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B.S. Sorensen
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P2.01 - Poster Session/ Treatment of Advanced Diseases – NSCLC (ID 207)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Advanced Diseases - NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.01-017 - Genetic Variations in the EGFR Gene Predicts Outcome in Advanced NSCLC Patients Treated with Erlotinib (ID 812)
09:30 - 09:30 | Author(s): B.S. Sorensen
- Abstract
Background:
Genetic variations in the epidermal growth factor receptor (EGFR) gene may alter protein expression or function and influence response to tyrosine kinase inhibitors. This study evaluates the role of genetic polymorphisms in the EGFR gene in advanced non-small cell lung cancer (NSCLC) patients treated with erlotinib. EGFR mutation status was known for all patients.
Methods:
Genotypes for -216G>T, -191C>A and 181946C>T in the EGFR gene were retrospectively evaluated by DNA sequencing and polymerase chain reaction in 354 Caucasian patients with advanced NSCLC. Hundred and seven of the patients had a somatic EGFR mutation, and all patients had been treated with erlotinib. Genotypes were correlated with clinical characteristics and outcome. A multivariate analysis was conducted adjusting for clinical relevant factors, including EGFR mutation status, using Cox proportional hazards model. A subgroup analysis was performed based on the EGFR mutation status.
Results:
Patients harboring at least one variant T allele (CT or TT) at position 181946 had a significantly longer median progression-free survival (PFS) (5.6 versus (vs.) 2.9 months; p =0.032) and overall survival (OS) (8.3 vs. 6.7 months; p=0.032) compared to patients with the CC genotype. The result remained significant in a multivariate analysis; PFS, adjusted hazard ratio (AHR)=0.73 (95% confidence interval (CI): 0.55-0.98); OS, AHR=0.72 (95%CI: 0.54-0.97). Patients carrying -216GT or TT genotypes showed a trend to a better clinical outcome compared to those with the GG genotype. The -216GT or TT and 181946CT or TT combined genotypes showed an even more pronounced association with clinical outcome compared to patients with the -216GG and 181946CC genotype (PFS, AHR=0.66 (95%CI: 0.44-0.98); OS, AHR=0.58 (95%CI: 0.38-0.87)). A subgroup analysis demonstrated that the association might be most relevant in EGFR mutation-positive patients; PFS, AHR=0.27 (95% CI: 0.11-0.68); OS, AHR=0.33 (95% CI: 0.13-0.83).
Conclusion:
A combination of 181946C>T and -216G>T polymorphisms in the EGFR gene seems to be a potential predictor of longer PFS and OS in advanced NSCLC patients treated with erlotinib; especially in EGFR mutation-positive patients. A prospective randomized study is wanted to confirm our data.
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 3
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-073 - PD-L1 Expression Is Induced by MET in an Erlotinib-Resistant Cell Line with MET Amplification (ID 833)
09:30 - 09:30 | Author(s): B.S. Sorensen
- Abstract
Background:
The programmed cell death receptor 1 (PD-1) and its ligand PD-L1 have proved to be of significant importance in lung cancer. Production of PD-L1 helps the cancer cells evade the immune system by inactivating T-cells. Clinical trials investigating the effect of treating lung cancer patients with monoclonal antibodies targeting the PD-L1 and PD-1 shows promising results. Expression of PD-L1 is associated with epidermal growth factor receptor (EGFR) mutational status. Further, expression can be significantly decreased by targeting EGFR with tyrosine kinase inhibitors (TKIs). In vitro studies suggest that this initial regulation of PD-L1 expression by EGFR occurs through the Erk pathway. Though, currently not much is known about expression of PD-L1 when TKI-resistance develops. We have developed erlotinib-resistant cell lines. The resistant cell line gained a MET amplification. We demonstrate that PD-L1 is increases in the resistant cells and that this increment is induced by MET signalling.
