Browsing Over 91 Presentations
2P - Lung immune prognostic index (LIPI) can identify the fast-progressor to immune checkpoints inhibitors (ICI) in microsatellite instability (MSI) or mismatch repair deficient (dMMR) tumours
- Edouard Auclin (Paris, France)
- Edouard Auclin (Paris, France)
- Perrine Vuagnat (Villejuif, France)
- Cristina Smolenschi (Villejuif, France)
- Julien Taieb (Paris, France)
- Jorge Adeva Alfonso (Madrid, Spain)
Abstract
Background
MSI-H/dMMR is considered the first predictive marker of efficacy for ICIs with tissue/site-agnostic approval. However, around 39% of cases are refractory and no additional biomarker has been identified. We explored the prognostic value of pretreatment LIPI in MSI-H/dMMR patients (pts) treated with ICI, particularly to identify the fast-progressors (FP).
Methods
Multicenter retrospective study of pts with metastatic MSI-H/dMMR tumors treated with ICIs from Apr2014 to May2019. Biological and clinical data were collected; LIPI was calculated based on dNLR [neutrophils/leucocytes-neutrophils]>3 + LDH>Upper Limit of Normality (ULN), as reported. LIPI groups were: good (0 factor), intermediate (interm.; one factor) and poor (2 factors). Primary endpoint was overall survival (OS), including the FP (OS < 3 months); secondary endpoints were progression free survival (PFS).
Results
A total of 151 pts were treated, mainly female (59%), median age of 64y, with performance status (PS) >1 (68%), and sporadic dMMR status (68%). ICI was the 1st or 2nd line in 59%. The most frequent tumors types were gastrointestinal (66%) and gynecological (22%). LIPI groups were distributed as follows: good n=67 (47%), interm. n=62 (43%), poor n=14 (10%). The median (m) follow up was 32 months (m.). 24m OS rates were 71.1%, 54.2% and 14.3% for good, interm and poor risk groups, respectively (P<0.0001). After adjustment on tumor site, metastatic sites and PS, LIPI remains independently associated with OS (HR poor: 3.2, 95%CI:1.3-7.9, P=0.03). Overall, the FP rate was 16%; up to 35.7% in poor LIPI group vs. 7.5% in good LIPI (P=0.02). The odds ratio for FP event among the poor group was 6.9 [95%CI: 1.7-28.6; P=0.01]. Overall, mPFS was 10.5m. (7.1-35.1); by LIPI groups: 20.9m. (8.4-NR) for good, 9.9m. (2.8-NR) for interm. and 2.3m. (1.8-NR) for the poor group (P<0.0001).
Conclusions
LIPI identifies dMMR pts that do not benefit from ICI treatment, particularly the fast-progressors. It should be included as stratification factor for future trials.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
E. Auclin: Travel/Accommodation/Expenses: Mundipharma; Honoraria (self): Sanofi Genzymes. J. Taieb: Honoraria (self): Merck, Roche, Amgen, Lilly, Sanofi, Samsung, MSD, Servier, Celgene, Pierre Fabre; Advisory/Consultancy: Roche, Merck KGaA, Amgen, Lilly, MSD, Servier, Pierre Fabre, Sanofi, Samsung; Speaker Bureau/Expert testimony: Servier, Amgen, Roche, Sanofi, Merck, Lilly, Pierre Fabre. B. Besse: Research grant/Funding (institution): Abbvie, Amgen, AstraZeneca, BeiGene, Blueprint Medicines, BMS, Boehringer Ingelheim, Celgene, Cristal Therapeutics, Daiichi-Sankyo, Eli Lilly, GSK, Ignyta, IPSEN, Inivata, Janssen, Merck KGaA, MSD, Nektar, Onxeo, OSE immunotherapeutics, Pfizer, Pharma Mar. C. Massard: Advisory/Consultancy: Amgen, Astellas, AstraZeneca, Bayer, BeiGene, BMS, Celgene, Debiopharm, Genentech, Ipsen, Janssen, Lilly, MedImmune, MSD, Novartis, Pfizer, Roche, Sanofi, Orion. L. Mezquita: Research grant/Funding (self): Bristol Myers Squibb, Boehringer Ingelheim, Amgen; Advisory/Consultancy: Roche Diagnostics, Takeda; Honoraria (self): Bristol Myers Squibb, Tecnofarma, Roche; Travel/Accommodation/Expenses: Roche; Non-remunerated activity/ies: AstraZeneca. A. Hollebecque: Advisory/Consultancy: Gritstone Oncology, Eisai Co., Ltd., Amgen, Servier and Merck Serono. All other authors have declared no conflicts of interest.
