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P.P. Massion
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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): P.P. Massion
- 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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O18 - Cancer Control and Epidemiology II (ID 133)
- Event: WCLC 2013
- Type: Oral Abstract Session
- Track: Prevention & Epidemiology
- Presentations: 1
- Moderators:M.R. Spitz, L. Irving
- Coordinates: 10/29/2013, 10:30 - 12:00, Bayside 103, Level 1
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O18.05 - DISCUSSANT (ID 3998)
11:10 - 11:25 | Author(s): P.P. Massion
- Abstract
- Presentation
Abstract not provided
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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P2.20 - Poster Session 2 - Early Detection and Screening (ID 173)
- Event: WCLC 2013
- Type: Poster Session
- Track: Imaging, Staging & Screening
- Presentations: 1
- Moderators:
- Coordinates: 10/29/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P2.20-006 - Autoantibodies to a panel of lung cancer-associated antigens can provide significant discrimination between malignant and non-malignant lung nodules (ID 1902)
09:30 - 09:30 | Author(s): P.P. Massion
- Abstract
Background
EarlyCDT®-Lung, a clinical blood test that detects autoantibodies to lung cancer-associated antigens, has shown high specificity in case-control validation studies[(1)].The performance of this test in routine clinical use was audited in an initial series of 1612 patients tested by EarlyCDT-Lung who signed HIPAA authorization permitting disclosure of their health information to Oncimmune®; the reported specificity and sensitivity (91%/41%) of the test was as predicted by case-control studies[(2)].Methods
A prospective audit was conducted of 423 individuals known to have a lung nodule for whom lung cancer-associated autoantibodies were measured by EarlyCDT-Lung. Physicians were contacted following patient testing by EarlyCDT-Lung to determine whether a cancer diagnosis had been made or a pulmonary nodule identified by imaging. Imaging and pathology reports were reviewed. This report focuses on patient outcomes at 6 months following EarlyCDT-Lung, and specifically on the 318/423 individuals for whom a lung nodule was detected prior to EarlyCDT-Lung testing. The EarlyCDT-Lung panel was modified in November 2010 from a 6 autoantibody (AAB) panel to 7AAB to improve specificity of the test[(3)] ; there were 152/318 individuals with nodules who had the 6AAB test and 166/318 who had the 7AAB test. Analyses comparing EarlyCDT-Lung results by malignant and non-malignant nodules were made using chi-squared tests.Results
Of the 423 individuals with nodules, there were 77 patients diagnosed with a lung cancer, and 346 were deemed to have a non-malignant nodule; 32/77 and 76/346 were positive for EarlyCDT-Lung, respectively (p=0.0004). Overall, this represented a 2-fold increased incidence of lung cancer with a positive result. Of the 318 individuals with lung nodules known prior to testing by EarlyCDT-Lung, the number of positive tests were 27/62 lung cancers and 43/256 non-malignant nodules (p= 0.000005); therefore, a positive result reflected a 2.7-fold increased incidence in this group. Considering nodule size, there was no difference for nodules <8mm, but the number of lung cancers in this group was small at only n=3. For nodules between 8-20mm and ≥20mm, a positive EarlyCDT-Lung test was statistically more likely to signify a lung cancer (p=0.06 & p=0.002, respectively; p=0.00008 combined). When only the 7AAB test was assessed, which has greater specificity, for 8-20mm and ≥20mm nodules a positive EarlyCDT-Lung test remained significantly more likely to indicate a lung cancer even though the numbers in each group were relatively small, n=58 & n=52, respectively (p=0.01 & p=0.004, respectively; p=0.0001 combined). For the 7AAB test overall and also for indeterminate nodules (8-20mm), a positive result represented a 3.5-fold increased incidence of lung cancer.Conclusion
EarlyCDT-Lung positivity reflects a statistically significant increased risk of malignancy for lung nodules ≥8mm. This varies from 2-fold to 3.5-fold depending on nodule size. These data confirm that EarlyCDT-Lung adds to the armamentarium of the pulmonologist in assessing the risk of malignancy in nodules ≥8mm. More data are required for lung nodules <8mm size. References: (1) Boyle P, et al. Ann Oncol. 2011;22:383-389. (2) Jett JR, et al. J Thoracic Oncology 2012;7:S222. (3) Chapman CJ, et al. Tumor Biol. 201;33(5):1319-1326.
