Browsing Over 138 Presentations
28P - Simultaneous unbiased and absolute quantification of a 500 protein panel in pancreatic cancer plasma using HRM mass spectrometry (ID 192)
- H. Yu
- H. Yu
- J. Vowinckel
- C. Escher
- D. Heinzmann
- N. Dupuis
Abstract
Background
Recent studies have demonstrated of utility of quantifying circulating proteins for early disease detection, prediction of therapeutic response, and treatment monitoring. Although the utility is clear, standardization of measurement methods for a large number of proteins from plasma remains challenging. Here, plasma proteins are detected using hyper-reaction monitoring (HRM) mass spectrometry in samples from normal and pancreatic cancer subjects. The data is acquired and analyzed simultaneously with unbiased label-free quantification of all proteins and absolute quantification of proteins from a > 500-protein panel constructed from stable-isotope standard (SIS) peptides.
Methods
Plasma samples from subjects with Stage IV pancreatic cancer (PC, n = 6) and age matched healthy donors (n = 15) were prepared for mass spectrometry. Prior to analysis, a panel of SIS peptides, covering 582 plasma proteins, was spiked into each sample. All samples were acquired using nano-flow liquid chromatography with separation over a one-hour gradient coupled online to a Thermo Scientific Q Exactive HF mass spectrometer. Protein data was extracted using Spectronaut (Biognosys) and statistical analysis was conducted to identify disease associated biomarker candidates.
Results
Analysis of the PQ500 panel enabled absolute quantification of 282 proteins across all samples. Univariate statistical testing identified 29 candidate proteins (27 up- and 2 down-regulated; q-value > 0.05 and fold change > 1.5). Key dysregulated proteins include CRP, SAA1, and C9. With unbiased, label-free quantification, 414 proteins were quantified, with 87 significantly regulated. In addition to the acute phase protein candidates identified in the PQ500 panel, 12 adhesion related protein candidates were identified (e.g. TLN1, MYH9, TPM4), 9 of which were decreased in PC. Notably, membrane associated ICAM1 and VCAM1, both potential therapeutic targets, were increased in PC.
Conclusions
Combining PQ500 with unbiased label-free quantification enables comprehensive characterization of the plasma proteome, while at the same time providing absolute quantification for a large subset of well annotated, clinically relevant proteins.
Legal entity responsible for the study
Biognosys AG, Schlieren, Switzerland.
Funding
Biognosys AG, Schlieren, Switzerland.
Disclosure
H. Yu, J. Vowinckel, C. Escher, D. Heinzmann, N. Dupuis: Employee: Biognosys AG.
31P - Comprehensive genomic profiling of Chinese esophageal squamous cell carcinoma patients (ID 141)
- Y. Ji
- Y. Ji
- Y. Wu
- W. Fu
- L. Liu
- Z. Tian
- S. Wen
- K. Zhang
- M. Yao
- A. Liu
- Y. Zhou
Abstract
Background
Esophageal squamous cell carcinoma (ESCC) is the most important pathological type of esophageal cancer with high incidence and limited efficient therapies in China and worldwide. Understanding of ESCC genomic features is advantageous for exploring clinical therapeutic strategies.
Methods
Deep sequencing targeting 450 cancer genes was performed on FFPE and matched blood samples collected from 90 Chinese ESCC patients(pts) with a median age of 60 years old. Genomic alterations (GAs) including single nucleotide variations, short and long indel, gene rearrangements and copy number variations were analyzed. Tumor mutation burden (TMB) was assessed in all samples by standard NGS algorithms. The expression of PD-L1 in 44 samples was evaluated by IHC (28-8 Ab).
