Browsing Over 400 Presentations
Metastases to and from the lung
8P - Noncanonical Wnt11, a tumor suppressive gene by antagonizing canonical Wnt signaling, represents a putative molecularly therapeutic target in lung cancer
- Xiangyu Wang (HK)
- Xiangyu Wang (HK)
- Lili Li (HK)
- Tony S.K. Mok (HK)
- Qian Tao (HK)
Abstract
Background
Most studies focused on the role of canonical Wnt signaling pathway, an increasing field of research, however, is concerning about the noncanonical Wnt pathways. The role of Wnt11, a noncanonical Wnt family member, has not been established in lung cancer. Epigenetic inactivation of tumor suppressive genes through promoter CpG methylation is a fundamental regulatory process during tumorigenesis.
Methods
The expression levels of Wnt11 were assessed in human normal tissues and lung cancer cell lines panel by semi-quantitative reverse transcription-PCR(RT-PCR). The promoter CpG methylation of Wnt11 were tested in bisulfite treated DNA by methylation-specific PCR (MSP). Western blots assay, colony formation assay, cell proliferation assay, wound-healing assay, dual-luciferase reporter assay and apoptosis assay were used to characterize the changes induced by overexpression of Wnt11.
Results
In our study, analysis of Wnt11 expression revealed it was broadly expressed in human normal adult and fetal tissues, while it's frequently downregulated or silenced in multiple lung cancer cell lines. By performing methylation-specific PCR (MSP), promoter CpG methylation of Wnt11 were frequently detected in multiple lung cancer cell lines. Functional assays show that ectopic expression of Wnt11 could suppress tumor cell growth, possibly through inducing apoptosis. Moreover, Wnt11 represses canonical Wnt/β-catenin signaling and AKT signaling pathway. Wnt11 overexpression also reversed EMT and downregulated stem cell markers.
Conclusions
Together our data suggest that in lung cancer, Wnt11 is lost by methylation and represents a tumor suppressor by antagonizing canonical Wnt/β-catenin signaling and AKT signaling pathway. Restoration of Wnt11 expression through demethylation could be an important therapeutic approach in the treatment of lung cancer.
Legal entity responsible for the study
The Chinese University of Hong Kong
Funding
RGC (TBRS #T12-401/13R), China Natural Science Foundation (NSFC #81572327), Johns Hopkins Singapore, and VC special research fund from The Chinese University of Hong Kong
Disclosure
The author has declared no conflicts of interest.
144PD - Leptomeningeal metastases in EGFR-mutated non-small cell lung carcinoma: Management after tyrosine kinase inhibitors
- Ronan Flippot (FR)
- Ronan Flippot (FR)
- Edouard Auclin (FR)
- Pamela Biondani (IT)
- Emilie Le Rhun (FR)
- David Planchard (FR)
- Caroline Caramella (FR)
- Cécile Le Pechoux (FR)
- Ludovic Lacroix (FR)
- Laura Mezquita (FR)
- Benjamin Besse (FR)
Abstract
Background
Leptomeningeal metastases (LM) in non-small-cell lung carcinoma (NSCLC) are associated with poor outcome. Tyrosine kinase inhibitors (TKIs) are active in LM+ EGFR mutated (EGFRm) patients (pts), but optimal patient's management after failure of TKIs is unknown.
Methods
We included consecutive pts with EGFRm NSCLC who had LM progression during first-line EGFR TKI, defined as diagnosis of LM during TKI treatment or progression of known LM after first-line TKI, treated in our institution. Clinical and pathological data were retrospectively collected. We evaluated overall survival (OS), progression-free survival (PFS), clinical response rate (CRR), and disease control rate (DCR) defined as clinical response or stable disease >2 months.