3P - Association between inflammation index and nutritional status and the effectiveness of immunotherapy in NSCLC treatment
- Simona Tolu (Cagliari, Italy)
- Simona Tolu (Cagliari, Italy)
- Francesca Balconi (Cagliari, Italy)
- Nicole Liscia (Cagliari, Italy)
- Dario Spanu (Cagliari, Italy)
- Mara Persano (Cagliari, Italy)
Abstract
Background
Immunotherapy is an important therapeutic strategy for NSCLC, but only about 20% of patients had benefit. To identify predictive markers is crucial for a proper patient selection. Few trials assessed the correlation between nutritional/inflammation status and the effectiveness of immunotherapy.
Methods
A retrospective trial included patients (pts) with metastatic lung adenocarcinoma treated with immunotherapy from June 2017 to October 2019. We evaluated the following parameters: body mass index, weight loss, body composition by BIVA and computed tomography (CT) at L3-L4, C-reactive protein (CRP), albumin, hemoglobin, absolute lymphocytes count, patient performance status (PS), anorexia and quality of life (by miniCASCO questionnaire). Clinical response (CR) according iRECIST criteria, overall survival and progression-free survival (PFS) were assessed. All pts were evaluated every 4-6 months.
Results
We included 18 patients. CR significantly correlated with CRP (r = 0.4943; CI95% 0.05164-0.7746; p=0.0315) and muscle mass index (MMI) calculated by CT at baseline (r = 0.4955; CI95% 0.05328- 0.7752; p=0.031). We also found a significant correlation between PFS and CRP (r = -0.7304; CI95% -0, 8928 to -0.3999; p = 0.0006), MMI (r = 0.8229; CI95% 0.2119-0.6623; p = 0.0255) and PS at baseline ( r = -0.5101; CI95% -0.7890 to -0.05667; p = 0.0306). OS correlated significantly with baseline CRP (r = -0.6637; CI95% -0.8631 to -0.2851; p = 0.0027) and MMI at CT (r = 0.584; CI95% -0.2370-0.6472; p = 0.0304). At multivariate analysis CRP was an independent predictive factor of CR (p = 0.0213), PFS (p = 0.0006) and OS (p = 0.0027). The miniCASCO correlated positively with PS (r = 0.567; p = 0.036) and negatively with CR (r = -0.438; p = 0.010). Moreover, pts with partial response and stable disease had a significant decrease of CRP and a significant increase of MMI and hemoglobin compared to pts with progressive disease.
Conclusions
Our results showed, even in a limited sample size, the negative correlation of inflammation and poor nutritional status with CR in NSCLC pts treated with immunotherapy. Blocking inflammation and the related nutritional impairment may be crucial in improving efficacy of immunotherapy in advanced lung cancer pts.
Legal entity responsible for the study
S. Tolu, C. Madeddu.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
4P - IgM-rheumatoid factor as a novel biomarker for a reduced survival in anti-PD-1 treated NSCLC patients through the decrease of CD137+ T-cells
- Alessio Ugolini (Rome, Italy)
- Alessio Ugolini (Rome, Italy)
- Ilaria Zizzari (Rome, Italy)
- Fulvia Ceccarelli (Rome, Italy)
- Andrea Botticelli (Rome, Italy)
- Tania Colasanti (Rome, Italy)
Abstract
Background
Despite anti-PD-1 targeting with Immune-Checkpoint Inhibitors (ICIs) has markedly improved the survival of Non-Small Cells Lung Cancer (NSCLC) patients, the onset of both primary and secondary resistances still occur in the majority of patients. The association between autoimmunity and cancer is an area of particular interest being the latter, as in the case of autoantibodies, an indication of a dysfunctional immune system.
Methods
We enrolled 42 patients with metastatic NSCLC before and during anti-PD-1 treatment, evaluating circulating levels of different autoantibodies and Peripheral Blood Mononuclear Cells (PBMCs) populations.
Results
The presence of IgM-Rheumatoid Factor (IgM-RF) in patients sera was strongly associated (OR, 7,66; 95% CI, 1.62 to 36.18; p=0.005) with the development of early progression. IgM-RF positivity resulted also as an important prognostic factor for a worse outcome in terms of both PFS (p=0.035) and OS (p=0.034), with a more marked reduction of PFS rate (p=0.002) identified when patients were further stratified based on IgM-RF titers. IgM-RF+ patients showed a significant reduction (p=0.02) of the circulating tumor-specific CD137+ T-cell population. To confirm the importance of this T-cell population in driving patients response, an higher percentage of CD137+ T-cells at baseline correlated with a better outcome in terms of both PFS (p=0.006) and OS (p=0.002). Mechanistic experiments demonstrate that IgM-RF preferentially bound to naïve and central memory T-cells (p<0.0001) and a robust impairment (p=0.0001) of their migratory ability in response to CCL-19 was observed when exposed to IgM-R.