Results
The most commonly found GAs were mutations in TP53 (94.4%), FGF3 (43.3%), CCND1 (43.3%), FGF4 (42.2%), FGF19 (42.2 %), CDKN2A (36.7%), NOTCH1 (25.6%), PIK3CA (22.2%), and ERBB2 amp(2.2%).Compared with TCGA data, the frequency of TP53 and ERBB2 amp mutations was similar, while the frequency of NOTCH1 mutations was significantly higher (25.6% vs 11%) and the frequency of EGFR amp was lower (5.6% vs 19%) in Chinese cohort. In addition, 4 of 90 samples harbored germline mutations (SDHA, RAD51C, PALB2 and BCL2L11). Among these GAs, 73.3% mutations were in cell cycle (62.2%) and PI3K/AKT (42.2%) pathway. In Chinese ESCC pts, the median TMB was 7.0 muts/Mb, and some pts showed high TMB (33.3%pts≥10 muts/Mb,11.1%pts≥20 muts/Mb). 15.6% pts (TMB≥10 muts/Mb) harbored chromosome 11q13 (FGF3/4/19 and CCND1) amp, which may be related to immunotherapy hyper-progression. Based on the IHC analysis, 10 of 44 Chinese pts showed positive (TPS≥1%) PD-L1 expression, and 7 of them also showed high TMB (≥10 muts /Mb). However, no correlation was found between high TMB and PD-L1 expression.
Conclusions
In this study, we found that the frequencies of GAs, such as EGFR and NOTCH1 alterations, were different between Chinese and western ESCC pts. Compared to Western ESCC pts, the positivity of PD-L1 expression was similar, while TMB was higher in Chinese ESCC pts. These findings suggested potential therapeutic targets for targeted and immunotherapies of Chinese ESCC pts.
Legal entity responsible for the study
OrigiMed.
Funding
Has not received any funding.
Disclosure
M. Yao, A. Liu, Y. Zhou: Employee: OrigiMed. All other authors have declared no conflicts of interest.
32P - Clinical correlation between different CKIT exon mutations and clinical outcome imatinib mesylate treatment in gastrointestinal stromal tumor (GIST) patients (ID 71)
- G. Zakaria
- G. Zakaria
- N. Allahloubi
- A. Bahnasy
- O. Khorshid
Abstract
Background
The clinical behavior of GISTs is highly variable. This study aims at detection of different histo-pathological tumor features and correlation with different clinical aspects after treatment with imatinib, based on C-KIT exon mutation status.
Methods
This is a retrospective study that included all cases diagnosed as GIST who presented to NCI from 2005 to 2017, The following data were collected from the patient’s files: age, gender, tumor site, size, mitotic rate, histological grade, capsular rupture, risk stratification by Joensuu criteria, treatment setting, date of start and end of treatment, dose and toxicity. KIT mutation was assessed on tumor tissues of all patients; clinical correlation between different clinical aspects after treatment with imatinib, based on C-KIT exon mutation status, was done.
Results
Eighty-nine cases of GIST presented to NCI in the period September 2005 to January 2017. Median age at diagnosis was 48 years old with a median follow up of 22 months. More than 75% of the patients had positive C-KIT mutation, while it was negative in 24.7 % of the patients. C-kit positive mutations were significantly associated with tumors more than 5 cm, high mitosis, and with high tumor risk stratification by Joensuu criteria in more than fifty percent of the patients. Exon 9 mutations had poor ORR (55.6 %) compared to those with exon 11(67.6%) (P = 0.33), with the latter having PFS of 55 months compared 120 months for exon 9 mutations, (P = 0.002). No statistically difference in OS was observed with exon 9 (70 months) compared to exon 11 mutations (77 months) (P = 0.55).
Conclusions
C-kIT-positive mutation per-se is an independent poor risk factor, associated with more aggressive tumor features whereas response to imatinib was affected by exon mutations with exon 11 having a tendency for better ORR, compared to exon 9 mutation, with the latter having longer PFS compared with exon 11, with no statistically difference in OS with exon 9 compared to exon 11 mutations.
Legal entity responsible for the study
NCI.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
33P - Proteomic analysis of UKF-NB-4 cells reveals a stimulatory activity of MT-3 on cellular senescence and apoptosis (ID 88)
- M. Merlos Rodrigo
- M. Merlos Rodrigo
- H. Buchtelova
- V. Strmiska
- A. Jimenez Jimenez
- I. Casal
- V. Adam
- Z. Heger
Abstract
Background
Metallothioneins (MTs) family is a intracellular and cysteine-rich proteins with a high affinity to metals. MT-3 could play important neuromodulatory and neuroprotective roles. MT-3 has been also found up-regulated in a number of cancers. Neuroblastoma (Nbl) is a cancer is the most common extra-cranial solid tumour of childhood. The main aim was to provide novel insights into the molecular mechanisms of hMT-3 up-regulation and to elucidate the effects beneath the MT-3 up-regulation in Nbl cells.