Results
We included 66 pts treated between Apr. 2003 and Sept. 2016, with a median age of 54 years [26–79]; 51 (77%) were females; 56 (85%) non-smokers. Twenty-three tumors (35%) had exon 19 deletion, 23 (35%) L858R exon 21 mutation, 10 (15%) T790M mutation. Median number of previous lines was 2 [1–7], and 19 pts (29%) had additional intrathecal treatment. 2nd line TKI was given to 36 pts (55%): 19 (53%) received erlotinib, 10 (28%) high dose (HD) erlotinib (300 mg daily), 3 osimertinib, 4 other 1st/2nd generation TKI (3 gefitinib, 1 afatinib). Median PFS and OS from LM progression were 3 months (m) [CI95% 2–3] and 7 m [CI95% 3–16], respectively. CRR and DCR for 2nd-line TKI were 43% and 77%. Nine pts (25%) were alive at 10 m (6 erlotinib, 1 HD erlotinib, 2 osimertinib). Median OS for erlotinib, HD erlotinib, osimertinib and other 1st/2nd generation TKI were 8 m (CI 95% 7–16), 3 m (CI 95% 2-not reached (NR)), NR (CI 95% NR-NR), and 2.5 m (CI 95% 0-NR), respectively. Patients treated with erlotinib, of whom 79% received prior afatinib or gefitinib, had better OS compared to patients treated with other 1st/2nd generation TKI (8 m
Conclusions
2nd-line TKI can increase survival in LM+ EGFRm NSCLC previously treated with TKI. Sequential erlotinib after prior gefitinib or afatinib seems to be a suitable strategy. Increasing erlotinib dose has demonstrated clinical benefit.
Legal entity responsible for the study
Gustave Roussy
Funding
Has not received any funding
Disclosure
All authors have declared no conflicts of interest.
43P - A network-based signature to predict the survival of non-smoking lung adenocarcinoma
- Qixing Mao (CN)
- Qixing Mao (CN)
- Feng Jiang (CN)
- Lin Xu (CN)
Abstract
Background
A substantial increase in the number of non-smoking lung adenocarcinoma (LAC) patients draws extensively attention in the past decades. Effective biomarkers are needed to identify high-risk patients to guide the therapy. Here, we provided a network-based signature to predict the survival of non-smoking LAC.
Methods
Gene expression profiles were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Significant gene co-expression networks and hub genes were identified by Weighted Gene Co-expression Network Analysis (WGCNA). Potential mechanisms and pathways of co-expression networks were analyzed by Gene Ontology (GO). The predictive signature was constructed by penalized Cox regression analysis and tested in two independent datasets.
Results
Two distinct co-expression modules were significantly correlated with non-smoking status across four GEO datasets. GO revealed that nuclear division and cell cycle pathways were main mechanisms of the blue module and that genes in the turquoise module were involved in lymphocyte activation and cell adhesion pathways. Seventeen genes were selected from hub genes at an optimal lambda value and built the prognostic signature. The prognostic signature distinguished the survival of non-smoking LAC (training: hazard ratio (HR) = 3.696, 95%confident interval (CI): 2.025–6.748, p < 0.001; testing: HR = 2.9, 95%CI:1.322–6.789, p = 0.006; HR = 2.78, 95%CI:1.658–6.654, p = 0.022) and had moderate predictive abilities in the training and validation datasets.
Conclusions
The prognostic signature is a promising predictor of non-smoking LAC patients, which might benefit to clinical practice and precision therapeutic management.
Legal entity responsible for the study
Lin Xu
Funding
National Natural Science Foundation of China (Nos. 81472702, 81501977 and 81672294)
Disclosure
All authors have declared no conflicts of interest.
Immunotherapy in the first-line setting: What have we achieved?
- Martin Reck (DE)
- Martin Reck (DE)
97P - Multistep prediction of cardio-pulmonary morbidity after lung cancer surgery
- Nazar Lukavetskyy (UA)
- Nazar Lukavetskyy (UA)
- Ruslan Litviniak (UA)
- Ihor Hipp (UA)
- Taras Fetsych (UA)
Abstract
Background
The aim of the study is to establish “multistep” criteria to clarify the high-risk patients with resectable lung cancer. The purpose of the present study was to identify preoperative risk factors in lung cancer patients.
Methods
Retrospective review of the clinical records of all patients operated on thoracic department in 2010–2011. None of the patient received preoperative chemo and/or-radiotherapy. Patients older than 70 years, benign lung lesions, lung metastases, or patients after non-curative lung resection were excluded. A total of 168 patients met criteria for the study. All factors were divided into 3 groups: initial (36 factors incl. TNM, histology, presence of comorbidities etc), functional (29 factors – lung function parameters, echocardiography), and surgery-related (14 factors incl. type of surgery and lymphadenectomies etc.). We analyzed postoperative mortality, pulmonary complications, arrhythmia and hypertension. All of the variables that were found to be significant in the univariate analyses were entered into the multivariate analyses using a forward step-wise logistic regression model in all group separately.