Conclusions
IgM-RF can be ascribed as a novel biomarker that is able to predict the development of early progression and, in addition, as a prognostic factor for a reduced PFS and OS in NSCLC patients in treatment with anti-PD-1 ICIs. The reduction of anti-tumor CD137+ T-cells that was observed in IgM-RF+ patients could make account for the reduced survival of the patients, since the frequency of this population in the blood of NSCLC patients resulted as an independent prognostic factor for a better outcome.
Legal entity responsible for the study
The authors.
Funding
Università Sapienza di Roma.
Disclosure
All authors have declared no conflicts of interest.
5P - Uncovering the evolution of glioblastoma proteome landscape from primary to the recurrent stage for development of novel diagnostic and predictive biomarkers
- Nazanin Tatari (Hamilton, ON, Canada)
- Nazanin Tatari (Hamilton, ON, Canada)
- Shahbaz Khan (Toronto, ON, Canada)
- Julie Livingstone (Toronto, ON, Canada)
- Chitra Venugopal (Hamilton, ON, Canada)
- Jennifer Chan (Calgary, AB, Canada)
Abstract
Background
Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. A wealth of literature describes the biology of primary GBM (p-GBM), but we currently lack an understanding of how GBM evolves through therapy to become a very different tumor at recurrence, which may explain why therapies against p-GBM fail to work in recurrent GBM (r-GBM). Therefore, to understand the evolution of r-GBM, we aimed to characterize patient-matched p-GBM and r-GBM proteome and identify potential therapeutic targets for r-GBM.
Methods
We collected one of the world’s largest patient-matched p-GBM and r-GBM samples from the Hamilton Health Sciences for gene expression profiling, proteomic analyses and tissue microarray (TMA) construction. Nano-String analysis was performed for GBM subtype identification. Furthermore, patient demographics was generated for survival analysis. The top potential therapeutic targets for r-GBM were identified by proteomic analysis and were validated on TMA using immunohistochemistry. The essentiality of each protein in r-GBM will be assessed using CRISPR KO studies and the top hit will be selected for pre-clinical testing.
Results
6798 proteins were detected by shotgun, label-free proteomic analyses. Differential expression analysis on the surface proteins revealed a distinct set of proteins overexpressed in r-GBM among which 7 proteins were selected as top potential therapeutic targets for r-GBM. Besides, the patients were grouped based on survival rate and the differential expression analysis revealed significantly enriched proteins and pathways in short-term survivors which cause aggressive phenotypes in GBM. In addition, consensus clustering identified five protein clusters which show distinction between primary vs recurrent tumors. Our data also strongly supports a preponderance of immune regulatory/suppressive genes as important drivers of r-GBM.
Conclusions
This study resulted in identification of diagnostic and predictive biomarkers which is extremely complementary and instructive for the development of new poly-therapeutic paradigms for GBM patients at the recurrent level and will lead to improvement of patient’s survival.
Legal entity responsible for the study
The authors.
Funding
McMaster University and University of Toronto.
Disclosure
All authors have declared no conflicts of interest.
6P - Role of inflammatory cytokines in distant metastasis of non-small cell lung cancer
- Olga E. Savelieva (Tomsk, Russian Federation)
- Olga E. Savelieva (Tomsk, Russian Federation)
- D Pismenny (Tomsk, Russian Federation)
- Liubov Tashireva (Tomsk, Russian Federation)
- Marina Zavyalova (Tomsk, Russian Federation)
- Vladimir Perelmuter (Tomsk, Russian Federation)
Abstract
Background
Inflammation is an essential component of the tumor microenvironment. Cytokines involved in inflammation can also promote the formation of premetastatic niches and distant metastases (according to D. Layden's theory). The aim of this study was to identify which cytokines are associated with the distant metastases in NSCLC.
Methods
The prospective study included 35 patients, male – 27 (77 %), female – 8 (23 %) with T1–4N0–2M0 non-small cell lung cancer (NSCLC) treated at Cancer Research Institute, Tomsk National Research Medical Center. Seventeen (49 %) of the 35 patients received 2–3 courses of neoadjuvant chemotherapy (NACT). The concentration of IL-1b, IL-2, IL-4, IL-6, IL-10, IL-12, IL-17a, IL-33, TNFa, IFNg, CXCL-8 (IL-8), CCL-2 (MCP-1), CCL-5 (RANTES), CXCL-12 (SDF-1) and VEGFA was determined in the serum by the Luminex xMAP technology in accordance with the protocols of manufacturers (“Milliplex MAP Kit”, Merck Millipore, USA). All statistical analyses were performed in the GraphPad Prism version 8.3.0 (GraphPad Software, USA).
Results
ogistic regression analysis made it possible to identify cytokines associated with the distant metastases. Thus, in patients who did not receive NACT, high concentrations of IL-6 and CXCL-12 (SDF-1) and the histological type of tumor (squamous cell carcinoma) were associated with a high risk of distant metastases (χ2 = 15.7; p = 0.0013). In patients after NACT a high concentration of IL-4 and a histological type of tumor (adenocarcinoma) were associated with a high risk of distant metastases (χ2 = 10.7; p = 0.0047).
