Virtual Library
Start Your Search
S. Kao
Author of
-
+
ED13 - Treatment of Malignant Pleural Mesothelioma (ID 282)
- Event: WCLC 2016
- Type: Education Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:H. Lee Kindler, N. Van Zandwijk
- Coordinates: 12/07/2016, 11:00 - 12:30, Hall C1
-
+
ED13.02 - Tissue-Based Biomarkers (ID 6496)
11:15 - 11:30 | Author(s): S. Kao
- Abstract
- Presentation
Abstract:
Introduction: Malignant pleural mesothelioma (MPM) is difficult to diagnose and accurate prediction of patient outcomes still relies on a range of clinical scores. Despite extensive efforts in the last decade, there are few tumour-based molecular markers that can accurately contribute to diagnosis and prediction of disease course. Recent reports describing the mutational and transcriptional landscape of MPM tumours have revealed a number of changes that may yield clinically useful biomarkers following further development and validation studies. Diagnosis: The definitive MPM diagnosis relies on a tissue biopsy and demonstration of invasion. Diagnostic markers consist of a combination the expression of mesothelial-specific proteins and absence of markers of adenocarcinoma. Recent advances have shown that the mutation of the tumour suppressor BAP1 leads to loss of nuclear staining, and that this is highly specific for discriminating mesothelioma from benign conditions. As in some cases MPM has neither BAP1 mutation nor loss of nuclear staining, sensitivity is lacking, but this can be improved by incorporating detection of CDKN2A genomic loss using FISH. Assessment of additional mutations and fusion genes recently identified in MPM may represent useful markers for future development. Characteristic changes in microRNA expression are present in MPM, and these form the basis of a highly accurate molecular test for the differential diagnosis of MPM from other tumours affecting the pleura. Prognosis: Clinical and pathological parameters remain the best predictors of disease outcome, and although some molecular markers have demonstrated prognostic significance, these are yet to be validated. Histopathological subtype is an accurate prognostic indicator, with the epithelioid subtype associated with significantly better outcomes than the non-epithelioid biphasic and sarcomatoid types. The variation within epithelioid tumours is well recognised, and epithelioid tumours with a pleomorphic morphology have poor prognosis, similar to patients with non-epithelioid tumours. Recent results from transcriptomic analyses have revealed subsets within epithelioid and non-epithelioid tumours which more accurately describe prognosis. These include the two-cluster C1/C2 classification system based on a 3 gene predictor, and the 4 clusters (sarcomatoid, epithelioid, biphasic-epithelioid and biphasic-sarcomatoid) derived from RNA-seq analysis. MicroRNA expression has also been linked to outcome. Early studies revealed prognostic significance of miR-29c-3p, with higher levels corresponding to longer survival. More recently, microRNA expression profiles differing between long and short survivors yielded a 6-microRNA score that predicted outcome in two surgical series. Whether TCGA data confirm these observations remains to be determined. In addition to RNA and protein biomarkers, the cellular composition of tumours influences patient outcomes. It is likely that the mix of cell types within tumour samples also contributes to biomarker expression, especially for RNA extracted from whole tumours. For some proteins, differential expression in the stromal and tumour compartments is of prognostic value, for example in the case of SPARC expression. The importance of the immune cell infiltrate was recently investigated in a large number of epithelioid samples revealing that greater numbers of tumour-infiltrating CD4+ and CD8+ T lymphocytes (TILs), as well as fewer tumour-associated macrophages (TAMs) of the M2-type correlate with survival. In addition, the ratio of the TAMs/TILs was also shown to predict outcome in epithelioid MPM. Other cell populations associated with vascular and lymphatic invasion are also linked to survival. Prediction: Unlike lung cancer, few actionable mutations are present in MPM that predict sensitivity to targeted agents, and clinical trials with these drugs have yielded disappointing results. Markers for single agent chemotherapy and the standard cisplatin/pemetrexed doublet have also been investigated in retrospective studies attempting to link patient outcomes with gene (mRNA and protein) expression and polymorphisms. Multiple reports have linked levels of TS protein, but not mRNA, to outcomes with pemetrexed-based chemotherapy. As expected from a multi-targeted agent, other levels of other proteins such as folypoly-glutamate synthase (FGPS) and the reuced folate carrier (RFC) were also associated with tumour response and patient outcomes. However, a subsequent study with a similar number of patients suggested that both TS and FPGS lack predictive value. With respect to DNA repair genes involved in cisplatin activity, ERCC1 and others have been evaluated, but results are again inconclusive. The picture is complicated by assessment of target genes in patients treated with two interacting agents (with or without subsequent surgery), and the true value of these genes awaits carefully controlled prospective analyses. The recent breakthrough success of immune checkpoint inhibiting antibodies targeting CTLA4 and the PD-1/PD-L1 axis in melanoma and lung cancer has seen these agents applied to MPM patients. With response rates of around 25% for PD-1 targeting antibodies pembrolizumab and nivolumab in MPM, new predictive markers are needed to improve patient selection and for health economics reasons. Although the Keynote trial included patients based on positivity of PD-L1 staining, PD-L1 status appears to have little value in predicting response rate. Ongoing research into immune cell involvement may shed more light on this. Future directions: Continuing research in this area should learn from limitations of the biomarker studies of the last decades to improve the search for useful molecular markers. Large prospective trials are needed to carefully evaluate predictive markers. Alternative approaches such as the analysis of live cell populations taken from fine-needle aspirates and investigation of circulating tumour cells and tumour-derived markers in the circulation (DNA, exosomes) may yield novel markers. Conclusions: Extensive research into tumour-based markers for MPM is gradually making progress. New markers to assist in diagnosis and prognosis have been identified, but the selection of accurate predictive markers has so far remained elusive. Next-generation sequencing has identified multiple new candidate markers requiring further investigation, and may provide breakthroughs in the future.