Methods
To increase the expression of MT-3 Nbl (UKF-NB-4) cells were transiently transfected with a plasmid containing MT-3 gene (pcDNA3.1-GFP-hMT-3-TOPO). Separations of tryptic digests were carried out on an Easy-nLC 1000 nano system. MS analysis was performed using a Q-Exactive MS. The mass spectrum *.raw file was searched against the human SwissProt 57.15 database using MASCOT search engine (version 2.3, Matrix Science).
Results
The efficiency of transfection analysed through a fluorescence of GFP tag expressed at the C-terminus of MT-3 showed more 70% transfection efficiency for both constructed plasmids (mock and MT-3). From the total of common proteins in dataset (hMT-3 vs. mock), 176, 20 and 1244 proteins were quantitatively identified with up-regulation, down-regulation, and no significant differences between hMT-3 and mock treatments. Noteworthy, the bioinformatical analyses revealed the exclusive expression (induced by MT-3) and up-regulation proteins of a number of proteins affecting biological pathways related to mitotic cell cycle, cellular responses to stress, positive regulation of proteolysis, negative regulation of cell cycle and programmed cell death.
Conclusions
Our proteomic data shed some light on the proteins involved in inducing senescence and apoptosis in tested Nbl cells with up-regulated MT-3. Organisms with renewable tissues had to evolve mechanisms to prevent the development of cancer. Cellular senescence and apoptosis are among those mechanisms. Further experiments will be performed to functionally verify these data to provide novel insights into the Nbl biology. These might be useful to develop novel therapeutic protocols utilizing MT-3 as prognostic biomarker or therapeutic target.
Legal entity responsible for the study
Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, CZ.
Funding
European Research Council (ERC) under the European Uniońs Horizon 2020 Research and Innovation Programme (grant agreement No. 759585).
Disclosure
All authors have declared no conflicts of interest.
34P - Impact of treatment with bilastine for PD-1/PD-L1 inhibitors induced rash (ID 125)
- T. Hirata
- T. Hirata
Abstract
Background
PD-1/PD-L1 inhibitors are novel anti-cancer agents for various tumors. PD-1/PD-L1 inhibitors induced rash occurred in 20% to 30%. The therapy for rash includes anti-histamine and corticosteroid. Bilastine is a non-sedating second-generation H1-antihistamine. Bilastine showed the efficacy for urticaria, prurigo and cutaneous pruritus. However, its effectiveness for PD-1/PD-L1 inhibitors induced rash is unknown. The objective of this retrospective study was to evaluate the efficacy of bilastine for PD-1/PD-L1 inhibitors induced rash.
Methods
We identified 224 patients who received PD-1/PD-L1 inhibitors (nivolumab, pembrolizumab, atezolizumab) at the Kure Medical Center from September 2014 to October 2018. PD-1/PD-L1 inhibitors induced rashes were observed in 84 patients (37.5%). They were classified into 4 groups on the basis of the systemic antihistamine and topical corticosteroid therapy: the (1) bilastine and corticosteroid group (n = 18), (2) another anti-histamine and corticosteroid group (n = 22), (3) bilastine group (n = 20); and (4) another antihistamine group (n = 24). Adverse events were graded according to the Common Terminology Criteria for Adverse Events (version 4.0). This study was approved by the Kure Medical Center IRB.
Results
The bilastine and corticoegsteroid group had significantly shorter the median duration of topical corticosteroids and antihistamine than the another antihistamine and corticosteroid group (p<0.01). Bilastine group had significantly shorter the period of systemic medications than the another antihistamine group (p<0.01). The incidence of adverse events was observed as follows, somnolence in 3% (1/38), headache 3% (1/38) and dizziness in 3% (1/38) in the bilastine and corticosteroid group and bilastine group. There were no serious adverse events.