Conclusions
The concentration of serum cytokines involved in inflammation and the formation of the premetastatic niche varies in patients with NSCLC. A high risk of the distant metastases is associated with high concentrations of IL-6, CXCL-12 (SDF-1) and IL-4 and histological type of NSCLC. Also, it is necessary to remember that the NACT in some cases promotes the distant metastases.
Legal entity responsible for the study
The authors.
Funding
The Council for Grants of President of Russian Federation (Grant SS-2701.2020.7).
Disclosure
All authors have declared no conflicts of interest.
7P - Peripheral blood-based biomarkers of prognosis and treatment response in patients with non-small cell lung cancer treated with PD-1 inhibitors
- Ioannis Tourkantonis (Athens, Greece)
- Ioannis Tourkantonis (Athens, Greece)
- Dimitra Grapsa (Athens, Greece)
- Andriani Charpidou (Athens, Greece)
- Ioannis Gkiozos (Athens, Greece)
- Helen Gogas (Athens, Greece)
Abstract
Background
To date, there remains an urgent need for more accurate biomarkers to predict clinical outcomes in patients with advanced-stage non-small cell lung cancer (NSCLC) treated with PD-1 inhibitors. The primary aim of our study was to evaluate the prognostic and predictive value of peripheral blood-based biomarkers, both at baseline (pre-treatment) and post-treatment, in this challenging clinical setting.
Methods
A retrospective study of the clinicopathological features and treatment data of 117 patients with advanced-stage NSCLC, treated with nivolumab or pembrolizumab at the Oncology Unit of Sotiria Athens General Hospital, was performed. Baseline and post-treatment absolute counts of neutrophils (ANC), lymphocytes (ALC), monocytes (AMC), eosinophils (AEC) and platelets (PLT), LDH as well as the ratio of neutrophils to lymphocytes (NLR), platelets to lymphocytes (PLR) and myeloid to lymphoid cells (M:L) were correlated with treatment response, durable clinical benefit (defined as absence of disease progression at 6 months) and progression-free survival (PFS).
Results
58,1% of patients had no immune-related adverse events (IrAEs), while rash and hyperthyroidism were observed in 17.9% and 12.8% of patients, respectively. Durable clinical benefit (DCB) rates were significantly lower in patients with increased pretreatment ANC, AMC, PLT, NLR, PLR, M:L and PLT ≥ 400 K/μl as well as post-treatment ANC ≥ 7500/μl, AMC ≥ 650/μl, NLR ≥ 5 and PLR > 160. Increased pretreatment PLR and PLT ≥ 400K/μ as well as increased post-treatment ANC, AMC, PLT, NLR, PLR, M:L, LDH, ANC > 7500/μl, AMC > 650/μl, PLT > 400K/μl, NLR > 5 and PLR > 160 were all correlated with reduced PFS. In multivariate analysis, increased pretreatment PLR [HR (95% CI): 0,79 (0,63 − 0,99); p=0,040] was independently correlated with worse PFS.
Conclusions
Pre-treatment PLR may independently predict prognosis in advanced NSCLC patients treated with PD-1 inhibitors. With the exception of ALC and AEC, pretreatment and/or post-treatment levels of all remaining blood cell counts and indices evaluated were shown to correlate either with DCB and/or PFS, albeit only in univariate analysis.
Legal entity responsible for the study
Konstantinos Syrigos.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
8P - Immune cell subsets in peripheral blood are associated with primary resistance to immunotherapy as frontline treatment in NSCLC
- Hugo Arasanz (Pamplona, Spain)
- Hugo Arasanz (Pamplona, Spain)
- Miren Zuazo (Pamplona, Spain)
- Luisa Chocarro (Pamplona, Spain)
- Ana Isabel Bocanegra Gondan (Pamplona, Spain)
- Maite Martínez-Aguillo (Pamplona, Spain)
Abstract
Background
Kagamu H et al. and our group recently reported the association between high levels of effector and highly differentiated CD4 T cells in peripheral blood and response to ICI in pretreated NSCLC (Zuazo M, 2019; Kagamu H, 2020). We have evaluated the dynamics of immune cell populations in patients receiving pembrolizumab as first line.
Methods
PBMCs from 25 patients with advanced NSCLC receiving pembrolizumab alone or concomitant with chemotherapy were obtained from peripheral blood before treatment. Cell subpopulations have been studied by flow cytometry according to the expression of CD3, CD4, CD8, CD11b, CD14, CD27, CD28, CD56, CD64, CD66b, CD116, CD163 and CD206.
