the influencing factors. analysis was conducted in order to testify its role in predicting patients’ prognosis. Results: The TILs OX40/OX40L expression was negatively correlated with the PD-L1 expression. PD-1expression was negatively correlated with the TILs expression (R ¼ 0.250, [p ¼ 0.003]), it was also negatively correlated with the OX40L expression (R ¼ 0.386, [p ¼ 0.0001]). PD-1expression was positively with TILs grades and negatively correlated with the TILs OX40L expression (R ¼ [X1, 95%CI 3.552-8.176, p ¼ 0.0001; X2, 95%CI 0.216-0.683], [p ¼ 0.0001]). expression of TILs OX40 varied significantly among tumor OX40, OX40L, L1, TILs and pathology types. Tumor OX40L expression, TILs OX40L express 1 expression, PD-L1 expression and TILs were considered as risk factors for TILs expression. The staging and TILs OX40L were considered as risk factors for vival (OS) while stage and gender were risk factors for recurrence-free survival The low-expression of OX40 was related to longer RFS, OS and better prognosis. Conclusions: OX40 plays a pivotal role in NSCLC, which was closely correlated with immunological factors, RFS and prognosis.
Volume 30 | Supplement 5 | October 2019
164P
Effect of serum survivin on survival among non-small cell lung cancer patients: NCI experience
R.A. Rashed1, M. Rahouma2, R. Abo Elfetouh1, H. Aziz3, M.K. Kamel2 1 Clinical Pathology, National Cancer Institute-Cairo University, Cairo, Egypt, 2Surgical Oncology, National Cancer Institute-Cairo University, Cairo, Egypt, 3Medical Oncology, National Cancer Institute-Cairo University, Cairo, Egypt Background: Survivin is a protein that inhibits apoptosis and has been shown its role in cancer progression, tumor angiogenesis, tumor cell resistance to chemotherapeutics and ionizing radiation. We aimed to evaluate the importance of survivin in lung cancer patients and identify its role in disease progression and outcome. Methods: We prospectively enrolled advanced non-small cell lung cancer (NSCLC) patients (2015-2017). Serum survivin expression levels were detected in the peripheral blood using real-time RT-PCR. The primary outcomes were to identify overall survival (OS), progression free survival (PFS) and time to progression (TTP) while the secondary outcomes were to identify the associations between different variables and survivin cut-off determined by receiver operating characteristic (ROC) curve. Chi(X2) and Mann Whitney-U tests were used. Kaplan-Meier survival curves were used and compared using Log-rank. Cox regression was used to identify if survivin was a predictor of survival. Results: 66 patients were recruited with median age of 55 years (Inter-quartile range: 47- 63.3), 74.2% were males. Adenocarcinoma represented 59.1%. 12 cases developed progressive disease (PD) with 8 cases had bone metastasis after PD. Median OS, TTP and PFS was 17.1 months (95%CI 13.1-20.9), 11.0 (95%CI 7.3-14.8) and 8.9 (95%CI 8.1-9.8) respectively. Chosen cut-off for survivin was 3.80 (Area under ROC curve¼0.644 (95%CI¼0.51-0.78), P ¼ 0.044) that was associated with better median TTP and PFS of 12.0 vs 4.9 months and 9.0 vs 4.9 months in low survivin ( 3.8 vs high (>3.8) groups (P ¼ 0.001 and 0.006) respectively. Survivin >3.80 was associated with worse TTP (Hazard ratio (HR) 5.66 (95%CI 1.8-17.7; P ¼ 0.003). Higher survivin was associated with bone metastasis after PD (100% vs 26.3 in low survivin (P ¼ 0.014). Conclusions: Survivin is a significant predictors of time to progression and progression free survival in advanced NSCLC. Bone metastasis is common in high survivin group.
Table: 164P Kaplan Meier survival curves estimated median survival (in months) for
Disclosure: All authors have declared no conflicts of interest.
doi:10.1093/annonc/mdz239 | v51
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz239.069/5577743 by guest on 26 October 2019
162P
Legal entity responsible for the study: The authors. Funding: This study was supported in part by a grant from National Natural Science Foundation of China (81802255), Shanghai Pujiang Program (17PJD036) and a grant from Shanghai Municipal Commission of Health and Family Planning Program (20174Y0131). National key research & development project (2016YFC0902300). Major disease clinical skills enhancement program of three year action plan for promoting clinical skills and clinical innovation in municipal hospitals, Shanghai Shen Kang Hospital Development Center Clinical Research Plan of SHDC (16CR1001A). The fundamental research funds for the central universities. Disclosure: All authors have declared no conflicts of interest.