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P3.20 - Poster Session 3 - Early Detection and Screening (ID 174)
- Event: WCLC 2013
- Type: Poster Session
- Track: Imaging, Staging & Screening
- Presentations: 1
- Moderators:
- Coordinates: 10/30/2013, 09:30 - 16:30, Exhibit Hall, Ground Level
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P3.20-006 - Proteomic analysis of the bronchial epithelium to develop a molecular signature of risk for lung cancer (ID 2008)
09:30 - 09:30 | Author(s): P.P. Massion
- Abstract
Background
A small percentage of at-risk individuals ultimately develop lung cancer. This warrants a search for a strategy to identify individuals who will be developing lung cancer. The bronchial epithelium represents the field of carcinogenesis and may serve as surrogate tissue for biomarker of risk. Therefore we hypothesized that proteomic alterations in the histologically normal airway epithelium from risk stratified individuals allow us to derive a signature of risk of developing lung cancer.Methods
We have collected bronchial brushings specimens from risk stratified individuals (Bach PB et al. 2003) and categorized them as Control (group 1), low (group 2) and high (group 3) risk groups. We collected three bronchial brushings specimens from each individual in a single session for acquiring shotgun proteomics (n=30). We also collected brushings from cancer patients whose risk criteria are similar to low (group 5) and high (group 6) risk groups as well as a group of never smoker lung cancer patients (group 4). Shotgun proteomics data were acquired from 3 technical replicates of pooled specimens from 5 individuals. Candidate biomarkers were selected based on group comparison and trend analysis.Results
We have acquired shotgun proteomics data from bronchial brushings specimen from individuals at-risk for lung cancer development. A total of 4973 proteins have been identified. Jonchere-Terpestra trend test was performed among control, low risk and high risk groups (Groups 1, 2, and 3). Expression level of 316 proteins were altered (trend p <0.05) with 238 proteins demonstrating upward and 78 proteins downward trends. DNA repair and oxidative stress and the galactose metabolic enzyme pathway were enriched in the upward trend analysis.Conclusion
We identified a proteomic candidate signature of risk of developing lung cancer from histologically normal bronchial epithelial cells. Integration of these results with those upcoming from two other molecular platforms will allow us to narrow down the molecular aberrations most predictive of risk. This signature will be validated in an independent cohort. Such signature of risk for lung cancer may serve as a powerful tool for lung cancer risk assessment and may provide the basis of patient selection for surveillance programs and chemoprevention. This work is funded by RO1 CA102353to PPM.
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PL04 - How Can We Stop the Epidemic of Lung Cancer? (ID 75)
- Event: WCLC 2013
- Type: Plenary Session
- Track: Prevention & Epidemiology
- Presentations: 1
- Moderators:C. Amos, C. Zhou
- Coordinates: 10/30/2013, 08:15 - 09:45, Plenary Hall, Ground Level
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PL04.4 - Biomarker-Driven Programs for Lung Cancer Screening (ID 641)
09:20 - 09:40 | Author(s): P.P. Massion
- Abstract
Abstract
The purpose of this presentation is to define a potential role for biomarkers 1) in the risk assessment of lung cancer among individuals considered for screening and 2) in the diagnostic evaluation of screening detected lung nodules. We will distinguish types of biomarkers design for the screening of lung cancer and their desired performance characteristics. We will describe current front runner candidates biomarkers and discuss how one could envision using those in the clinic. Suggested reading: The state of molecular biomarkers for the early detection of lung cancer. Hassanein M, Callison JC, Callaway-Lane C, Aldrich MC, Grogan EL, Massion PP. Cancer Prev Res (Phila). 2012 Aug;5(8):992-1006.