Results
Higher levels of CD116+ CD66b+ neutrophils (21.1% vs 3.8%, p=0.045) and CD11b+ CD56+ CD14- NK cells (22.6% vs 12.7%, p=0.003) were associated with progression, while responders had lower levels of CD4+ CD27- CD28- cells (p = 0.032). Over the mean (OTM) CD4+ CD27- CD28- and NK cell levels were associated with shorter PFS (NR vs 8.3 wk, p = 0.026 and 64.1 vs 2.9 wk, p= 0.005). OTM neutrophils were associated with shorter OS (71.7 vs 9.9 wk, p = 0.012). ROC analysis showed an association between OTM neutrophils and progression as best response (AUC 0.903, p=0.005), with a threshold of 6.2% for a 90% specificity and 75% sensitivity. A score based on OTM neutrophils, NK and CD4+ CD27- CD28- cells discriminates patients according to their mPFS (0 = 64 wk, 1 = 22.9 wk, 2-3 = 2.86 wk; p=0.029).
Conclusions
Pretreatment immune cell subpopulations in peripheral blood quantified by flow cytometry might be useful to predict immunotherapy efficacy. Myeloid and CD27- CD28- CD4 cells cells might play relevant role in primary resistance to ICI.
Legal entity responsible for the study
IdiSNA, Navarra Institute for Health Research.
Funding
Asociación Española Contra el Cáncer (AECC), Instituto de Salud Carlos III.
Disclosure
All authors have declared no conflicts of interest.
9P - Circulating tumour cells (CTCs) count and PD-L1 expression in untreated extensive small cell lung cancer patients treated in the REACTION trial, a phase II study of etoposide and cis/carboplatin with or without pembrolizumab (NCT02580994)
- Jessica Menis (Padova, Italy)
- Jessica Menis (Padova, Italy)
- Paolo Bironzo (Torino, Italy)
- Gervais Radj (Caen, France)
- Laurent Greillier (Marseille, France)
- Isabelle Monnet (Creteil, France)
Abstract
Background
SCLC is characterized by large number of CTCs that have demonstrated prognostic value. We evaluated CTC count and PD-L1 expression on CTCs in the REACTION trial, a multicenter, open-label, randomized phase II trial.
Methods
In the REACTION trial, patients with ED-SCLC, unselected for PD-L1, with PS 0/1 and controlled brain metastases who achieved an objective response after 2 X Pl-E were randomized 1:1 to experimental arm (EXP) P in combination with 4 X Pl-E then P up to a total of 35 cycles vs. 4 X Pl-E in the control (CTRL) arm. Cross-over to P-Pl-E was allowed for CTRL. Primary endpoint was progression free survival (PFS) from randomization. CTCs were collected with Streck tubes after registration and during the first 2 cycles of induction chemotherapy (at the discretion of the investigator), before randomization and every 2 cycles during treatment and at end of treatment.
Results
Between Feb 7, 2018 and Oct 31, 2019, 125 patients were recruited (61 in EXP arm vs 64 in CTRL arm) with 119 (58 vs 61) eligible and receiving at least one dose of treatment (Per Protocol [PP] population). Median age was 65 vs 63.5 years with the majority being male (72 vs 56%), PS 1 (62 vs 60%), and rare brain metastases (8 vs 11%). Most patients had partial response (PR) to the induction chemo (98% in each arm). 19 patients crossed over to P-E-Pl. Among 124 patients who started treatment, grade ≥3 adverse events were observed in 43 vs 36%, while only 2 patients (1 in each arm) had grade 5 toxicity. Among PP patients, 107 PD or deaths were observed. The response rate was 61% (67 vs 56%). Median follow-up time with respect to OS was 14.2 months in EXP and 14.0 months in CTRL arm. Median PFS (80% CI) was 4.7 months (4.5, 5.3) vs 5.4 (4.9, 5.5), HR = 0.84 (0.65, 1.09) and 1-sided p=0.194. Median OS (80% CI) was 12.3 months (10.2, 14.5) vs 10.4 (8.5, 11.6), HR = 0.73 (0.54, 1.0) and 1-sided p=0.097.
Conclusions
P combined with Pl-E was well tolerated, did not improve PFS but OS was significantly improved. CTC analysis are in finalization and results will be presented during the congress.
Clinical trial identification
NCT02580994.
Legal entity responsible for the study
European Organization for Research and Treatment of Cancer.
Funding
Merck Sharp & Dohme.
Disclosure
All authors have declared no conflicts of interest.
10P - Genomic profiles of CD47 in breast tumours predict outcome and are associated with immune activation and enrichment of pro-tumoral macrophage markers
- Alberto Ocaña (Madrid, Spain)
- Alberto Ocaña (Madrid, Spain)
- María Del Mar Noblejas Lopez (Albacete, Spain)
- Mariona Baliu-Piqué (Madrid, Spain)
- Cristina Nieto-Jiménez (Salamanca, Spain)
- Francisco J. Cimas (Albacete, Spain)
Abstract
Background
Targeting the innate immune system has attracted attention with the development of antibodies against CD47, an immune checkpoint for macrophage-mediated phagocytosis. Anti-CD47 antibodies block the inhibition of the phagocytic activity of macrophages caused by the up-regulation of CD47 expression on tumor cells.
