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P.B. Illei
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MINI 12 - Biomarkers and Lung Nodule Management (ID 109)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Screening and Early Detection
- Presentations: 1
- Moderators:J.M. Siegfried, H.I. Pass
- Coordinates: 9/07/2015, 16:45 - 18:15, 401-404
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MINI12.13 - Early Detection of Lung Cancer Using DNA Methylation in Plasma and Sputum (ID 1691)
17:55 - 18:00 | Author(s): P.B. Illei
- Abstract
Background:
Lung cancer is the worldwide leading cause of cancer-related mortality. Almost 85% of lung cancer cases are diagnosed at late stages with a five-year-survival probability at the time of diagnosis of 16.8%. The National Lung Screening Trial (NLST) showed a 20% reduction in lung cancer mortality using low-dose computed tomography (CT) screening, but there was also a 96.4% false positive rate. Lung cancer screening might be improved through cancer specific biomarkers detected in body fluids such as plasma or sputum. Previous studies using DNA methylation failed to achieve adequate sensitivity because of use of infrequently methylated genes and detection techniques unable to detect the small amounts of DNA yielded from blood and sputum. We sought to improve the diagnostic accuracy using gene promoter methylation in blood and sputum through the use of Methylation On Beads (MOB) and a highly lung-cancer specific panel of genes for detection of lung cancer.
Methods:
We conducted a prospective case-control study obtaining cases and controls from the Lung Cancer Spore. Cases had pathological confirmation of Non-Small Cell Lung Cancer (NSCLC) lesion stage IA or IB. Controls were defined as patients with pathological confirmation of non-cancerous lesion in the surgical specimens. Plasma, sputum and CT scans were obtained pre-operatively. We quantified methylation levels and the amplification cycle threshold from sputum and plasma samples by using MOB and quantitative methylation specific real-time PCR lung cancer-related genes previously identified from The Cancer Genome Atlas (TCGA). This panel of genes include: CDO1, TAC1, HOXA7, HOXA9, SOX17 and ZFP42.
Results:
A total of 210 subjects fulfilled inclusion criteria, including 150 patients with NSCLC and 60 patients with non-cancerous lesions. All six genes were methylated in significantly more people with cancer than without cancer in both plasma and sputum (p<0.001) with the exception of HOXA9 in sputum, which was methylated in more than 90% of people with cancer and more than 90% of people without cancer. After adjusting by age and pack·year, the methylated genes that were significantly associated with risk of lung cancer stage IA & IB from blood samples were: CDO1 (p=0.009), TAC1 (<0.001), HOXA9 (p=0.005), SOX17 (<0.001) & ZFP42 (p=0.003) and from sputum samples were: CDO1 (p=0.066), TAC1 (p=0.007), ZFP42 (p=0.009). Sensitivity and specificity for lung cancer diagnosis using the 3 best genes in plasma was 91% and 68% respectively and for sputum 91% and 88%. Area under the curve for 3 best genes in plasma was 0.78 95% confidence interval (CI) (0.69-0.87) (p<0.001) and for the best 3 genes in sputum 0.88 95% CI (0.77-0.99) (p<0.001).
Conclusion:
This study shows that its is possible to obtain high diagnostic accuracy for Lung Cancer in early stages using a panel of methylated promoter genes in Plasma and Sputum, by using Methylation-on-beads. These epigenetic biomarkers could potentially be used to identify patients with high risk of lung cancer development. reducing unnecessary tests and increasing the chance to diagnose lung cancer at earlier stages
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MINI 27 - Biology and Other Issues in SCLC (ID 152)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Small Cell Lung Cancer
- Presentations: 1
- Moderators:P.A. Bunn, Jr, J. Sage
- Coordinates: 9/09/2015, 16:45 - 18:15, 605+607
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MINI27.03 - PD-L1 Expression in Small Cell Lung Carcinoma: An Immunohistochemical Analysis of 26 Cases Using Two Anti-PD-L1 Antibodies (ID 2936)
16:55 - 17:00 | Author(s): P.B. Illei
- Abstract
- Presentation
Background:
Small cell lung carcinoma (SCLC) represents 15% of lung cancers and is treated using chemotherapy +/- radiation but despite initial responses most recur within a few months and become resistant to therapy. Novel immune checkpoint inhibition of programmed death-1 (PD1) targeted therapy has shown promise in other solid tumors including non-small-cell lung cancer (NSCLC) and malignant melanoma. In some tumor types correlation with response and significant expression of programmed death- ligand 1 (PD-L1), the lead candidate biomarker of anti-PD-1 therapy, has been described but no data is available regarding expression levels in SCLC. Here we report the rate of PD-L1 expression in SCLC and in associated tumor infiltrating immune cells lymphocytes and macrophages.
