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E. Jantus-Lewintre
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MO05 - Prognostic and Predictive Biomarkers II (ID 95)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:J. Hu, S. O'Toole
- Coordinates: 10/28/2013, 16:15 - 17:45, Parkside Auditorium, Level 1
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MO05.09 - Activation of the classical complement pathway: a novel biomarker for the early diagnosis and prognosis of lung cancer (ID 964)
17:05 - 17:10 | Author(s): E. Jantus-Lewintre
- Abstract
- Presentation
Background
Numerous diagnostic and prognostic molecular markers have been proposed for lung cancer. However, genetic heterogeneity has limited the success of these initiatives. This limitation may be overcome by the use of biomarkers related to the host response to cancer. In this study we tested the capacity of lung cancer cells to activate the complement system and evaluated the diagnostic performance of complement-activation fragments. We demonstrate for the first time that lung cancer cells efficiently activate the classical complement pathway and that fragments of complement activation are of value for detection and prognosis of lung cancer at a very early stage.Methods
We first assessed complement activation in bronchial epithelial and lung cancer cell lines. C4d, a degradation product of complement activation, was determined in 90 primary lung tumors; in bronchoalveolar lavage supernatants from 50 patients with lung cancer and 22 non-malignant respiratory diseases; and in plasma samples from different cohorts, including: advanced (n=133) and early (n=84) non-small cell lung cancer patients, subjects with inflammatory lung diseases (n=133) and asymptomatic individuals enrolled in a lung cancer CT-screening program (n=190; 32 of them with lung cancer).Results
Lung cancer cells treated with normal human serum activated complement and deposited C3 more efficiently than non-malignant bronchial epithelial cells. Incubation of cells with different buffer conditions, complement depleted sera and complement inhibitors showed that lung cancer cells bind C1q and activate complement through the classical complement pathway. In a set of lung cancer cell lines, a significant correlation was found between C1q binding and C4 or C3 deposition. The presence of phosphatidylserine inhibited C1q binding and diminished complement activation. Based on these results, C4d, a classical pathway-derived split product, was evaluated as a possible diagnostic or prognostic biomarker in lung cancer. Many lung primary tumors (adenocarcinomas and squamous cell carcinomas) deposited C4d. More importantly, survival was decreased in patients with high C4d deposition in their tumors (HR=3.06; 95% CI=1.18-7.91). Moreover, C4d levels were increased in bronchoalveolar lavage fluid from lung cancer patients as compared to patients with non-malignant respiratory diseases (0.61 ± 0.87 vs. 0.16 ± 0.11 µg/ml, respectively; P<0.001). C4d levels in plasma samples from lung cancer patients at both advanced (III and IV) and early (I and II) stages were also increased compared with control subjects (4.13 ± 2.02 vs. 1.86 ± 0.95 µg/ml, P<0.001; and 3.18 ± 3.20 vs. 1.13 ± 0.69 µg/ml, P<0.001, respectively). In addition, C4d plasma levels were associated with shorter survival in patients at advanced (HR=1.59; 95% CI=0.97-2.60) and early stages (HR=5.57; 95% CI=1.60-19.39). Plasma C4d levels were dramatically reduced after surgical removal of lung tumors. Finally, plasma C4d levels were associated with increased lung cancer risk in asymptomatic individuals: OR=4.38; 95% CI=1.61-11.93.Conclusion
Lung tumors activate the classical complement pathway and generate C4d, a stable complement split product. Moreover, C4d is increased in biological samples from lung cancer patients, is associated with poor prognosis, and may be of clinical value for the early detection of lung cancer.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO10 - Molecular Pathology II (ID 127)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Pathology
- Presentations: 1
- Moderators:W.A. Franklin, A. Mahar
- Coordinates: 10/28/2013, 16:15 - 17:45, Bayside 104, Level 1