Annals of Oncology
160P
Table: 159P Cohort 2: St Andrews
71.64 23.7 - Overall
66 32.57 - Disease Related
16 (41%) 23 (59%)
26 (41%) 37 (59%)
3 (8%) 8 (20%) 28 (72%)
52 (88%) 7 (11%) 0 (0%)
HR 0.93 (0.88 0.98), p ¼ 0.007 ** HR 0.97 (0.94 1.00), p ¼ 0.065 . HR 0.92 (0.87 0.97), p ¼ 0.003 ** HR 0.93 (0.88 0.99), p ¼ 0.025 *
HR 0.90 (0.83 0.97), p ¼ 0.005 ** HR 0.86 (0.75 0.98), p ¼ 0.023 * HR 0.92 (0.87 0.98), p ¼ 0.010 * HR 0.97 (0.93 1.00), p ¼ 0.088 .
Multivariate Cox regression CD8 HR 0.92 (0.88 0.97), p ¼ 0.003 ** PD-L1 HR 0.96 (0.92 1.00), p ¼ 0.053 . CD3 HR 0.90 (0.85 0.95), p ¼ 0.0004** CD68 HR 0.92 (0.86 0.99), p ¼ 0.023 *
HR 0.92 (0.86 0.99), p ¼ 0.029 * HR 0.84 (0.74 0.97), p ¼ 0.015 * HR 0.94 (0.88 1.00), p ¼ 0.060 . HR 0.98 (0.94 1.02), p ¼ 0.294
Median age Median survival time (months) T stage T2 T3 N stage N1 N2 N3 Univariate Cox regression CD8 PD-L1 CD3 CD68
Conclusions: Our multicentre and multi-assay study suggests that the density of CD8 positive cells in the tumour core is a robust prognostic factor in MIBC. Further investigation of PD-L1 and CD3 cell density is warranted. Legal entity responsible for the study: Definiens AG; The Walter and Eliza Hall Institute of Medical Research; University of St Andrews. Funding: Definiens AG. Disclosure: K. Nekolla: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. N. Brieu: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. C.G. Gavriel: Research grant / Funding (self), Definiens is a full subsidiary of AstraZeneca: Definiens AG. M. Widmaier: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. A. Budco: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. D. Medrikova: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. I. Kanchev: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. M. Testori: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. J. Chan: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. D.J. Harrison: Advisory / Consultancy, Member: Scientific Advisory Board: Definiens AG; Full / Part-time employment: NuCana plc; Leadership role, Director: Industrial Centre for AI Research in Digital Diagnostics. M. Baehner: Full / Part-time employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG. P.D. Caie: Research grant / Funding (institution): Definiens AG. B. Tran: Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Amgen; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Travel / Accommodation / Expenses: Astellas; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Bayer; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self): BMS; Honoraria (self), Advisory / Consultancy, Speaker Bureau / Expert testimony, Research grant / Funding (self), Research grant / Funding (institution), Non-remunerated activity/ies: Janssen-Cilag; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (institution): Novartis; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Sanofi; Honoraria (self), Advisory / Consultancy: Tolmar; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Ipsen; Research grant / Funding (self), Research grant / Funding (institution): AstraZeneca; Research grant / Funding (self): Pfizer; Research grant / Funding (self), Research grant / Funding (institution): Servier; Research grant / Funding (institution): Aslan; Research grant / Funding (institution): GSK; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Akeso; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Aptevo; Leadership role, Chair - GU Tumour Group: Cancer Trials Australia; Leadership role, Chair - Germ Cell Tumour Subcommittee, Member - Scientific Advisory Committee: ANZUP; Leadership role, Member - Scientific Advisory Committee: Biogrid; Leadership role, Member - Scientific Advisory Committee: Parkville Cancer Clinical Trials Unit; Leadership role, CoChair - Molecular Tumour Board: Victorian Comprehensive Cancer Centre. G. Schmidt: Full / Parttime employment, Definiens is a full subsidiary of AstraZeneca: Definiens AG; Shareholder / Stockholder / Stock options: AstraZeneca; Licensing / Royalties, Royalities "Tissue Phenomics" ISBN 9789814774888: Pan Stanford Publishing. All other authors have declared no conflicts of interest.