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.
-
+
OA02 - Novel Targets and Biomarkers in Malignant Pleural Mesothelioma (ID 369)
- Event: WCLC 2016
- Type: Oral Session
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:L.E. Raez, M. Jakopovic
- Coordinates: 12/05/2016, 11:00 - 12:30, Stolz 2
-
+
OA02.03 - Circulating Fibroblast Growth Factor 18 is Elevated in Malignant Pleural Mesothelioma Patients - A Multi-Institutional Study (ID 5988)
11:20 - 11:30 | Author(s): S. Kao
- Abstract
- Presentation
Background:
Malignant pleural mesothelioma (MPM) is a rare but devastating malignancy. Despite the search for new promising treatment approaches, the outcome for most MPM patients remains dismal. Therefore, the identification of novel biomarkers is urgently needed in order to identify patients with a better prognosis and to support personalized therapeutic decisions. In our previously published study, we were able to show that fibroblast growth factor 18 (FGF18) is overexpressed in MPM tissue specimens and cell models. The objective of this study was the evaluation of FGF18 as a circulating biomarker in MPM.
Methods:
Plasma was collected from 107 MPM patients at the time of diagnosis or before surgical resection. Samples were included from the Medical University of Vienna, University Hospital Center in Zagreb and from The Concord Repatriation General Hospital and Strathfield Private Hospital in Sydney. Samples from 49 healthy volunteers and from 8 patients with non-malignant pleural diseases served as controls. Circulating FGF18 was measured by enzyme-linked immunosorbent assay and correlated to clinical, pathologic and radiologic parameters.
Results:
Plasma FGF18 level was significantly elevated in MPM patients vs. healthy controls (P<0.0001). A slight increase of circulating FGF18 level was also detected in patients with pleuritis or fibrosis (vs. control, P=0.0067). Sarcomatoid (n=7) morphology was associated with high FGF18 levels when compared to the epithelioid (n=77) histology (P=0.0064). Importantly, MPM patients presenting with FGF18 levels below the median had a significantly longer overall survival when compared to those with high FGF18 levels (median survival 625 versus 382 d, P=0.0038). Data on multivariate analysis, disease-free survival, correlation with other biomarkers and tumor volume will be presented at the conference.
Conclusion:
Our findings reveal that FGF18 is a promising blood-derived candidate biomarker in MPM. Furthermore FGF18 may support the histological classification of MPM and the identification of MPM patients with poor prognosis. .
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.
-
+
P3.02c - Poster Session with Presenters Present (ID 472)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Advanced NSCLC
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P3.02c-055 - Incidence and Grade of Pneumonitis in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients Treated with Anti-PD-1 Antibodies (ID 4538)
14:30 - 14:30 | Author(s): S. Kao
- Abstract
Background:
Advanced non-small cell lung cancers (NSCLC) can be treated with anti-PD1 (programmed cell death 1) antibodies. Anti-PD-1 therapy can lead to immune mediated adverse events. This study examines the incidence of pneumonitis, a potentially fatal complication, in patients with advanced NSCLC treated with anti-PD-1 antibodies at 3 large hospitals in Sydney, Australia.
Methods:
NSCLC patients commenced on pembrolizumab (2 mg/kg or 10 mg/kg Q3W) or nivolumab (3 mg/kg Q2W) were assessed for adverse events including pneumonitis. Patient demographics, treatment history and immune mediated complications were collected. Pneumonitis was graded according to the Common Terminology Criteria for Adverse Events Version 4.0. Pneumonitis treatment and clinical outcomes were collected. Serial imaging was reviewed with a blinded radiologist.