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MO10.07 - ALK immunohistochemistry and fluorescence in-situ hybridization in Lung adenocarcinomas from the ETOP Lungscape tumour cohort (ID 2267)
16:50 - 16:55 | Author(s): E. Jantus-Lewintre
- Abstract
- Presentation
Background
The European Thoracic Oncology Platform LungScape database contains 2614 cases of primary resected lung carcinoma from 16 centres with patient demographics, pathological tumour data and detailed clinical follow-up. A total of 1281 cases of adenocarcinoma with >2 years clinical follow-up were selected for analysis of ALK status by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Test positive cases were matched, in order of importance at ratio 1:2, by stage, gender, smoking status, study centre, year of surgery and age with test negative cases -both for IHC and for FISH testing.Methods
Testing was performed in all centres using the same protocol (IHC: Novocastra 5A4 clone antibody at 1:10 dilution, Novolink detection system. FISH: Abbott Vysis ALK break-apart probe). Each centre passed an external QA test using unknown cases in a tissue microarray before conducting the LungScape tumour testing. IHC was scored according to three intensity scores (1+, 2+, 3+) using ‘objective’ methodology previously described [1]. Maximum staining intensity was recorded. Any IHC staining was defined as IHC positive result. FISH preparations were assessed according to the Vysis protocol on all 82 IHCpositive cases plus their 164 IHCnegative matches.Results
FISH sensitivity was 87% for IHC 3+. IHCpositive/FISHnegative cases (n=54) were mostly IHC 1+ (75.9%), sometimes IHC 2+ (18.5%) and rarely IHC 3+ (5.5%). The frequency of never smokers was higher in the ALK IHCpositive group (29.3%) versus IHCnegative group (18.3%) {p=0.011}. Age, gender and tumour stage did not differ between IHC groups. The hazard of an event for IHCpositive cases decreases by 32% in relapse-free survival {RFS; p=0.03} and by 38% in either time-to-relapse {TTR; p=0.02} or overall survival {OS; p=0.016}. Multivariate models -adjusted for patient and tumour characteristics- indicated that IHC-ALK was a significant predictor for all three time-to-event outcomes (RFS, TTR, OS). In stratified Cox analysis, significantly higher OS was retained in the IHCpositive (HR=0.59, p=0.04) and FISHpositive (HR=0.34, p=0.03) cases in the matched cohorts, while conditional logistic regression yielded non-significant associations with 3-year survival status.IHC cases, n=1281 FISH positive(264 tested) IHC negative 1199 (93.6%) 0 (0.0% of 164 controls) FISH specificity: 100% IHC 1+ 43 (3.35%) 2 (4.6% of IHC 1+) IHC 2+ 16 (1.25%) 6 (37.5% of IHC 2+) IHC 3+ 23 (1.8%) 20 (87% of IHC 3+) IHC any positive 82 (6.4%) 28 (34.1% of IHC+) FISH sensitivity: 34.1% Conclusion
In this large cohort of surgically resected primary lung adenocarcinoma: ALK IHC positivity was 6.4%. IHC 3+ staining (prevalence 1.8%) showed 87% probability of ALK FISH positivity ALK IHC positivity was higher in never smokers and related to better clinical outcome ALK testing can be reliably implemented across multiple laboratories {1} Ruschoff et al. Virchows Arch. 2010;457(299-307).Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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MO21 - Prognostic and Predictive Biomarkers V - EGFR (ID 98)
- Event: WCLC 2013
- Type: Mini Oral Abstract Session
- Track: Medical Oncology
- Presentations: 1
- Moderators:D.C. Lam, S.M. Lee
- Coordinates: 10/30/2013, 10:30 - 12:00, Bayside Auditorium A, Level 1
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MO21.05 - Integrated genomic analysis by whole exome and transcriptome sequencing of tumor samples from EGFR-mutant non-small-cell lung cancer (NSCLC) patients with acquired resistance to erlotinib. (ID 1426)
10:50 - 10:55 | Author(s): E. Jantus-Lewintre
- Abstract
- Presentation
Background
NSCLC patients with EGFR mutations initially respond to EGFR tyrosine kinase inhibitors (TKIs) but ultimately relapse. Sub-genomic molecular studies indicate that the EGFR T790M mutation and the activation of MET, PI3K, AXL, HER2 and MAPK can lead to acquired resistance to EGFR TKIs. To date, no integrated comprehensive genomic investigation of EGFR TKI resistance has been reported.Methods