Methods
Public genomic data was used to identify genes highly expressed at mRNA level in breast tumors with elevated CD47 expression. Samples included in KM Plotter Online Tool were used as exploratory cohort and the METABRIC study was used as a confirmatory dataset. Tumor Immune Estimation Resource (TIMER) platform was employed to analyze the association between the presence of tumor immune infiltrates and the expression of the selected genes. Gene set enrichment analysis (GSEA) was performed to assess enrichment of the indicated gene-sets with up-regulated genes.
Results
We identified 142 genes positively correlated with CD47 (Spearman correlation SC>0.4 and p<0.05), of which 83 (58.5%) predicted favorable relapse free survival (RFS) and 32 (22.5%) predicted detrimental RFS. From those associated with favorable RFS, we selected the genes with immunologic biological functions including regulation of T cell mediated cytotoxicity and positive regulation of defense response, to define a CD47-immune signature composed by PTPRC, HLA-E, TGFBR2, PTGER4, ETS1 and OPTN. In the Basal-like and HER2+ breast cancer subtypes, the expression of the CD47-immune signature predicted favorable outcome for RFS and overall survival (OS). The expression of the six genes composing the signature correlated with the presence of immune infiltrates, mainly dendritic cells, neutrophils, CD8+T and CD4+T cells: and with gene expression signatures of T cell activation. Finally, CD47 up-regulated genes associated with favorable outcome correlated with pro-tumoral macrophages.
Conclusions
We describe a CD47-immune gene signature composed of 6 genes associated with favorable outcome, T cell activation and pro-tumoral macrophages in breast cancer tumors expressing high levels of CD47.
Legal entity responsible for the study
The authors.
Funding
Instituto de Salud Carlos III (PI19/00808), ACEPAIN, Diputación de Albacete, CIBERONC and CRIS Cancer Foundation (to A. Ocaña). Ministry of Economy and Competitiveness of Spain (BFU2015-71371-R), The Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003) and CIBERONC, The Scientific Foundation of the AECC and the CRIS Foundation (to A. Pandiella). MdM. Noblejas-López was supported by Spanish Ministry of Education (FPU grant; Ref.: FPU18/01319). The work carried out in our laboratories received support from The European Community through the regional development funding program (FEDER). B. Győrffy was supported by the NVKP_16-1-2016-0037, 2018-1.3.1-VKE-2018-00032 and KH-129581 grants.
Disclosure
A. Ocaña: Research grant/Funding (institution): Entrechem; Travel/Accommodation/Expenses: Merck; Advisory/Consultancy: Daiichi Sankyo. A. Pandiella: Advisory/Consultancy: Daiichi Sankyo. All other authors have declared no conflicts of interest.
12P - The correlation between non-coding RNA and response rate to immune-checkpoint inhibitors
- Dmitrii Shek (Campbelltown, Australia)
- Dmitrii Shek (Campbelltown, Australia)
- Scott Read (Blacktown, Australia)
- Adnan Nagrial (Blacktown, Australia)
- Matteo Carlino (Wollstonecraft, Australia)
- Jacob George (Westmead, Australia)
Abstract
Background
Immune-checkpoint inhibitors (ICIs) have revolutionized clinical oncology in recent years. ICIs are monoclonal antibodies (mAbs) that block inhibitory CTLA-4 and PD-1 signalling pathways and boost cytotoxic T cell antitumor activity. Currently, there is a lack of knowledge regarding factors associated with ICI efficacy and safety. Non-coding RNAs (ncRNAs) are abundant (up to 70% of the human genome) regulators of gene expression, with proven abilities to promote cancer drug resistance. This study aims to determine an association between tumour ncRNA and response to ICI therapy.
Methods
Gene expression data was downloaded from the NCBI GEO database. Effect-size (standardized mean difference [SMD]) was calculated using Hedges’ g method and further meta-analysis was conducted in Stata v16 software. DAVID online bioinformatics tool was used to determine proteins and pathways associated with abnormally expressed ncRNAs.
Results
We identified two datasets derived from patients undergoing anti-PD-1 mAb (nivolumab) therapy: GSE79691 (metastatic melanoma [MM]) and GSE67501 (renal cell carcinoma [RCC]). Both studies evaluated RNA from formalin-fixed paraffin embedded (FFPE) specimens. MiR-27B (p=0.02) and miR-let7D (p=0.003) were significantly higher among non-responders to ICI therapy compared to responders in both datasets. In particular, SMD was 4.57 (miR-27B) and 3.9 (miR-let7D) higher among non-responders in both studies with low study heterogeneity scores (I2=22.67% and T2=0.36). In comparison, analysis of datasets GSE99898 (MM) and GSE74174 (RCC) using kinase inhibitors found no significant association between treatment response and the aforementioned microRNAs. Because miR-27B and miR-let7D influence PI3K/Akt and Wnt/β-catenin signalling pathways, further studies are required to validate whether these microRNAs modulate cancer progression in general or are unique to ICI therapy response.
