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W.T. Vigneswaran
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MINI 38 - Biology and Prognosis (ID 167)
- Event: WCLC 2015
- Type: Mini Oral
- Track: Thymoma, Mesothelioma and Other Thoracic Malignancies
- Presentations: 2
- Moderators:R. Tsuchiya, M. Wynes
- Coordinates: 9/09/2015, 18:30 - 20:00, 702+704+706
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MINI38.11 - Tumor Volume and Epithelioid Differentiation Are Independent Predictors of Survival in Malignant Pleural Mesothelioma (ID 2428)
18:30 - 20:00 | Author(s): W.T. Vigneswaran
- Abstract
- Presentation
Background:
Maximal cyto-reductive surgery with adjuvant therapy provides survival advantage in selected patients with malignant pleural mesothelioma (MPM). Extended pleurectomy and decortication (EPD), a lung sparing procedure, provides an opportunity to measure the tumor volume. We hypothesized that tumor volume is a better predictor of survival than the T and N, because it represents tumor burden more accurately. Currently the significance of epithelioid differentiation in the biphasic histology also remains poorly understood. We report our experience with patients undergoing EPD and the implication of tumor volume and epithelioid differentiation in overall survival.
Methods:
We evaluated 116 patients who underwent EPD for MPM. The following variables were assessed: age, gender, histology, tumor volume and pathological T and N stage. The tumor volume of resected specimens was measured using a water displacement method. All histological examinations were performed by a single pathologist, and the percent epithelioid histology was estimated in all patients. A Cox regression model was used to identify significant predictors of survival. Kaplan-Meier was used to summarize overall and subgroup survival.
Results:
There were 95 males and 21 females with a median age of 68 years (range 43-88 years). Epithelioid differentiation was 100% in 60 patients, 50-95% in 35 patients, and less than 50% in 21 patients (no patient with pure sarcomatoid histology was included in this report). Mean tumor volume was 642+/- 400ml. Tumor volume was between 100-299cc in 20 patients, between 300-599cc in 37 patients, and >600cc in 54 patients. In 5 patients the volume was not estimated. Six patients (5%) died within 30 days. Two-year survival from EPD was 28%. Median survival was 15.7 months. Percent epithelioid differentiation (p=0.0004) and tumor volume (p=0.001) were significant predictors of survival. T (p=0.05) stage, but not N stage, was a significant predictor of survival. Tumor volume was a predictor of T stage (p=0.05). No relationship between N stage and either tumor volume or histology was observed.
Conclusion:
Percent epithelioid differentiation and tumor volume are independent predictors of survival in MPM patients undergoing EPD.
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MINI38.12 - Multiplex Immunofluorescence Identifies Differences in Immune Microenvironment & Prognostic Biomarkers between Mesothelioma Subtypes (ID 3217)
18:30 - 20:00 | Author(s): W.T. Vigneswaran
- Abstract
- Presentation
Background:
Malignant mesothelioma (MM) is a universally lethal disease, which develops in the pleura, peritoneum, pericardium, and tunica vaginalis. MM is commonly associated with a prominent inflammatory reaction, including extensive macrophage infiltration. Early reports indicate presence of tumor infiltrating lymphocytes (TILs), PD-L1 expression (Kindler et al ASCO 2014), and activity of anti-PD-1 therapy (Alley et al AACR 2015). However, quantitative evaluation of multiple immune markers in a large mesothelioma cohort and evaluation of prognostic and biologic implications has not been reported.
Methods:
We performed multiplex immunofluorescence (IF) staining and automated, quantitative density assessments in a clinically annotated cohort of 109 malignant mesotheliomas (58 epithelioid, 43 biphasic, 8 sarcomatoid). Staining for PD-1, PD-L1 (immune checkpoint), FOXP3 (T-regulatory cells), and CD8 (TILs) was performed using a quantitative, multiplex IF system (TissueFax), and a multi-tumor-validated, quantitative StrataQuest analysis algorithm in order to identify specific immune cells and respective densities. Gene expression data (TCGA) was analyzed to confirm individual correlations. Staining for CD206 (macrophages) is ongoing.
Results:
PD-L1 density correlated with more aggressive histology, and was highest in sarcomatoid (median density score of 3016), and biphasic (2720) tumors compared with epithelioid tumors (1740). Using a cutoff of 5% PD-L1 density by area 19% of epithelioid, 38% of sarcomatoid, and 44% of biphasic tumors were deemed PD-L1 positive. PD-L1 expression exhibited a bimodal distribution (peaks at both high and low PD-L1 densities). Also with the biphasic tumor cohort expression of PD-L1 correlated with worse outcome (P=0.02), while PD-1 and CD8 did not have prognostic implications (and could not distinguish histologic subtypes). By contrast in epithelioid MM CD8 infiltration density showed a trend towards improved prognosis (P=0.06) (and correlated with PD-1 expression), while PD-L1 expression was not prognostic. Interestingly, PD-1/CD8 and PD-L1 expression did not correlate regardless of histology (R=0.02-0.08), suggesting macrophage-driven PD-L1 expression. Gene expression data supported this hypothesis and staining for M2-related macrophage markers is ongoing. In epithelioid tumors FOXP3 T-regulatory cell density showed a trend towards worse prognosis (P=0.07). In biphasic and sarcomatoid tumors prognosis was poor regardless of FOXP3 expression. Data on stromal versus tumor expression patterns is being processed.