Conclusions
Bilastine treatment reduced the need for topical corticosteroids use and shortened the period of topical corticosteroids for PD-1/PD-L1 inhibitors induced rash with acceptable safety profiles. Bilastine may be more effective than another antihistamine for PD-1/PD-L1 inhibitors induced rash.
Legal entity responsible for the study
Taizo Hirata.
Funding
Has not received any funding.
Disclosure
The author has declared no conflicts of interest.
35P - Enhancement of high-LET radiation-induced lung cancer cell apoptosis by Antennapedia proteins (ANTP)-SmacN7 (ID 139)
- Y. Xie
- Y. Xie
Abstract
Background
The aim of the present study was to investigate the mechanisms underlying the radiation-sensitising effect from antennapedia proteins (ANTP)-SmacN7 on induction of apoptosis in lung cancer cells irradiated with high-LET ionizing irradiation (IR) from accelerated carbon and iron particles.
Methods
Two cultured human non-small lung cancer (NSCLC) cell lines, A549 and NCI-H460, were irradiated with low-LET X-irradiations or high-LET IR with or without treatment of ANTP-SmacN7. Change of cell survival, induction of apoptosis and cell cycle progression, and alterations in both death and survival signals for apoptosis, were studied by colony formation assay, flowcytometry, and Western blot analysis, respectively.
Results
Showed that at the LD50 for clonogenic cell killing by high-LET iron particles, compared to the low-LET X-rays irradiations, high-LET IR was more efficient for clonogenic cell killing and induction of apoptosis, which was correlated with cell G2/M phase progression. In addition, ANTP-SmacN7 markedly promoted apoptotic cell killing through inhibition of X-linked inhibitor of apoptosis protein (XIAP) and activation of caspase-3 and 9. Furthermore, both antiapoptotic and proapoptotic molecular response was correlated with the apoptotic cell killing and in accordance with the results of clonogenic cell killing.
Conclusions
These findings provide useful information to contribute to the improvement of high-LET clinical radiotherapy for NSCLC from the point of view of pharmaceutical radio-sensitization.
Legal entity responsible for the study
Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, PRC.
Funding
Has not received any funding.
Disclosure
The author has declared no conflicts of interest.
36P - Structural diversity of the cardenolide calotropin renders it as a targeted therapy for harnessing TNBC progression through tuning nitric oxide (NO) levels (ID 183)
- R. Ellayeh
- R. Ellayeh
- R. Youness
- H. Askary
- A. Abdelmotaal
- R. Assal
Abstract
Background
Triple negative breast cancer (TNBC) is the most aggressive breast cancer (BC) subtype. It has the worst prognosis, highest recurrence and metastatic rates. Due to the clinical and molecular heterogeneity of TNBC, there is an emerging need to identify new molecular therapeutic targets. Nitric oxide (NO) has a dual role in cancer depending on its levels. At low concentrations, NO promotes tumor growth, while at high concentrations, NO has an anti-neoplastic function. Natural compounds have emerged as signaling pathways’ regulators in various tumors. Cardenolides specifically have potent cytotoxic effects in different cancers as lung and liver cancer. Our group has isolated the cardenolides, Calotropin and 7,8-dehydrocalotropin from Calotropisgigantea (L.) Dryand (Apocyanaceae). Calotropin showed potent cytotoxicy against non-small cell lung cancer, glioblastoma and prostate cancer, but has never been investigated against BC. Our aim was to investigate the anticancer effects of the isolated compounds on MDA-MB-231 TNBC cells by functional characterization and unravel their role in regulating NO levels in BC.
Methods
MDA-MB-231 cells were treated with serial dilutions (1, 5, 10, 20, 60 and 100 μM) of calotropin and 7,8-dehydrocalotropin. Their cytotoxic activities were assessed using MTT for cellular viability and IC50 values were obtained. Cellular migration and colony forming ability were measured using scratch and colony forming assays, respectively. NO production was measured using Greiss reagent.
Results
Both calotropin and 7,8-dehydrocalotropin were able to decrease cellular viability, migration and colony formation of MDA-MB-231 cells in a dose-dependent manner. Calotropin reduced NO levels in MDA-MB-231 cells. However 7,8-dehydrocalotropin did not have any significant effects in regulating NO.