Methods:
Immunohistochemistry (IHC) for PD-L1 using two monoclonal antibodies (clone 5H1 and clone SP142) and for CD3 (clone PS1) was performed on standard formalin fixed paraffin embedded tissue sections of 21 resected SCLC specimens (median age: 67) and three additional tumors with pre- and post-therapy biopsies. Since there is no generally accepted scoring system for PD-L1 expression we chose to evaluate staining in tumor cells and immune cells infiltrating the tumor nests and in adjacent stroma using a 4 tier semi quantitative scoring system (score 0 -no or <1%, 1+ 1-<5%, 2+ 5-25% and 3+ >25% of cells staining). Both cytoplasmic and membranous staining was accepted as positive. The number of tumor infiltrating lymphocytes (TIL) were estimated utilizing a CD3 stain while macrophages were identified on corresponding H&E stains.
Results:
PD-L1 staining of tumor cells and Immune Cells (TIL & Macrophage) are shown in the table below. Membranous PD-L1 staining was only seen in two tumors and in variable number of immune cells with 2+ or 3+ PD-L1 scores. The majority of positive staining was cytoplasmic with both antibodies. The staining intensity was stroger with the 5H1 antibody. The paired pre- and post-therapy samples were all negative for PD-L1.
* Tumors with membranous staining; IC: immune cellsClone/score PD-L1 staining in 5H1 Tumor IC in tumor IC in stroma 0 (<1%) 19/21 (90%) 7/21 (33%) 5/21 (24%) 1+ (1-<5%) 1/21 (5%)* 11/21 (53%) 6/21 (29%) 2+ (5-25%) 1/21 (5%)* 3/21 (14%) 7/21 (33%) 3+ (>25%) 3/21 (14%) SP142 Tumor IC in tumor IC in stroma 0 (<1%) 20/21 (95%) 8/21 (38%) 10/21 (48%) 1+ (1-<5%) 1/21 (5%)* 11/21 (52%) 7/21 (33%) 2+ (5-25%) 2/21 (10%) 4/21 (19%) 3+ (>25%)
Conclusion:
Most SCLC are tumor membrane PD-L1 negative by IHC. A subset of SCLC contain PD-L1 positive TILs and/or macrophages in the tumor and the stroma. No up regulation of PD-L1 expression was seen in a small pilot sample of matched pre- and post-therapy biopsies. It is unclear whether PD-L1 expression assessed by IHC will be a predictive marker for PD-1 targeted therapy in SCLC. Preliminary data indicates single agent and combined checkpoint inhibitors (PD1 plus CTLA-4 inhibitors) are active in previously treated SCLC indicating additional research is required to understand their mechanism of action in a tumor type that has seen no therapeutic advances in the last two decades.
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P1.08 - Poster Session/ Thymoma, Mesothelioma and Other Thoracic Malignancies (ID 224)
- Event: WCLC 2015
- Type: Poster
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.08-009 - Hepatocyte Growth Factor (HGF) Expression in Malignant Mesothelioma: A Potential Predictive Marker for <em>met/</em>HGF-Targeted Therapy? (ID 2908)
09:30 - 09:30 | Author(s): P.B. Illei
- Abstract
Background:
Malignant mesothelioma (MM) is an aggressive neoplasm predominantly involving the pleura with less than 2 years median patient survival time and limited systemic therapeutic options. The HGF-MET axis is important in cell proliferation and homeostasis. Dysregulation of the pathway has been linked to tumorigenesis. Met overexpression has been used as a predictor of response to Met-targeted therapy with limited success. HGF is the only known ligand for Met, but intratumoral HGF levels have not been studied in MM. In a preclinical glioblastoma model autocrine signaling by HGF was predictive for Met-Targeted therapy. Our aim was to evaluate HGF expression patterns and to assess the feasibility of non-isotopic bDNA in situ hybridization to reliably detect HGF expression in MM.
Methods:
We analyzed HGF expression using non-isotopic branched-DNA in situ hybridization on an automated platform in 39 samples of MM. In a subset of cases manual in situ hybridization was also performed. Immunohistochemistry for c-met using a rabbit monoclonal antibody and semiquantitative scoring system proposed for NSCLC was also available for 33 tumors. The cohort included 10 peritoneal (3 male and 7 female, age range 15-77; median 64.5) and 29 pleural tumors (24 male and 5 female, age range 24-88; median 67.4). There were 28 epithelioid, 10 biphasic and 1 sarcomatoid tumors. HGF expression was scored as none, weak, moderate or strong (normal placenta and surrounding benign tissue served as controls).
Results:
Moderate to strong HGF expression was seen in 7 cases (6 strong, 1 moderate), weak expression was noted in 10 tumors while 22 were negative. Met IHC was only available for 3 of the 6 strong HGF expressing tumors. Of the 16 met positive tumors only 1 showed strong HGF expression while the majority were HGF negative (10) or weak positive (5). Intratumoral heterogeneity and both paracrine and autocrine HGF expression were also observed. The automated and manual in situ hybridization methods showed concordant results.
