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A. Thomas
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ORAL 25 - Biology and Other Issues in SCLC (ID 125)
- Event: WCLC 2015
- Type: Oral Session
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:J. Sage, L. Montuenga
- Coordinates: 9/08/2015, 10:45 - 12:15, 605+607
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ORAL25.01 - Screening for Small Cell Lung Cancer: Analysis of the National Lung Cancer Screening Trial Data (ID 2145)
10:45 - 12:15 | Author(s): A. Thomas
- Abstract
Background:
Given its widely metastatic nature at the time of diagnosis and the lack of effective therapies, early detection could theoretically have a beneficial impact on small cell lung cancer (SCLC) patient survival. However in the National Lung Screening Trial (NLST), there was no survival advantage for SCLC in the low dose computed tomography (LDCT) arm versus the chest radiography (CXR) arm. We investigated whether LDCT could detect SCLC and whether such screen detection offered a stage and/or survival benefit.
Methods:
Subjects randomized to the LDCT arm in NLST received three annual LDCT screens. Incident cancers were tracked with annual surveys and confirmed with medical records, with abstractors coding lung cancer stage and histology. “Best” stage was defined as pathologic stage if available, otherwise clinical stage. Deaths were tracked with the annual surveys and supplemented by the National Death Index. Cancer was denoted as screen-detected if it was diagnosed within one year of a positive screen or if it was diagnosed after a longer period but with no time gap between diagnostic procedures of more than one year. An interval cancer was defined as a cancer diagnosed within one year of a negative screen. Non-screen detected or interval cancers were denoted as non-screened if the subject did not receive any NLST screens or otherwise as post-screening.
Results:
26,722 subjects were randomized to the LDCT arm (median follow up 6.5 years; 59% men; median age at enrollment 62). 143 SCLCs were diagnosed [49 (34.2%) screen-detected, 15 (10.5%) interval, 79 (55.2%) non-screened/ post-screening]. The ratio of interval to screen detected cases was significantly higher for SCLC (15/49=0.31) than for NSCLC (29/591=0.05); p < 0.0001. 123 of 143 (86%) SCLCs were detected at late-stages (best stage III/IV); the unfavorable stage-distribution persisted among screen-detected, interval and non-screened/ post-screening cases with only 15 (10.5%) detected in early-stages. Three-year lung cancer-specific survival was 72% for early-stage versus 11% for late-stage disease. There was no significant difference in five-year survival between screen-detected, interval and non-screened/post-screening SCLCs (15.3%, 20.0% and 13.8%, respectively). Unlike NSCLC, even at small nodule sizes the proportion of screen-detected SCLCs that were late stage was very high.
Conclusion:
Analysis of SCLC detected in the NLST LDCT arm show that yearly LDCT screens do not detect a significant number of early stage SCLCs. Compared with NSCLC, a higher proportion of SCLCs are interval-detected than screen-detected. Further, there is no stage-shift or survival benefit for screen- detected SCLCs compared with interval or post-screen detected cases. To our knowledge this is the largest analysis to date of SCLC detected in a screening study. Our results indicate that in order for a screening modality to be successful for SCLC, it is necessary (but not sufficient) to be able to detect it earlier than does LDCT.
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ORAL 40 - Biology 1 (ID 154)
- Event: WCLC 2015
- Type: Oral Session
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:C. Brambilla, R. Bueno
- Coordinates: 9/09/2015, 16:45 - 18:15, 702+704+706
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ORAL40.01 - PD-L1 Is Highly Expressed in Malignant Mesothelioma and PD-1<sup>+ </sup>Lymphocytes within Malignant Effusions Induce PD-L1 Expression (ID 553)
16:45 - 18:15 | Author(s): A. Thomas
- Abstract
- Presentation
Background:
The PD-1 and PD-L1 pathway is an immune checkpoint, which protects normal tissues from immune attack by curbing the effector T-cell response but can also prevent anti-tumor immune response. However their role in mesothelioma is not well understood. The present study aimed to understand the PD-1 and PD-L1 expression levels and their interactions in mesothelioma patients.
Methods:
Sections of formalin-fixed, paraffin-embedded pleural and peritoneal mesothelioma tumor samples from patients who were evaluated for various clinical trials at the NCI Center for Cancer Research were tested for PD-L1 expression (Anti-PD-L1 rabbit monoclonal recombinant primary antibody MKP-1B-196-10; Merck-Serono). PD-L1 expression on primary and established mesothelioma cell lines, malignant pleural effusions and ascites of mesothelioma patients were assessed using a commercial anti-PD-L1 antibody and analyzed by flow cytometry. Paired malignant effusion and peripheral blood samples were tested for PD-1 and PD-L1 expression on immune cells. Co-cultures of autologous tumor cells and T cells grown from malignant effusions of a mesothelioma patient were evaluated to understand the PD-1 and PD-L1 interaction.
Results:
Tumor samples from 65 patients included 44 peritoneal and 21 pleural mesotheliomas; 55 with epithelioid histology and 10 of other subtypes (sarcomatoid 2, biphasic 3, uncategorized 5). 41 of 65 (63%) tumors were positive for PD-L1 expression (defined as >5% PD-L1 expression on tumor cells, of any intensity) with levels of expression ranging from 5% to 80% of tumor cells, and intensities from 1+ to 3+. 24 (37%) were negative including 10 with focal staining. A higher proportion of males had tumor PD-L1 expression than females (73% vs. 46%; p=0.04). There was no association between PD-L1 expression and primary site of disease, age, race, histology and distant metastasis. Patients with PD-L1 positive tumors had a numerically inferior overall survival than patients with PD-L1 negative tumors (23.0 months vs.33.3 months; p=0.35). All 6 primary and 4 established mesothelioma cell lines tested showed basal expression of PD-L1. This was enhanced on treatment with IFN-γ. The fraction of cells expressing PD-L1 in malignant effusions ranged from 17 to 43%. Malignant effusions from 2 of 3 patients had high PD-1 expression on both CD4[+] and CD8[+] T cells. In addition, CD8[+] T cells in malignant effusions had significantly higher levels of PD-L1 expression compared to CD8[+] T cells in peripheral blood (7.47±2.75 % T cells versus 1.97±1.22% T cells; p=0.03). Autologous lymphocytes when co-cultured with tumor cells from malignant effusion, recognized tumor cells and induced IFN-γ mediated PD-L1 expression on their surface.
Conclusion:
High PD-L1 expression in mesothelioma patient tumor samples and tumor cells derived from malignant effusions, as well as presence of PD-1[+] T cells in these effusions indicates the prominent role of PD-1/PD-L1 pathway in maintaining an immunosuppressive milieu in mesothelioma. Thus, inhibiting this pathway could be useful therapeutically.
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