v50 | Biomarkers
Y-K. Shi1, S. Jiang1, Y. Qin1, H. Jiang2, B. Liu3, J. Shi2, F. Meng4, P. Liu1, J. Yang1, S. Yang1, X. He1, S. Zhou1, L. Gui1, H. Liu5, J. Lin5 1 Department of Medical Oncology, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, National Cancer Center/National Clinical Research Center for Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China, 2Department of Medical Oncology, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China, 3Department of Pathology, Suzhou Municipal Hospital, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China, 4Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, China, 5Medicine, Burning Rock Biotech, Guangzhou, China Background: Diffuse large B-cell lymphoma (DLBCL) is heterogenous morphologically, clinically and genetically. Although half of patients could be cured by frontline RCHOP, approximately 10%-15% are refractory or relapse within the 1st year. Here, we investigated the molecular landscapes of patients with diverse responses to R-CHOP. Methods: Targeted sequencing was performed on baseline samples of 105 DLBCL patients. After a median follow-up of 67 months, 63 (60.0%) patients had refractory or relapsed disease. All patients received R-CHOP(-like) regimen as the first-line treatment. After excluding double-hit and primary central system lymphoma, 81 patients with measurable disease before initial treatment and followed over 1 year were included for survival analysis. Patients who received less than a partial remission in the first-line setting or those relapsed within the first 12 months since the initiation of the treatment were defined as having primary refractory. Results: Collectively, we identified 1162 mutations spanning 103 genes from this cohort. The most commonly seen mutations included PIM1(33%), MYD88 (29%), BCL2 (29%), TP53 (29%), CD79B (25%) and KMT2D (24%). Patients with TP53 mutations were more likely to have primary refractory disease (41.7% vs 7.4%, p ¼ 0.002). For those with TP53 disruptive mutations, primary refractory is also more common (22.9% vs. 0%, p ¼ 0.006). Interestingly, BCL-2 somatic hypermutation (SHM) was only seen in patients without primary refractory disease (p ¼ 0.014). The International prognostic index (IPI) score and other clinical characteristics were comparable between the 2 groups. Furthermore, TP53 mutations were correlated with shorter PFS (p ¼ 0.001) and OS (p ¼ 0.049). Next, we investigated mutation landscape in patients with WT TP53 (n ¼ 58) and found that patients harboring MYD88 L265P had significantly inferior PFS than those with WT or non-265P (p ¼ 0.046). Conclusions: We revealed that patients with TP53 mutation are more likely to have primary refractory to standard R-CHOP. This study also showed the prognostic potential of MYD88 L265P in those with WT TP53 and indicated that distinct subgroups could be identified by TP53 and MYD88 L265P mutations. Legal entity responsible for the study: The authors. Funding: Has not received any funding. Disclosure: All authors have declared no conflicts of interest.
161P
Differential expression of various miRNAs in pediatric cytogenetically normal acute myeloid leukemia (CN-AML)
V. Gaur1, S. Chaudhary2, A. Tyagi2, S. Bakhshi2, P. Sharma1, S. Kumar2 Amity Institute Of Biotechnology, Amity University, Noida, India, 2Medical Oncology, All India Institute of Medical Sciences, Delhi, India
1
Background: Dysregulation of various miRNAs has been linked to the initiation and progression of several cancers including acute myeloid leukemia (AML). However, their role in pediatric cytogenetically normal AML (CN-AML) is still unclear. The objective of the present study was to identify deregulated miRNA expression patterns and their correlation with survival outcome in pediatric CN-AML. Methods: The study was approved by Institutional Ethical Committee. Informed written consent was taken from all the subjects. Bone marrow (BM) samples from 36 pediatric CN-AML patients and 20 pediatric controls (with solid tumors without BM involvement) were collected and used for isolation of mononuclear cells, genomic DNA and total RNA. Various clinical parameters were accessed and mutation status (NPM1 and FLT3-ITD) determined by PCR. Total RNA from 10 samples (5 CN-AML and 5 controls) was used for global miRNA profiling on Illumina HiSeq2500 platform and data were analysed using bioinformatic pipeline. For all 36 CN-AML patients, cDNA was prepared using TaqMan advanced miRNA cDNA synthesis kit followed by qPCR using TaqMan advanced miRNA assay for selected miRNAs. Results: Global miRNA profiling revealed differential expression of 168 miRNAs of which 66 were upregulated and 102 were downregulated (fold change>1.5, p 0.05) in pediatric CN-AML patients. Interestingly, 40 miRNAs belonging to human 14q32 miRNA cluster were significantly downregulated in CN-AML patients. The expression of 11 miRNAs selected for qPCR-based validation based on their involvement in signalling pathways in AML (and other cancers), were found to be dysregulated in 36 patients. Most of these miRNAs were found to target genes involved in the initiation and progression of AML. Importantly, there was a significant correlation between expression levels of miR-75, miR-589, miR-4446, miR-889, and miR-654 and survival outcomes like Event-free, Disease-free, and Overall survival. Clinical parameters like
Volume 30 | Supplement 5 | October 2019
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz239.069/5577743 by guest on 26 October 2019
Cohort 1: Melbourne
Molecular profiling and prognostic significance of TP53 mutations in diffuse large b cell lymphoma: Identifying a high-risk subgroup
abstracts
Annals of Oncology TLC, ANC, LDH, Blast percentage were also significantly correlated with survival outcomes. Conclusions: Along with various genetic abnormalities, deregulation in the expression of miRNAs might be an important contributor to the development of pediatric CNAML. Legal entity responsible for the study: The authors. Funding: Department of Biotechnology, Government of India. Disclosure: All authors have declared no conflicts of interest.