Results:
A total of 104 patients between 2012 and 2016 were treated with anti-PD-1 therapy. Median age for included patients was 67. Fourteen (14%), 35 (34%), and 53 (51%) had anti-PD-1 as first, second, or third and subsequent line treatment respectively. Nine patients (9%) developed pneumonitis. Three patients (4%) developed grade 3 (G3) or higher pneumonitis including one patient (1%) that died due to pneumonitis. All patients with ≥G3 pneumonitis required hospital admission with one requiring admission to a high dependency unit. None of the patients with ≥G3 pneumonitis were retreated with anti-PD1 therapy. All patients with ≥G3 pneumonitis died within 5 weeks of their diagnosis of pneumonitis. Seven patients with pneumonitis were treated with steroids. The median length of treatment with steroid was 29 days. Pneumonitis involved both lungs in 3 patients. Of the remaining 6 patients – 2 had all right lung lobes involved, 2 had two lobes and 1 had one lobe. Fifteen (14%) patients had a history of receiving concurrent chemoradiotherapy prior to anti-PD-1 therapy. A further 6 (6%) had curative intent radiotherapy and 15 (14%) had palliative radiotherapy to the thorax prior to anti-PD1 therapy. One of the patient with G3 pneumonitis had previously received radiotherapy to the chest. No association between prior radiotherapy and pneumonitis was seen.
Conclusion:
The incidence of pneumonitis is rare but our real-life multi-institutional experience demonstrates an incidence higher than reported in the literature. This complication can be life threatening and onset of ≥G3 pneumonitis is associated with short survival.
-
+
P3.03 - Poster Session with Presenters Present (ID 473)
- Event: WCLC 2016
- Type: Poster Presenters Present
- Track: Mesothelioma/Thymic Malignancies/Esophageal Cancer/Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 12/07/2016, 14:30 - 15:45, Hall B (Poster Area)
-
+
P3.03-033 - The Influence of Geographic and Socioeconomic Factors on Prognosis and Treatment Provision in Malignant Pleural Mesothelioma (ID 5941)
14:30 - 14:30 | Author(s): S. Kao
- Abstract
Background:
Whilst the impact of clinico-pathological factors on the prognosis of malignant pleural mesothelioma (MPM) is well understood, socio-economic and geographic factors have received less attention. Although the majority of Australians reside in major cities, a dispersed population lives in regional and remote areas, where access to clinical services may be limited. We investigated the association between geographic and socio-economic factors and treatment provision and survival in a large series of patients from New South Wales.
Methods:
All patients awarded compensation by the NSW Dust Diseases Board (2002-2009) following diagnosis with MPM were assessed. Geographic remoteness, distance from oncological multidisciplinary teams (MDT) and socioeconomic status according to the index of relative socio-economic advantage and disadvantage (IRSAD), were assessed with known prognostic factors using Kaplan Meir and Cox-regression analysis. Chi-square testing compared categorical variables to analyse the impact of these factors upon clinical features and treatment received. Cancer Registry incidence data was assessed to allow comparison of the compensated DDB cohort to all NSW MPM cases.
Results:
We assessed 910 patients: Geographic remoteness (major city 67%; regional/remote 33%), distance to MDT (<10km 65%, <50km 92%). Geographic distribution was comparable to cancer registry data. Median overall survival was 10.0 months. On multivariate analysis, non-epithelioid histological subtype (HR.2.19); male gender (HR=1.37); age >70 (HR=1.39) and IRSAD status by decreasing quintile (HR=1.07) were independent prognostic factors, with a pronounced survival difference between highest and lowest IRSAD quintiles (8.4 vs 12.8 months). A trend to improved survival when residing in major cities (10.6 vs 8.8 months; p=0.162) and within 50km of MDT (10.3 vs 7.8 months;p=0.539) was noted. Patients geographic location and distance to MDT affected the use of palliative radiotherapy (p<0.05) however did not impact chemotherapy, adjuvant radiotherapy or extrapleural pneumonectomy provision. Socioeconomically disadvantaged patients were less likely to receive chemotherapy (40.3% vs 47.7%; p=0.032), with pronounced disparity between the most socioeconomically advantaged and disadvantaged quintiles (54.2% vs 37.6%;p=0.001).
Conclusion:
Despite ‘universal’ health care and the support of a compensation scheme, socioeconomic disadvantage was an independent prognostic factor for MPM in NSW Australia. A significant reduction in chemotherapy utilisation was noted, particularly in highly socioeconomically deprived areas. Furthermore, a trend to improved survival was noted in patients residing in major cities within closer proximity to oncology units, though treatment provision did not differ. Prospective research analysing specific factors including comorbidity, income, and individual preference will be required to better understand these findings in both compensated and non-compensated individuals.