Conclusions
Calotropin showed more potent cytotoxicity on MDA-MB-231 cells compared to 7,8-dehydrocalotropin. Calotropin acts as a negative regulator of NO production, whereas 7,8-dehydrocalotropin failed to regulate NO production. This could be attributed to the structural difference between both compounds. Thus calotropin can be developed as a targeted therapy against BC.
Legal entity responsible for the study
German University of Cairo.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
37P - Genomics and pharmacogenomics analyses of cancer cell lines using the CellMinerCDB and CellMiner web-applications (ID 168)
- W. Reinhold
- W. Reinhold
- Y. Pommier
Abstract
Background
Complimentary datasets and functionality that facilitate comparisons of genomic, molecular and pharmacological data within the NCI-60 cancerous cell lines, Cancer Cell Line Encyclopedia (CCLE), Genomics of Drug Sensitivity in Cancer (GDSC), Cancer Therapeutics Response Portal (CTRP), NCI/DTP small cell lung cancer (SCLC), and NCI Almanac cell line sets are provided by the CellMiner (
Methods
Pharmacogenomics analyses using CellMiner compare the 60 cancerous cell lines of the NCI-60 using five tools, and include 22 data sets. Pharmacogenomics analyses using CellMinerCDB compare the NCI-60, CCLE, GDSC, CTRP, NCI/DTP SCLC, and NCI Almanac cell line data six, using eight tools, and include 29 data sets. Both provide multiple ways to download or query that data, and are described in detail in their respective urls.
Results
Data for the NCI-60, providing the most extensive public set of cell line molecular and drug activity data (generated by the NCI Developmental Therapeutics Program
Conclusions
Exploration of the relationships between and among molecular alterations and pharmacological responses in cancer cell lines from the omic perspective is facilitated by this rich set of data and functionalities.
Legal entity responsible for the study
The National Cancer Institute, USA.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
1P - PIWI proteins play oncogenic functions in pancreatic cancer (ID 142)
- W. Li
- W. Li
- J. Martinez Useros
- M. Fernández-Aceñero
- N. García Carbonero
- J. García-Foncillas
Abstract
Background
Human homologues of PIWI proteins identified are PIWIL1, PIWIL2, PIWIL3 and PIWIL4 (Sasaki et al. 2003). Aberrant expression of these proteins has been associated with hallmarks of cancer, and have also a potential prognostic and diagnostic markers for different cancers (Suzuki et al. 2012). However, their functional and clinical significance in pancreatic ductal adenocarcinoma (PDAC) remains unknown. The purpose of this study was to dissect the role of PIWI proteins and their prognostic relevance.
Methods
PIWI proteins expression were analyzed by western blot in human PDAC derived cell lines and one non-transformed pancreatic cell line. Functional experiments were performed with PIWIL3 and/or PIWIL4 downregulated PDAC derived cell lines and one non-transformed cell line. Immunohistochemistry was performed to evaluate expression of PIWI proteins in 124 PDAC samples from Fundacion Jimenez Diaz Hospital, and with 124 validation cohort from TGCA. Then, association between PIWI proteins expression and survival was assessed.
Results
Only PIWIL3 and PIWIL4 showed differential expression in PDAC cell lines. Both wound-healing and transwell assay showed a decrease in migration ratio after PIWIL3 and/or PIWIL4 downregulation (P < 0.05). Furthermore, both PIWIL3 and/or PIWIL4 are necessary for the maintenance of undifferentiated phenotype highlighted by a reduction in size and number of pancreatic spheres after PIWIL3 and/or PIWIL4 downregulation (P < 0.05). On the other hand, PIWIL1 associated with shorter survival (P = 0.056), and this finding was validated in the TGCA cohort (P = 0.021). PIWIL2 associated significantly to shorter survival (P = 0.046) in our training set, and validation set exhibited a high trend toward significance (P = 0.051). Although PIWIL3 and PIWIL4 did not show association with survival in our training set, validation set revealed a statistically significant association of PIWIL4 with shorter overall survival (P = 0.027).