Methods:
The lung cancer cell line HCC827 with a deletion in exon 19 in the EGFR gene, was treated with increasing concentrations of erlotinib over 5 months until resistance developed. MET gene amplification in the resistant cells was confirmed by PCR. The resistant cell line was used for studying the effect of EGFR and MET inhibitors on PD-L1 expression.
Results:
The HCC827 erlotinib-resistant (ER) cell line gained a MET gene amplification, as seen in previous studies. In the initial phase of erlotinib treatment the expression of PD-L1 decreases. As the dose increases and resistance starts to develop the expression of PD-L1 increases. Activation of Erk is intact in HCC827ER as compared to the parental HCC827 cell line; most likely due to the activation of MET. When HCC827ER cells are treated with the MET inhibitor crizotinib, expression of PD-L1 decreases. When erlotinib is combined with crizotinib an additional effect on PD-L1 expression is observed. These results indicate that increased PD-L1 expression in erlotinib-resistant cell lines may be caused by activation of Erk through MET signalling.
Conclusion:
Our data demonstrates that Erk-dependent PD-L1 expression is increased in cells with erlotinib resistance caused by MET gene amplification. This mechanism might even be general and include several by-pass resistance mechanisms. Our findings suggest that the role of the PD-L1/PD-1 system should also be studied in erlotinib resistant tumors.
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P2.04-076 - Dynamics of Soluble PD-1 during Treatment with EGFR-TKI in Advanced NSCLC Patients (ID 1186)
09:30 - 09:30 | Author(s): B.S. Sorensen
- Abstract
Background:
The programmed cell death receptor-ligand pathway (PD-1/PD-L1) is hijacked by tumors in order to evade immune response. Therapy with monoclonal antibodies against PD-1 or PD-L1 in patients with advanced NSCLC has shown promising results in recent clinical trials. Preclinical studies indicate that the PD-L1 expression on tumor cells, and subsequently the PD-L1/PD-1 interaction, is increased when resistance to EGFR-TKI treatment in EGFR mutated NSCLC tumors occur. A soluble form of PD-1 receptor is present in the blood plasma, and can be detected in healthy individuals and in increased amounts in patients with autoimmune diseases and cancer. The dynamics of soluble PD-1 (sPD-1) during treatment and at the point of resistance to EGFR-TKI treatment is unknown. The aim of the present study is to assess the dynamics in plasma of EGFR mutated circulating tumor DNA and sPD-1 longitudinally during treatment with EGFR-TKI, and to study if the level of sPD-1 will increase at the time of resistance to EGFR-TKI treatment.
Methods:
Consecutive blood samples taken before initiation of treatment with erlotinib, during treatment, and at disease progression while on erlotinib from 20 patients with EGFR wildtype and 20 patients with EGFR mutated advanced NSCLC, has been collected, and will be analyzed. The amount of EGFR mutated circulating tumor DNA (in the EGFR mutated patients) and sPD-1 (all patients) will be detected by use of the Cobas® instrument (RMD) and ELISA (R&D systems), respectively. These results will be described and correlated to the clinico-pathological characteristics of the patients.
Results:
Preliminary results show that sPD-1 can be detected in plasma from lung cancer patients. The final results of the analysis will be presented at the conference.
Conclusion:
The present study is to our knowledge the first to describe the dynamics of soluble PD-1 during EGFR-TKI therapy in both EGFR mutated and EGFR wildtype patients treated with erlotinib. The results will elucidate on the role of sPD-1 as a potential biomarker of resistance to EGFR-TKI therapy. The clinical time point of increased sPD-1 in plasma could indicate a “window of opportunity”, in which these patients could be highly responsive to anti-PD-1 or anti-PD-L1 immunotherapy. Such findings have to be further investigated in prospective clinical trials.
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P2.04-096 - Liquid Biopsies in Patients with EGFR Mutated Non-Small Cell Lung Cancer Undergoing Curative Treatment (ID 1422)
09:30 - 09:30 | Author(s): B.S. Sorensen
- Abstract
Background:
A blood based test for detection of EGFR mutations has been developed. Studies have shown a correlation between level of mutations in the blood and course of the disease in stage IV patients, suggesting that the test could be used as a monitoring device. No studies have been conducted examining whether the blood test can be used to monitor patients who undergo curative treatment.