Conclusion:
In mesothelioma CD8, PD-1, PD-L1 and FOXP3 are widely expressed, with 19% of epithelioid, and 38-44% of sarcomatoid and biphasic tumors showing elevated PD-L1 density. PD-L1 expression correlates with a worse prognosis by subtype and in the biphasic tumor population. In epithelioid tumors PD-1 may indicate better outcome. PD-1 and PD-L1 expression do not correlate with each other in malignant mesothelioma, which relates to pro-tumorigenic macrophages leading to potentially interferon gamma independent PD-L1 expression.
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P1.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 233)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P1.04-012 - Using Computed Tomography Scans to Assess the Histology of Malignant Pleural Mesothelioma (ID 3003)
09:30 - 17:00 | Author(s): W.T. Vigneswaran
- Abstract
Background:
The purpose of this study is to assess the histology of malignant pleural mesothelioma using computed tomography (CT) based imaging.
Methods:
28 patients with malignant pleural mesothelioma were used (histologies: 17 epithelioid, 11 biphasic). A CT scan was acquired for each patient prior to surgical resection of the tumor. A radiologist identified and outlined the tumor boundary on each CT section that demonstrated tumor. These outlines were analyzed to determine the total volume of disease present, the mean volume of disease per outlined section, and the distribution of Hounsfield Unit (HU) values throughout the outlined tumor. These parameters were used to differentiate tumors of epithelioid and biphasic histologies. For each parameter, cutoffs were determined to maximize the extraction of biphasic cases from the entire cohort, while minimizing the extraction of epithelioid cases.
Results:
Discernable differences were extracted from the images of the two different histologies of the disease. Figure 1 shows the mean HU value, the standard deviation and skew in the distribution in the HU values, and the volume of tumor represented on each CT section demonstrating disease. With regard to HU distribution, the biphasic cases generally had a higher mean HU value. For example, 73% of the biphasic cases had a mean value greater than 30, compared to only 29% of the epithelioid cases. Biphasic cases also tend to have a more negative skew in their HU distribution; 73% of biphasic cases had a skew value less than -1, compared to 35% of epithelioid cases. It was also seen that biphasic cases also tended to have a higher volume of tumor present throughout their disease presenting CT sections. There were promising results from extracting the biphasic cases by using optimized cutoffs from gathered data. The criteria used were as follows: Cases that exhibited more than 9 mL of tumor per outlined CT section, or exhibited a mean HU value greater than 10 as well as a skew in HU values less than -1 were extracted from the cohort and identified as biphasic. Of the cases that match these criteria, 10 were actually biphasic while 6 were actually epithelioid. These results are 91% specific, missing only one biphasic case, and 65% specific, correctly excluding 11 of the 17 epithelioid cases. Figure 1 Figure 1 – Comparison of Epithlioid and Biphasic cell types.
Conclusion:
This study demonstrates that CT-based imaging may be a useful tool for the assessment of tumor histology through image analysis.
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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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P1.08-005 - Met and PI3K/mTOR as a Potential Combinatorial Therapeutic Target in Malignant Pleural Mesothelioma (ID 1700)
09:30 - 17:00 | Author(s): W.T. Vigneswaran
- Abstract
Background:
There are a number of genetic alterations such as BAP1 and NF2 that can occur in malignant pleural mesothelioma (MPM). Various studies have shown that both MET and its downstream key intracellular signaling partners PI3K and mTOR are known to be overexpressed and frequently mutated in MPM. Here we have examined the therapeutic efficacy of a new generation small molecule inhibitor of MET receptor tyrosine kinase ARQ 197 and phosphatidylinositol 3-kinase and mTOR (PI3K/mTOR) inhibitors BEZ-235 and GDC-0980 in MPM.
Methods:
The mesothelioma cells were treated with ARQ 197, NVP-BEZ235, or GDC-0980 alone or in combination for 72 hours and cell proliferation was measured by using Alamar Blue assay. Synergistic efficacy was determined by isobologram and combination-index methods of Chou and Talalay. Signaling was assessed by immunoblotting. The mechanism of inhibition was further studied by using apoptosis assays and cell cycle analysis. Cell motility was studied by using scratch assays. We also examined efficacy of the combination of ARQ 197 and GDC-0980 on in vivo tumor growth by using mouse xenograft models.
Results:
MPM cell lines over-express MET and its active form p-MET, PI3K, and p-AKT and total AKT. ARQ 197, NVP-BEZ235, and GDC-0980, when used alone, significantly inhibited the cell proliferation of mesothelioma cells in a dose dependent manner. The combination of MET and PI3K/mTOR inhibitors was synergistic in suppressing MPM cell growth as compared to any single drug alone. Treatment of ARQ 197, NVP-BEZ235, and GDC-0980 alone or in combination inhibited the phosphorylation of AKT and S6 kinase in mesothelioma cells. MET and PI3K/mTOR inhibitors affect cell growth of mesothelioma cells by cell cycle inhibition (cyclin D1) and induction of apoptosis (presence of cleaved PARP, by IF/ confocal microscopy). MET inhibitor ARQ 197 alone inhibits the cell motility of mesothelioma cells in scratch assay. The combination of ARQ 197/ GDC-0980 was much more effective than each single agent alone in inhibiting the tumor growth of mesothelioma xenografts in nude mice. Compared to the control mice (2946±403 mm[3]), the tumors of mice treated with ARQ 197(2262±317 mm[3]) and GDC-0980 (1631±229.57mm[3]) alone had a significant decrease in the tumor volume. The tumor volume of mice treated with the combination of ARQ 197 and GDC-0980 further decreased it to six fold (475±97.43 mm[3]) compared to the control mice.
Conclusion:
Our results suggest that the combined use of ARQ 197/NVP-BEZ235 and ARQ 197/GDC-0980 is far more effective than single drug use in suppressing MPM cell motility and growth in vitro and tumor growth in vivo and therefore merits further translational studies.