Conclusions
The present study demonstrate that PIWIL3 and PIWIL4 regulates PDAC aggressiveness by inhibiting cell migration and regulate undifferentiated phenotype of cancer cells. Furthermore, PIWIL1, PIWIL2 and PIWIL4 are potential prognostic biomarkers in PDAC.
Legal entity responsible for the study
Fundación Instituto de Investigación Sanitaria - Fundación Jiménez Díaz (G-85874949).
Funding
Spanish Ministry of Economy and Competitiveness.
Disclosure
All authors have declared no conflicts of interest.
5P - Establishment and application of a panel of PBMC-humanized mouse tumor models in cancer immunotherapy (ID 132)
- L. Bourre
- L. Zhang
- S. Qi
- H. Wu
- L. Zhao
- X. An
- W. Tan
- X. Fu
- M. Qiao
- Q. Shi
- W. Yang
Abstract
Background
To meet the rapidly growing I/O market, the demands for fast, relevant and cost effective mouse tumor model systems are also increasing. We developed a panel of straightforward humanized tumor models, designated as MiXeno platform.
Methods
CrownBio has established a sizable collection of MiXeno models where human PBMCs were reconstituted in the mouse system for the evaluation in vivo activity of immune checkpoint inhibitors or immune-modulators. These MiXeno models were characterized with tumor response to anti-PD-1 and anti-CTLA4 antibodies, and onset of possible graft versus host disease (GVHD) or graft versus tumor response (GVT) under different settings. To engage both host immune system and tumor antigens, we have developed some specific Mixeno tumor models by inoculating tumor cells over-expressing specific anti-tumor antigens (e.g. EGFR, CD47, Braf or PD-L1) into PBMC-humanized immunocompromised mice. Moreover, to improve capacity and consistency of MiXeno platform, we are conducting studies to characterize and validate commercialized frozen PBMCs for MiXeno model establishment.
Results
Models with over-expression of a variety of tumor antigens (e.g. EGFR, CD47, Braf, PD-L1...) were used to develop specific Mixeno tumor models. Meanwhile, in order to overcome the limitation of PBMC shortage, commercialized PBMC has been purchase and implanted into several xenograft models, and exhibit consistent tumor growth with fresh PBMC, as well as human immune component reconstitution. Up to date, a variety of test articles of different categories, including checkpoint inhibitors, T cell modulators and bispecific T cell engagers (e.g. EpCam-CD3, CD47/CD3, BCMA/CD3) have been evaluated using this platform. Merchandized I/O drugs, such as Pembrolizumab, are being tested in commercialized PBMC implanted immunocompromised mice.
Conclusions
MiXeno platform are valid model system for the human immuno-modulatory drugs including bispecific antibodies evaluation and will be optimized by introduction of specific Mixeno tumor models, commercial PBMC and B2M mice.
Legal entity responsible for the study
CrownBio.
Funding
CrownBio.
Disclosure
L. Bourre, L. Zhang, S. Qi, H. Wu, L. Zhao, X. An, M. Qiao, Q. Shi, W. Yang: Employee: CrownBio. All other authors have declared no conflicts of interest.
6P - Prognostic significance of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in non-small cell lung cancer (NSCLC) treated with immune checkpoint inhibitors (ID 197)
- S. Amaral
- S. Amaral
- M. Casal Moura
- J. Carvalho
- A. Chaves
- E. Jesus
- G. Sousa
Abstract
Background
Immunotherapy with programmed death receptor-1 (PD-1) antibodies has changed the paradigm of advanced NSCLC treatment. These checkpoint inhibitors showed better outcomes compared with standard treatment but reliable predictive markers are still lacking. High pre-treatment NLR and PLR have been associated with poor prognosis in several tumor types and recent studies suggest a potential role also in NSCLC. We thus conducted this study to evaluate the prognostic significance of NLR and PLR in our patients.
Methods
All patients with locally advanced and metastatic NSCLC treated with nivolumab and pembrolizumab from February 2016 to October 2018 were enrolled. NLR and PLR were determined by the division of neutrophils and platelets by lymphocytes in peripheral blood. Kaplan Meier method and Cox proportional hazardous analysis were conducted to assess the impact of NLR, PLR and other clinical factors on overall survival (OS) and progression free survival (PFS).