Methods:
Six patients with EGFR mutated tumors were monitored with continuous blood samples from the time of diagnosis until relapse, death or present date. The blood samples were tested for the level of EGFR mutations using the Cobas® EGFR Mutation Test developed for plasma DNA (Roche Molecular Systems, Inc.). Results were compared to the clinical course of the disease.
Results:
Operated without adjuvant chemotherapy (n=3, all patients with T1N0M0 disease). In two patients there were no measurable mutations in the blood samples at any point. One patient is at present date without sign of relapse after 3 years and attends follow up. The other patient died of non-cancer related causes. The third patient had declining level of mutations the first two years after the operation but the mutated DNA has never reached zero. Operated with adjuvant chemotherapy (n=1, T2N2M0). Mutations were measurable before operation and declined to zero after. One year after the operation, metastatic disease (CNS) was discovered along with a rise in mutation level, which again declined after local irradiation and initiation of erlotinib treatment. Chemoradiotherapy (n=2, T2N2-3M0). One of these patients had measurable levels of mutations initially, which declined to zero during the course of treatment with chemoradiotherapy and a supplement of erlotinib. Metastatic disease (CNS) was found during the treatment, and the patient proceeded with erlotinib treatment and cerebral irradiation. The patient died due to disease progression 9 months later, no measurable mutated DNA was identified. In contrast, another patient had no measurable mutations until after relapse was detected.
Conclusion:
Our results suggest that in some cases monitoring the level of EGFR mutations in the blood might be a valuable tool in the detection of relapse in patients who have undergone curative treatment for their lung cancer. Further investigations are warranted to elucidate the subject. We have initiated a project, where we prospectively follow all patients with EGFR mutated NSCLC regardless of stage and treatment modality and we examine their blood for EGFR mutations every time a blood sample is drawn.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-023 - Exosomes and Their Potential for Detection of Lung Cancer (ID 831)
09:30 - 09:30 | Author(s): B.S. Sorensen
- Abstract
Background:
A recent study showed that advanced lung adenocarcinoma patients have a distinct exosomal protein-profile compared to a matched group without cancer (Jakobsen et al., 2015, JEV). To improve the overall survival, it is however crucial to develop tools capable of detecting early stages of lung cancer as well. In addition, it is unsettled if different histologic subclasses result in distinct exosomal protein profiles. The aim of this study is to explore the potential of using exosomal proteins as biomarkers in lung cancer patients of all stages and of different histology histology.
Methods:
Plasma was isolated from patients suspected of having lung cancer. Patients diagnosed to be cancer free were defined as controls. Based on previous experiments a panel of 47 antibodies were selected for exosome-capture using a highly sensitive extracellular vesicle protein array (EV Array). 10 µl unpurified plasma was applied to the EV Array and captured exosomes were visualised by binding of biotin-conjugated CD9, CD63 and CD81 antibodies. The information from all 47 markers was investigated by multivariate analysis by partial least squares discriminant analysis (PLS-DA).
Results:
The study included 504 patients; 153 control patients and 351 patients with NSCLC (adenocarcinoma 70%, squamous cell 24%, other 6%). 51% had locally advanced or advanced disease and 49% had local disease. Multivariate analysis produced a combined marker model separating cancer patients from controls regardless of stage and histology. Area under the curve (AUC) was for each stage: I: 0.74 (0.68-0.82), II: 0.68 (0.57-0.79), III: 0.77 (0.62-0.91) and IV 0.79 (0.73-0.83). For all stages AUC was 0.755, CI (0.72-0.81) with sensitivity 0.70 and specificity 0.66. The accuracy of the test was 0.69.
Conclusion:
We demonstrate that the EV array is able to lung cancer in advanced as well as low stages regardless of histology.