Conclusions
We have established that miR-27B and miR-let7D are increased among non-responders to ICI therapy supporting their possible predictive role for ICI therapeutic response.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
13P - PD-L1 prevalence in advanced urothelial carcinoma by demographic and clinical characteristics
- Thomas Powles (London, United Kingdom)
- Thomas Powles (London, United Kingdom)
- Michiel Van der Heijden (Amsterdam, Netherlands)
- Arjun Balar (New York, NY, United States of America)
- Peter O'Donnell (Chicago, IL, United States of America)
- Christophe Massard (Villejuif, France)
Abstract
Background
High PD-L1 expression in tumor cells (TCs) and/or immune cells (ICs) has been linked to the efficacy of PD-1/PD-L1 inhibitors in urothelial carcinoma (UC). However, PD-L1 expression in tumor-infiltrating ICs has also been linked to improved prognosis in UC, which may confound analysis of its value as a predictive biomarker for immunotherapy. To better understand the prognostic role of PD-L1 in UC, we investigated the association of PD-L1 expression with clinical and demographic characteristics.
Methods
PD-L1 expression in tumor biopsy samples from studies CD-ON-MEDI4736-1108 (NCT01693562) and D4910C00010 (NCT02261220) was assessed using the VENTANA PD-L1 (SP263) Assay. The specimens were scored at TC≥25%, IC ≥25%, TC or IC≥25%. The clinically relevant cutoff of IC≥5% (as percentage of tumor area) was also derived. Prevalence was reported for various clinical and demographic groups and significance calculated using Fisher’s exact test, adjusted for multiple testing with Benjamini-Hochberg method.
Results
PD-L1 expression as defined by IC≥5% (as percentage of tumor area) was associated with the highest number of positive prognostic factors, including ECOG performance status, Bellmunt scores, absence of visceral metastases at baseline, and lower tumor burden (Table). TC/IC25% was associated only with absence of visceral metastases at baseline (adjusted p value 0.003). IC≥25% was independently associated with the absence of visceral metastases and favorable Bellmunt score, but TC≥25% alone was not.
Conclusions
Higher PD-L1 expression in ICs is associated with clinically favorable characteristics in UC. IC-driven PD-L1 algorithms such as IC≥5% (by tumor area) are more strongly associated with known favorable prognostic indicators than those incorporating TCs. These findings may have implications for clinical studies where PD-L1 expression is utilized as a selective biomarker.
Characteristic Category n % PD-L1 high (TC/IC≥25%) Adjusted P-value % PD-L1 high (IC≥5%) Adjusted P-value Smoking status Current 36 56 0.90 8.3 0.76 Former 182 51 14.3 Never 120 47 10.0 Baseline liver metastases N 221 53 0.32 14.9 0.15 Y 117 44 6.8 Baseline visceral metastases N 94 67 0.003 24.5 0.001 Y 244 43 7.4 Baseline lymph only invovlement N 287 46 0.05 9.1 0.002 Y 51 69 29.4 Ecog ps 0 114 54 0.50 21.9 0.002 1 224 48 7.1 2 1 0 0.0 Bellmunt score 0 74 53 0.32 23.0 0.03 1 136 54 12.5 2 105 40 5.7 3 23 61 4.3 Tumor burden <median 163 52 0.90 17.2 0.04 ≥median 175 48 7.4 Sample method collection Biopsy 234 46 0.32 12.8 0.87 Excision/Resection 61 57 9.8 Other 1 100 0.0 Sample location Metastatic 263 48 0.32 12.9 0.76 Primary 76 58 9.2
Clinical trial identification
NCT01693562, NCT02261220.
Editorial acknowledgement
Medical writing and editorial support provided by Ward A. Pedersen, PhD, of Parexel, funded by AstraZeneca.
Legal entity responsible for the study
AstraZeneca.
Funding
AstraZeneca.