Results
Thirty-two patients were treated, 20 with nivolumab and 12 with pembrolizumab. Median age was 61 (40-82); 63% were male; 91% had an ECOG PS ≤ 2; 37% received ≥ 2 prior systemic therapies and 78% had stage IV disease. Increased NLR or PLR values above mean were independent predictive factors for decreased PFS (11 vs. 6 months, HR 3.33 95%CI 0.97 - 11.3, p = 0.056 and 12 vs. 6 months, HR 3.9 95%CI 1.19 - 12.8, p = 0.025, respectively). NLR and PLR values higher than percentil 25 were predictive factors, when used in combination, for decreased OS (21 vs. 11 months, HR 12.363 95% CI 1.303 - 117.291, p = 0.028 and 13 vs. 11 months, HR 3.9 95%CI 1.19 - 12.8, p = 0.025, respectively). Other clinical factors (i.e. histology, tobacco use, age, gender, ECOG PS, metastatic sites) did not present any implication for OS and PFS, as determined by multivariate analyses.
Conclusions
Elevated pre-treatment NLR and PLR are associated with shorter OS and PFS in our cohort independently of other prognostic factors. Our results reinforce the potencial role of these markers as a predictive factor of poor prognosis for NSCLC patients. Prospective studies are warranted to validate these findings.
Legal entity responsible for the study
Susana Rocha Amaral.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
10P - Safety profile of epigenetic therapies in early phase trials: Do epidrugs deserve specific drug development processes? (ID 105)
- L. Leroy
- L. Leroy
- T. Satar
- C. Baldini
- P. Martin-Romano
- A. Hollebecque
- J. Michot
- V. Ribrag
- C. Massard
- X. Paoletti
- S. Postel Vinay
Abstract
Background
Targeting the epigenome has demonstrated efficacy in hematological malignancies, and results of recent phase 1 (P1) trials have shown promising activity in solid tumors. The number of novel epidrugs is increasing exponentially, with several first-in-class, first-in-human selective compounds now evaluated in P1 trials. Accurate knowledge of their safety profile and toxicity management beyond cycle 1 is essential to appropriate P2 dose recommendation.
Methods
All patients (pts) with hematologic or solid tumors enrolled in at least one epidrug P1 trial at Gustave Roussy Drug Development Department were retrospectively analysed. Baseline pts characteristics, treatment-related adverse events (AEs) – type, grade, date of occurrence, duration, resolution - toxicity management (medication, dose modification) and outcome were collected.
Results
A total of 243 pts (43,6% hematologic, 23,1% non-Hodgkin lymphoma (NHL), 33,3% solid tumors excluding NHL) were included in 15 epidrug monotherapy P1 trials between Jan 2010 and March 2017; 62% were male; median age was 65 yo and median treatment duration was 119 days; 1980 treatment cycles and 335 AEs were analysed: 118 (35%) (64 G1-2; 54 G3-4) and 217 (65%) (114 G1-2; 103 G3-4) AEs occurred during and after cycle 1 (C1; DLT period), respectively; 58% of AEs were hematological toxicities. The risk of G3-4 toxicity for hematologic pts was 15% and 11% during and after C1 respectively, and was 12% and 18% for solid tumors excluding NHL, and was 29% and 24% for pts with NHL. DLT occurred in 10 pts (4%). Dose reduction occurred in 15% of pts, after a median duration of 21 treatment days. Temporary and definitive treatment interruption for toxicity occurred in 21% and 9% of pts, respectively; 87% of these occurred after C1.
Conclusions
In P1 trials of epidrugs, 65% of high-grade AEs occur after cycle 1 and 42% are non-haematological toxicities. More pts with NHL than pts with solid tumors (excluding NHL) or hematological malignancies present their first severe AE during C1. The dose recommendation process may require fine-tuning according to each pt population. Like molecularly targeted or immune therapies, epidrugs have distinct toxicity profile requiring specific attention in their development process.
Legal entity responsible for the study
Gustave Roussy Institut.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.