Circulating tumour cells in head and neck and non-small cell lung cancer
K.J. O’Byrne Cancer Services, Princess Alexandra Hospital, Woolloongabba, Australia Background: Metastasis in cancer patients is reflected by measurable levels of circulating tumour cells (CTCs) in the blood of cancer patients. CTCs represent cancer cells from the primary and metastatic sites, thereby providing a comprehensive representation of the tumour burden of an individual patient. Methods: Our study was designed to use microfluidic devices for the capture of CTCs and novel culture formulations for the ex vivo expansion of CTCs. Head and Neck cancer (HNC) and non-small cell lung cancer (NSCLC) patients were recruited to investigate the prognostic role of CTCs (n ¼ 400). Results: We demonstrated a higher CTC capture efficiency using microfluidic CTC platforms. Molecular alterations present in the primary tissue were confirmed in the CTCs by DNA FISH (EGFR-amplification, ALK-translocations). The presence of CTC clusters was associated with the development of distant metastatic disease (P ¼ 0.0313). In a proof of principle study, we were able to demonstrate for the first time, short-term patient derived CTC cultures outside the patient’s body from 7/18 HNC samples (4/7 HPV-positive). Likewise CTC cultures were established from 6/40 NSCLC samples. Exome sequencing of CTC and white blood cells (as germline control) confirmed the presence of somatic mutations in the CTC culture with mutational signatures consistent with NSCLC. Additionally our preliminary data indicate that PD-L1 is frequently expressed on CTCs in HNC and lung cancer and an immunoscore may be able to identify patients likely to benefit from immunotherapy. Conclusions: Expanding CTCs outside the patient’s body allows for the recapitulation of the molecular diversity present within the tumour, understanding of the disease progression and testing of therapies. Legal entity responsible for the study: The author. Funding: Has not received any funding. Disclosure: The author has declared no conflicts of interest.
163P
OX40/OX40L protein expression in non-small cell lung cancer and its role in clinical outcome and relationships with other immune biomarkers
X. Zhang1, Y. He1, F.R. Hirsch2, C. Zhou3 1 Oncology, Shanghai Pulmonary Hospital, Tongji University, Shanghai, China, 2 Department of Medicine, Division of Medical Oncology, Mount Sinai New York, USA, 3Shanghai Pulmonary Hospital, Tongji University, Shanghai, China Background: Anti-tumoral immunotherapy of anti- programmed cell death (PD-1)/programmed cell death protein-ligand 1 (PD-L1) immune checkpoint demonstrated the efficacy and tolerability in patients with lung cancer. Apart inhibitory checkpoints, OX40, the co-stimulatory receptor related to T cell and proliferation, was valued identically. In this study, the relationship between OX40L among PD-1/PD-L1 and other immunological factors, as well as its role as the potential prognostic biomarker were analyzed in NSCLC. Methods: We investigated the relationship between OX40/OX40L, PD-1/PD-L1 and in surgical samples from 139 patients with NSCLC by immunohistochemistry (IHC). Factors related to OX40/OX40L expression were analyzed by logistic regression and linear regression. Cox analysis was also performed to find the influencing factors. analysis was conducted in order to testify its role in predicting patients’ prognosis. Results: The TILs OX40/OX40L expression was negatively correlated with the PD-L1 expression. PD-1expression was negatively correlated with the TILs expression (R ¼ 0.250, [p ¼ 0.003]), it was also negatively correlated with the OX40L expression (R ¼ 0.386, [p ¼ 0.0001]). PD-1expression was positively with TILs grades and negatively correlated with the TILs OX40L expression (R ¼ [X1, 95%CI 3.552-8.176, p ¼ 0.0001; X2, 95%CI 0.216-0.683], [p ¼ 0.0001]). expression of TILs OX40 varied significantly among tumor OX40, OX40L, L1, TILs and pathology types. Tumor OX40L expression, TILs OX40L express 1 expression, PD-L1 expression and TILs were considered as risk factors for TILs expression. The staging and TILs OX40L were considered as risk factors for vival (OS) while stage and gender were risk factors for recurrence-free survival The low-expression of OX40 was related to longer RFS, OS and better prognosis. Conclusions: OX40 plays a pivotal role in NSCLC, which was closely correlated with immunological factors, RFS and prognosis.