Conclusion:
Non-isotopic bDNA assay can be used to reliably detect HGF mRNA in mesothelioma tissue sections. A range of HGF expression levels can be seen with a subset of cases showing moderate to strong (18%) expression. Intratumoral heterogeneity is present and both paracrine and autocrine sources of HGF can be identified. The majority of c-met positive (2+ and 3+) tumors exhibit weak or no HGF expression with only 1 of 3 HGF strongly positive tumor showing positive (2+) c-met staining. Further studies are needed to determine if HGF expression can be used as a predictive marker for c-met/HGF targeted therapy in malignant mesothelioma.
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P3.03 - Poster Session/ Treatment of Locoregional Disease – NSCLC (ID 214)
- Event: WCLC 2015
- Type: Poster
- Track: Treatment of Locoregional Disease – NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.03-038 - A Multi-Center Trial Comparing Standard 22-Gauge and 22-Gauge Bibevel (ProCore) Needles for Endobronchial Ultrasound (ID 3036)
09:30 - 09:30 | Author(s): P.B. Illei
- Abstract
Background:
Endobronchial ultrasound fine needle aspiration (EBUS-FNA) is recommended as the first tissue sampling procedure for the staging and diagnosis of known or suspected lung cancer. With the advent of targeted agents for lung cancer therapy, there is an increasing demand to extend EBUS-FNA samples for molecular testing. While it has been shown to be adequate for EGFR mutational analysis in 77-96% of samples, as new discoveries are made the challenge is to obtain enough quality tissue via EBUS-FNA. Bibevel (ProCore) needle technology used during endoscopic ultrasound (EUS) procedures has been shown to provide larger samples of tissue for histologic diagnosis of gastrointestinal malignancies. This same needle technology may also provide more tissue during EBUS to allow for better histologic and molecular analysis than standard EBUS-FNA. The goal of this study is to determine the utility of the 22-gauge (G) ProCore EBUS needle by comparing it to standard single bevel 22G EBUS needles.
Methods:
This multicenter randomized trial will enroll 200 patients with known or suspected lung cancer during standard of care diagnostic/staging EBUS. A maximum of two lymph nodes (pathologic in size (>1cm) and/or hypermetabolic on PET/CT) will be included in the comparison. A total of 8 passes will be taken from each node (4 from the bibevel needle, 4 from standard) and cell blocks compared by a blinded pathologist . The primary outcome is tumor cells per mm[2]. Descriptive statistics will be used to characterize the study subjects and their outcomes with the 2 different needles. For the within-subject (i.e. between needle) comparisons of tumor quantity and ability to perform commercially available immunohistochemical stains and mutational analysis, non-parametric Wilcoxon signed rank tests will be used. Since cell block quality will be quantified as simply which needle’s sample provided the better sample, the non-parametric sign test will be used. All hypothesis testing will be 2-sided, using an alpha level of 0.05
Results:
Forty-one patients from three centers have been enrolled, with 48 lymph nodes sampled. There is an even gender distribution (22 (54%) male, 19 (46%) female). The majority are non-Hispanic white (n=30, 73%). 22 patients have (54%) have a malignant diagnosis, 12 (30%) a benign diagnosis, and 2 (5%) have been non-diagnostic. Minor complications include bleeding at the site in 7 (17%). There have been no major complications.
Conclusion:
Data for the primary outcomes have yet to be analyzed, however the trial design is feasible and thus far the use of two separate needles during EBUS has shown to be safe.
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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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P3.04-022 - The Johns Hopkins University TCGA Experience (ID 2874)
09:30 - 09:30 | Author(s): P.B. Illei
- Abstract
Background:
The Cancer Genome Atlas (TCGA) is a genomic mapping effort that characterizes and analyzes the major types of cancer. Specimens have to meet strict tissue criteria to become eligible for shipment to TCGA and used for genomic analysis. Johns Hopkins University (JHU) is a part of the TCGA network and we have sent numerous biospecimens for analysis. Our experience is catalogued over 3 different shipments and may be unique only to JHU. This paper will analyze if the JHU samples that have qualified for TCGA are representative of the overall selected lung cancer samples.
Methods:
We analyzed the JHU cohort using TCGA’s shipment qualification reports in addition to our biospecimen data pre-selected for TCGA. Specimens with at least 60% tumor qualified for TCGA and those that disqualified were because of lack of RNA. Specimens that were not eligible for shipment had less than 60% tumor.
Results:
There is a trend in older specimens being disqualified throughout the TCGA shipments. In contrast, those specimens that were cut but deemed ineligible to be sent to TCGA tended to be older, male, adenocarcinoma (p=0.003), and earlier stage (p=0.010) than those that were actually shipped. The majority of the specimens that were shipped were sent during shipment 1 (p<0.001) and the proportion of specimens sent were older (long surgery to cut duration) than younger comparing specimens with durations of 0 years, 1-10 years, and 11-21 years (p<0.001). Figure 1 Figure 2
Conclusion:
Our data suggests that older specimens were the most likely to be disqualified when shipped to the TCGA as well as those that were not sent but were cut for shipment. Future research should focus on developing more advanced technology that will allow the inclusion of a wide range of specimens that do not exclude a large part of the lung cancer population.