FFPE biopsies of erlotinib-sensitive and erlotinib-resistant tumors were obtained from 13 EGFR mutant NSCLC patients. The samples were analyzed by whole exome sequencing and whole transcriptome sequencing utilizing the Illumina HiSeq2500 platform. In addition, targeted gene sequencing was performed with the Illumina TruSeq Amplicon-Cancer Panel and run on the MiSeq system.Results
Erlotinib resistant NSCLC specimens harbored known resistance drivers, including EGFR T790M mutations (9/13; 69%), MET amplification (3/13; 23%), HER2 amplification (3/13; 23%), and AXL upregulation (3/13; 23%). Differential expression analysis between resistant and pre-treatment states revealed enrichment in the pre-treatment tumors of immune signaling pathways, and in the resistant tumors upregulation of ERBB2, mTOR, PI3 kinase and ribosomal signaling pathways. PI3K/AKT pathway upregulation also occurred through somatic mutations in AKT and LKB1 in the resistant tumors. Copy number analysis demonstrated both large scale and focal amplifications and deletions in the resistant tumors, including the focal loss of EGFR and gain of c-Myc and NKX2-1. There was strong correlation between the copy number changes observed and the expression mRNA levels of the involved cancer-associated genes. Of note, each resistant tumor exhibited greater copy number similarity to the corresponding matched pre-treatment sample compared to other tumors within the resistance cohort.Conclusion
We conducted the first ever comprehensive integrated genomic analysis of EGFR TKI resistant NSCLC patients, and identified both known and potentially novel drivers of EGFR TKI resistance. This study demonstrated the feasibility and utility of comprehensive genomic analysis in the clinical management of NSCLC receiving targeted therapy. Together, our data provide unprecedented insight into the molecular pathogenesis of escape from EGFR oncogene inhibition in NSCLC. We are now conducting a prospective observational study in additional NSCLC patients on targeted therapy.Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P2.02 - Poster Session 2 - Novel Cancer Genes and Pathways (ID 148)
- Event: WCLC 2013
- Type: Poster Session
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P2.02-013 - The importance of immunoregulatory genes in non small cell lung cancer (ID 2461)
12:54 - 13:11 | Author(s): E. Jantus-Lewintre
- Abstract
Background
In non small cell lung cancer (NSCLC) it is of vital importance to develop biomarkers that allow us to assign a more accurate prognosis for patients in early stages, so we can apply the right treatment at the right time, preventing that the cancer reaches advanced stages when the cure rate is close to zero.Methods
In this study we have selected a set of 9 genes related to immunoregulation and inflammation processes to analyze their relative expression on mRNA by qPCR in lung tissue samples from patients with NSCLC and resectable stage. CCL2 and CD1c genes showed a significantly lower expression in tumor tissue versus healthy tissue. After that, we analyzed the correlation between expression levels of these genes and relevant clinicopathological variables in the patients. Poorly differentiated tumors showed higher expression levels of CD209, CCL2, LGALS1 and LGALS2, whereas in smokers an increased expression of galectin LGALS1 was documented. Finally, survival analysis was performed using the Kaplan-Meier method to assess the utility of genes as prognostic biomarkers in this disease.Results
In the subgroup of patients with squamous cell histology, those with lower levels of expression of CCL22 showed a significant increase in overall survival (OS) and progression-free survival (PFS). In our cohort of patients with resectable NSCLC, survival analyses showed that elevated levels of galectin LGALS2 and CCL2 chemokine are associated with a better prognosis in overall survival (OS) and progression-free survival (PFS).Conclusion
The data obtained in our study provide further evidence about the necessity of tumors to manipulate the microenvironment around them as a prelude to progress and invade tissues.