Volume 30 | Supplement 5 | October 2019
164P
Effect of serum survivin on survival among non-small cell lung cancer patients: NCI experience
R.A. Rashed1, M. Rahouma2, R. Abo Elfetouh1, H. Aziz3, M.K. Kamel2 1 Clinical Pathology, National Cancer Institute-Cairo University, Cairo, Egypt, 2Surgical Oncology, National Cancer Institute-Cairo University, Cairo, Egypt, 3Medical Oncology, National Cancer Institute-Cairo University, Cairo, Egypt Background: Survivin is a protein that inhibits apoptosis and has been shown its role in cancer progression, tumor angiogenesis, tumor cell resistance to chemotherapeutics and ionizing radiation. We aimed to evaluate the importance of survivin in lung cancer patients and identify its role in disease progression and outcome. Methods: We prospectively enrolled advanced non-small cell lung cancer (NSCLC) patients (2015-2017). Serum survivin expression levels were detected in the peripheral blood using real-time RT-PCR. The primary outcomes were to identify overall survival (OS), progression free survival (PFS) and time to progression (TTP) while the secondary outcomes were to identify the associations between different variables and survivin cut-off determined by receiver operating characteristic (ROC) curve. Chi(X2) and Mann Whitney-U tests were used. Kaplan-Meier survival curves were used and compared using Log-rank. Cox regression was used to identify if survivin was a predictor of survival. Results: 66 patients were recruited with median age of 55 years (Inter-quartile range: 47- 63.3), 74.2% were males. Adenocarcinoma represented 59.1%. 12 cases developed progressive disease (PD) with 8 cases had bone metastasis after PD. Median OS, TTP and PFS was 17.1 months (95%CI 13.1-20.9), 11.0 (95%CI 7.3-14.8) and 8.9 (95%CI 8.1-9.8) respectively. Chosen cut-off for survivin was 3.80 (Area under ROC curve¼0.644 (95%CI¼0.51-0.78), P ¼ 0.044) that was associated with better median TTP and PFS of 12.0 vs 4.9 months and 9.0 vs 4.9 months in low survivin ( 3.8 vs high (>3.8) groups (P ¼ 0.001 and 0.006) respectively. Survivin >3.80 was associated with worse TTP (Hazard ratio (HR) 5.66 (95%CI 1.8-17.7; P ¼ 0.003). Higher survivin was associated with bone metastasis after PD (100% vs 26.3 in low survivin (P ¼ 0.014). Conclusions: Survivin is a significant predictors of time to progression and progression free survival in advanced NSCLC. Bone metastasis is common in high survivin group.
Table: 164P Kaplan Meier survival curves estimated median survival (in months) for
Disclosure: All authors have declared no conflicts of interest.
doi:10.1093/annonc/mdz239 | v51
Downloaded from https://academic.oup.com/annonc/article-abstract/30/Supplement_5/mdz239.069/5577743 by guest on 26 October 2019
162P
Legal entity responsible for the study: The authors. Funding: This study was supported in part by a grant from National Natural Science Foundation of China (81802255), Shanghai Pujiang Program (17PJD036) and a grant from Shanghai Municipal Commission of Health and Family Planning Program (20174Y0131). National key research & development project (2016YFC0902300). Major disease clinical skills enhancement program of three year action plan for promoting clinical skills and clinical innovation in municipal hospitals, Shanghai Shen Kang Hospital Development Center Clinical Research Plan of SHDC (16CR1001A). The fundamental research funds for the central universities. Disclosure: All authors have declared no conflicts of interest.