Results
Group 1. Our model identifies no risk factors for postoperative mortality and hypertension. Diabetes mellitus is associated with higher rates of arrhythmia. Predictors that are associated with pulmonary complication include: the history of second primary cancer, neuroendocrine tumours, rare type of lung tumours. Group 2. There are no risk factors for arrhythmia and hypertension. Left ventricular ejection fraction <45 is associated with postoperative mortality, forced expiratory flow at 25% – pulmonary complication. Group 3. The following criteria related with postoperative mortality – number of unobstructed (by tumours) lung segments, pulmonary complications – ventilation time, arrhythmia – number of resected lymph nodes, hypertension – surgery with resection adjacement structures.
Conclusions
There are risk factors associated with higher rates of specific postoperative mortality and morbidity but need to be validated by prospective study.
Legal entity responsible for the study
Lviv Medical University
Funding
Has not received any funding
Disclosure
All authors have declared no conflicts of interest.
88P - Feasibility of outpatient dinutuximab (D) and irinotecan (I) for second-line treatment of relapsed or refractory small cell lung cancer (RR SCLC): Part 1 of an open-label, randomized, phase 2/3 study
- Martin J. Edelman (US)
- Martin J. Edelman (US)
- Oscar Juan (ES)
- Alejandro Navarro (ES)
- Gil Golden (US)
- Amanda Saunders (US)
Abstract
Background
D, a chimeric monoclonal antibody that binds cell-surface GD2 expressed on SCLC, can cause significant pain. Combined tolerability with I in RR SCLC patients (pts) is unknown.
Methods
Part 1, an intrasubject dose-escalation lead in to the main study, investigated outpatient use of D + I. Eligibility: RR SCLC following first-line platinum-based therapy with a life expectancy of ≥12 weeks, PS 0-1. Pts received intravenous (IV) D and I (fixed dose 350 mg/m2) on Day 1 q 21-days. D was dosed 10 mg/m2, and increased 2 mg/m2/cycle, if pain was < Grade 2, no opioid medications were required, and prior dose was otherwise tolerated. Doses could be decreased based on toxicity observed. Pretreatment included IV hydration, antihistamines, and antipyretics. Pts were monitored for 4 hours after D. Pts remain on treatment until intolerance, progression, or death.
Results
12 pts were treated (8 male) in US and Spain. Mean (range) age was 68 (47–79) years. A median (range) of 3 (2–4) cycles were completed per pt. Median (range) D dose achieved was 14 (10–16) mg/m2. 121 adverse events (AEs) were reported in the
| AE | Grade, N subjects (%) | |||
|---|---|---|---|---|
| 1 | 2 | 3 | 4 | |
| Back pain | 5 (41.7%) | 1 (8.3%) | 1 (8.3%) | 0 |
| Pain in extremity | 3 (25.0%) | 0 | 0 | 0 |
| Abdominal pain | 1 (8.3%) | 1 (8.3%) | 0 | 0 |
| Arthralgia | 1 (8.3%) | 0 | 1 (8.3%) | 0 |
| Headache | 2 (16.7%) | 0 | 0 | 0 |
| Diarrhea | 10 (83.3%) | 2 (16.7%) | 0 | 0 |
| Nausea | 5 (41.7%) | 3 (25.0%) | 0 | 0 |
| Cough | 3 (25.0%) | 1 (8.3%) | 0 | 0 |
| Vomiting | 3 (25.0%) | 1 (8.3%) | 0 | 0 |
| Anaemia | 2 (16.7%) | 0 | 1 (8.3%) | 0 |
| Constipation | 3 (25.0%) | 0 | 0 | 0 |
| Decreased appetite | 3 (25.0%) | 1 (8.3%) | 0 | 0 |
| Asthenia | 2 (16.7%) | 1 (8.3%) | 0 | 0 |
| Dehydration | 2 (16.7%) | 0 | 0 | 0 |
| Fatigue | 1 (8.3%) | 1 (8.3%) | 0 | 0 |
| Hypomagnesaemia | 1 (8.3%) | 1 (8.3%) | 0 | 0 |
| Infusion related reaction | 1 (8.3%) | 0 | 0 | 0 |
Conclusions
D up to 16 mg/m2 + I have been tolerated with no unanticipated AEs. Part 2 of the study has begun and will randomize ∼460 subjects to: I vs. D + I vs. topotecan.