Disclosure
T.B. Powles: Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: AstraZeneca; Honoraria (self), Research grant/Funding (institution): BMS; Honoraria (self), Research grant/Funding (institution): Exelixis; Honoraria (self): Incyte; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Ipsen; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck/MSD; Honoraria (self), Research grant/Funding (institution): Novartis; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Research grant/Funding (institution): Seattle Genetics; Honoraria (self), Research grant/Funding (institution): Merck Serono; Honoraria (self), Research grant/Funding (institution): Astellas; Honoraria (self), Research grant/Funding (institution): Johnson & Johnson; Honoraria (self), Research grant/Funding (institution): Eisai; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche. M.S. van der Heijden: Advisory/Consultancy: Astellas Pharma; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca/MedImmune; Advisory/Consultancy, Research grant/Funding (self): Bristol Myers Squibb; Advisory/Consultancy: MSD Oncology; Advisory/Consultancy, Research grant/Funding (self): Roche/Genentech; Advisory/Consultancy: Seattle Genetics. A.V. Balar: Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): AstraZeneca/MedImmune; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Genentech/Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Merck; Advisory/Consultancy: Cerulean Pharma; Advisory/Consultancy: Incyte; Advisory/Consultancy: Pfizer/EMD Serono; Advisory/Consultancy: Seattle Genetics/Astellas; Research grant/Funding (institution): Seattle Genetics. P. O'Donnell: Shareholder/Stockholder/Stock options: Allergan; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Genentech/Roche; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Merck; Honoraria (self): Astellas Pharma; Honoraria (self), Research grant/Funding (institution): Seattle Genetics; Honoraria (self): OncLive; Honoraria (self): Atheneum Partners; Honoraria (self): Health Advances; Honoraria (self), Research grant/Funding (institution), Travel/Accommodation/Expenses: Janssen; Honoraria (self): Dedham Group; Honoraria (self): Schlesinger Associates; Honoraria (self): FirstWord Publication; Research grant/Funding (institution): Boehringer Ingelheim; Research grant/Funding (institution): AstraZeneca/MedImmune; Research grant/Funding (institution): Acerta Pharma; Research grant/Funding (institution): Bristol Myers Squibb. C. Massard: Advisory/Consultancy: Amgen; Advisory/Consultancy: Astellas Korea; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Bayer; Advisory/Consultancy: BeiGene; Advisory/Consultancy: Bristol Myers Squibb; Advisory/Consultancy: Celgene; Advisory/Consultancy: Debiopharm Group; Advisory/Consultancy: Genentech. J. Walker: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. A. Gupta: Advisory/Consultancy, Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. N. Angra: Travel/Accommodation/Expenses, Shareholder/Stockholder/Stock options, Full/Part-time employment: MedImmune/AstraZeneca. J. Cairns: Full/Part-time employment: AstraZeneca. B. Turriziani: Full/Part-time employment: AstraZeneca. M.C. Rebelatto: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. M. Scott: Shareholder/Stockholder/Stock options, Full/Part-time employment: AstraZeneca. S. Wildsmith: Full/Part-time employment: AstraZeneca.
14P - High CMTM6 and PD-L1 co-expression predict metastasis and poor prognosis in oesophageal squamous cell carcinoma
- Yuejun Luo (Beijing, China)
- Yuejun Luo (Beijing, China)
- Chaoqi Zhang (Beijing, China)
- Zhihui Zhang (Beijing, China)
- Guochao Zhang (Beijing, China)
- Liyang Xue (Beijing, China)
Abstract
Background
The newly identified immune checkpoint inhibitor CMTM6 (CKLF-like MARVEL transmembrane domain containing 6) is reported as a critical regulator of programmed death ligand (PD-L1) expression by modulating stability through ubiquitination and modulate T cell expression in several tumors. However, the role of CMTM6 has so far remained unclear in esophageal cancer, especially in esophageal squamous cell carcinoma (ESCCs). The aim of this study was to investigate the expression of CMTM6 and PD-L1 and to confirm their predictive roles in ESCC clinical prognosis.
Methods
We collected 137 ESCCs patients' pretreatment biopsies from multiple centers in China. CMTM6 and PD-L1 immunohistochemical expressions were evaluated. The correlation between CMTM6 and PD-L1 expression was also determined based on immunohistochemistry and RNA-sequencing data obtained from The Cancer Genome Atlas (TCGA) database. The prognostic value (overall survival (OS) and disease-free survival (DFS)) of CMTM6 and PD-L1 were also evaluated.
Results
CMTM6 expression was detected in approximately 70% of ESCCs tumor tissues, and CMTM6 was highly expressed in ESCCs tumor tissues compared to adjacent normal tissues. In addition, PD-L1 expression is always found in CMTM6 positive cases. CMTM6 expression was positively correlated with PD-L1 expression in immunohistochemical data (P<0.05). A positive correlation was also identified in the mRNA expression data (P<0.05). CMTM6 and PD-L1 expression were associated with cancer metastases, but not with patients’ age and gender. In univariate survival analysis found that positive CMTM6 and PD-L1 expression were correlated with poor OS (P<0.05) and inferior DFS (P<0.05). In multivariate survival analysis found that high CMTM6 and PD-L1 co-expression was significantly associated with poor OS (P<0.05) and inferior DFS (P<0.05).
Conclusions
CMTM6 expression is positively associated with PD-L1 expression. High CMTM6 and PD-L1 co-expression correlated with metastasis and predict the poor OS and inferior DFS. Thus, CMTM6 and PD-L1 co-expression can be a promising predictor useful for predicting ESCCs prognosis.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.