Clinical trial identification
EudraCT 2017-000758-20 ClinTrials NCT03098030
Legal entity responsible for the study
United Therapeutics Corporation
Funding
United Therapeutics Corporation
Disclosure
M.J. Edelman: Primary investigator for this corporate-sponsored research. O. Juan, A. Navarro: Principal investigator for this corporate-sponsored research. G. Golden, A. Saunders: Employed by United Therapeutics Corporation who is the sponsor of this study.
Target treatment combinations: Rationale and evidence
- David P. Carbone (US)
- David P. Carbone (US)
Presentation
146P - The clinical impact of comprehensive cfDNA genomic testing in lung cancer
- Smadar Geva (IL)
- Smadar Geva (IL)
- Anna Belilovski Rozenblum (IL)
- Roxana Grinberg (IL)
- Addie Dvir (IL)
- Lior Soussan-Gutman (IL)
- Laila C. Roisman (IL)
- Elizabeth Dudnik (IL)
- Alona Zer (IL)
- Ofer Rotem (IL)
- Nir Peled (IL)
Abstract
Background
Next-generation sequencing (NGS) of cell-free circulating tumor DNA (cfDNA) enables a non-invasive option for comprehensive genomic analysis of lung cancer patients. Currently there is insufficient data in regard to the impact of cfDNA analysis on clinical decision making. In this study, we evaluated the clinical utility of cfDNA sequencing on treatment strategy and progression-free survival in non-small cell lung cancer (NSCLC) patients.
Methods
In this retrospective study, data was collected from files of 116 NSCLC patients monitored between the years 2014–2017 in Israel. Plasma samples from stage IIIb/IV NSCLC patients were analyzed by a commercial test (Guardant 360), using hybrid capture, single molecule barcoding and massively parallel paired-end synthesis to sequence a targeted gene panel. This test allows the detection of somatic alterations such as point mutations, indels, fusions and copy number amplifications.
Results
116 consecutive NSCLC patients were included in this study. Median age at diagnosis was 63 years, male:female ratio was 1:1.7. 40% (47/116) were never-smokers, 83% (96/116) had adenocarcinoma. 41.4% (48/116) were tested before 1st line therapy (Group A), 34.5% (40/116) upon progression on chemotherapy or immunotherapy (Group B1) and 24.1% (28/116) upon progression on EGFR TKIs (Group B2). The most common genes were EGFR sensitizing mutations (25.9%, 30/116), MET amplifications and/or exon 14 skipping mutations or resistance point mutation (9.5%, 11/116) and EGFR T790M mutations (6.9%, 8/116). Clinical outcome of cfDNA analysis and targeted therapy for the entire cohort and for each group are summarized in the
Clinical Outcome of cfDNA Analysis and Targeted Therapy
| Total (n = 116) | Group A (n = 48) | Group B1 (n = 40) | Group B2 (n = 28) | |
|---|---|---|---|---|
| Drug-associated actionable Mutations (On/Off Lable) | 65% (75/116) | 65% (31/48) | 52.5% (21/40) | 82% (23/28) |
| Lung Cancer Related Actionable Mutations (NCCN guidelines) | 41% (48/116) | 31% (15/48) | 32.5% (13/40) | 71% (20/28) |
| Tretmanet change (Impact on Decision) | 26% (30/116) | 23% (11/48) | 25% (10/40) | 32% (9/28) |
| Response Evaluable | 93% (28/30) | 82% (9/11) | 100% (10/10) | 100% (9/9) |
| Response not Evaluable | 7% (2/30) | 18% (2/11) Early cessation of treatment d/t toxicity | 0% (0/10) | 0% (0/9) |
| Response Assessment (RECIST): CR | 4% (1/28) | 0% (0/9) | 0% (0/10) | 11% (1/9) |
| Response Assessment (RECIST): PR | 39% (11/28) | 44% (4/9) | 30% (3/10) | 44% (4/9) |
| Response Assessment (RECIST): SD | 32% (9/28) | 56% (5/9) | 20% (2/10) | 22% (2/9) |
| Response Assessment (RECIST): PD | 25% (7/28) | 0% (0/9) | 50% (5/10) | 22% (2/9) |
| Objective Response Rate | 43% (12/28) | 44% (4/9) | 30% (3/10) | 55.5% (5/9) |
| Disease Control Rate | 75% (21/28) | 100% (9/9) | 50% (5/10) | 78% (7/9) |
| Median Duration of Treatment | 5 months (6/28 ongoing) | 9 months (4/9 ongoing) | 3.5 months (0/10 ongoing) | 4 months (2/9 ongoing) |
| Durable Disease Control Rate (over 4 months) | 43% (13/30) | 64% (7/11) | 20% (2/10) | 44% (4/9) |
| Median PFS | 3.6 months | 7.3 months | 2.5 months | 3.3 months |
Conclusions
This study extends the evidence for clinical utility of comprehensive NGS testing by demonstrating durability of response to plasma-detected genomic alterations. cfDNA NGS changes treatment decisions in a significant number of patients in this retrospective study. It also has the potential to reduce undergenotyping of advanced NSCLC patients, while reducing costs and complications of biopsies, and facilitating more precise use of targeted therapy as well as immunotherapy.
Legal entity responsible for the study
Soroka Cancer Center, Ben-Gurion University, Beer Sheva, Israel.
Funding
Has not received any funding
Disclosure
S. Geva: Travel grant from Teva Pharmaceuticals, Honorarium from Guardant Health. A. Dvir, L. Soussan-Gutman: Employee of Oncotest (subsidiary of Teva pharmaceuticals), the distributor of Guardant360 in Israel. L.C. Roisman: Lectures fees: Roche, MSD, Pfizer, Astrazenca. A. Zer: Personal fees from Roche, grants and personal fees from BMS, personal fees from AstraZeneca, personal fees from BI, outside the submitted work. N. Peled: Advisor & Honorarium from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, FoundationMedicine, Gaurdant360, MSD, Novartis, NovellusDx, pfizer, Roche, Takeda. All other authors have declared no conflicts of interest.
Q&A
162P - Responses to EGFR TKIs and ALK TKIs in advanced NSCLC patients harboring concomitant EGFR and ALK alterations
- Shuyuan Wang (CN)
- Shuyuan Wang (CN)
- Tianqing Chu (CN)
- Bo Zhang (CN)
- Baohui Han (CN)
- Bo Yan (CN)
- RONG Qiao (CN)
Abstract
Background
Previous studies indicated that Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement are mutually exclusive in non-small cell lung cancer (NSCLC). However, cases diagnosed with concomitant EGFR and ALK alterations has been occasionally reported. This study aimed to assess the prevalence of this small subset patients and optimize clinical management.
Methods
We retrospectively collected clinical outcomes of 29 cases who had concomitant EGFR and ALK alterations from 5816 lung cancer patients tested EGFR mutation and ALK rearrangement between 2011–2017 in the Shanghai Chest Hospital. Meanwhile, we identified 103 cases harboring double positive mutations from a literature search. Of these 132 cases, 81 patients received EGFR tyrosine kinase inhibitor (EGFR-TKI) or ALK-TKI treatment.
Results
The frequency of EGFR/ALK co-alterations was 0.5% (29/5816; 95%CI:0.3%-0.7%) in NSCLC in our center. For all 132 cases, there is a prevalence of women (67 female, 46 male, 19 not reported), Asian (87Asian, 44 Caucasian, 1 not reported) and never smoker patients (77 never smokers, 21 smokers, 34 not reported). We divided the patients into three groups according to EGFR or ALK TKIs treatment: A: single EGFR TKI group (36 cases), B: single ALK TKI group (14 cases) and C: both TKIs (31 cases). All patients were assessed for TKIs responses. The disease control rate (DCR) of EGFR-TKI was 81.5%, whereas the DCR of ALK-TKI was 89.1%. The median PFS of three groups were 12.4, 15.9 and 24.1months, respectively (P = 0.02). The PFS of group A and C had statistically sigificant difference (P = 0.006). But the PFS of group A and B, B and C did not have statistical significance (P = 0.338, P = 0.335).
Conclusions
EGFR mutations and ALK rearrangement do coexist in NSCLC. In cases with double positive mutations, our preliminary study suggests that PFS of those who received double TKIs is longer than those who received only one TKI. Combination of both TKIs might be an appropriate choice. The result of the study indicates that ALK TKI might be preferentially administered when TKI is initiated as first-line treatment.
Legal entity responsible for the study
Wang shuyuan
Funding
Has not received any funding
Disclosure
All authors have declared no conflicts of interest.