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Raja Flores
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EP1.04 - Immuno-oncology (ID 194)
- Event: WCLC 2019
- Type: E-Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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EP1.04-15 - NSCLC Response Determinants to Chemoimmunotherapy: Deep Profiling of Tumors Following Neoadjuvant Cemiplimab and Chemotherapy (Now Available) (ID 1021)
08:00 - 18:00 | Author(s): Raja Flores
- Abstract
Background
Clinical trials have demonstrated synergistic effects of combination chemoimmunotherapy in patients with locally advanced and metastatic non-small cell lung cancer (NSCLC), however, our understanding is limited as to why and for whom PD-1 blockade with or without chemotherapy is effective, as is our understanding of the mechanism of synergy between these therapies.
While most patients with resectable NSCLC receive neoadjuvant or adjuvant chemotherapy, this intervention only changes the natural course of disease for ~5% of patients. Early studies have demonstrated major pathologic responses to neoadjuvant immunotherapy ± chemotherapy.
Method
To investigate the immunodynamic effect of PD-1 blockade and chemotherapy, and identify potentially more effective immune modifying targets or combinations, we will use novel immunophenotyping platforms to characterize the effect of this combination on the tumor. This trial will enroll 52 patients with Stage Ib-IIIa NSCLC into three cohorts receiving 2 cycles of 1) platinum-doublet chemotherapy, 2) the PD-1 antibody cemiplimab, or 3) combination chemoimmunotherapy. Following surgery, patients will receive additional adjuvant chemoimmunotherapy; in total all patients will receive 4 cycles of standard platinum-doublet chemotherapy and 8 cycles of cemiplimab. All patients will undergo pre-treatment biopsies of their tumor, and blood will be collected at 6 time-points before and after surgery.
The primary endpoint for this clinical trial is major pathologic response, defined as ≤10% viable tumor within resection. Secondary endpoints include: delay of surgery, disease-free survival, overall response rate, overall survival, measurement of adverse events, and change in CD8 T-cell infiltration.
Exploratory endpoints include in-depth analysis of the pre-treatment tumor biopsies and post-treatment surgical specimens, and paired blood. We will characterize proteomic and transcriptomic changes in the stromal and immune compartment of tumors at the histologic level using a multiplexed ion-beam imaging (MIBI)—a novel multiplex immunohistochemistry platform capable of analyzing >50 markers on a single section of tissue—and at the single-cell level using Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITEseq), a novel platform combining the proteomic data-potential of mass cytometry (CyTOF) and the transcriptomic data-potential of single cell RNA sequencing including TCR sequencing. Feasibility of this multi-pronged approach has been demonstrated on untreated NSCLC (unpublished data, submitted as abstract to WCLC by our group).
To probe for biomarkers correlating with response or resistance to therapy, we will perform unbiased analysis of peripheral blood lymphoid and myeloid populations by CyTOF, and measure nearly 100 soluble factors in serum using Olink.
Result
This trial opened to accrual April 2019.
Conclusion
Section not applicable.
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IBS06 - Multimodality Treatment - Realtime Data from National Registries (Ticketed Session) (ID 37)
- Event: WCLC 2019
- Type: Interactive Breakfast Session
- Track: Mesothelioma
- Presentations: 1
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 07:00 - 08:00, Dublin (1997)
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IBS06.02 - Real Time Data from US (SEERS) (Now Available) (ID 3332)
07:00 - 08:00 | Author(s): Raja Flores
- Abstract
- Presentation
Abstract
Real time data for Mesothelioma in US
Maaike van Gerwen, Naomi Alpert, Andrea Wolf, Raja Flores, Emanuela Taioli
Introduction
The association between asbestos exposure and malignant mesothelioma has been well established. Exposure to asbestos mainly occurs through work although environmental exposure has been documented. Several countries have put in place an active epidemiologic surveillance of mesothelioma cases.
Through a PubMed and Google Scholar search using the key words “mesothelioma” and “registry”, and by reviewing data sources of studies described in a review of environmental exposure and malignant mesothelioma, we identified existing mesothelioma registries. Countries with mesothelioma specific registries are Australia, Belgium, France, Germany, Italy, Japan, South Korea, South Africa, Turkey, and the UK. Nation-wide coverage is obtained in Italy, Australia and South Korea. Registries in Australia, France, Italy, and South Korea use interviews to obtain exposure data from the patient or a close relative, although none of these countries has a tissue bank. The UK has a mesothelioma tissue bank although it is not linked with the National Mesothelioma Audit registry. All registries have or will develop linkage with death index registries to monitor survival outcomes. (Table 1)
The Scandinavian countries including Norway, Sweden, Finland and Denmark, have a population based cancer registry that includes mesothelioma and is linked to other databases, such as an occupational database, thus has more comprehensive information on each case.
Mesothelioma surveillance in the US to date
Currently, no nation-wide, mesothelioma specific registry exists in the US. Various existing databases are used to investigate mesothelioma, for instance the National Cancer Database has been used to look at prognostic factors; gender and race differences in mesothelioma survival have been studied using the Surveillance, Epidemiology, and End Results (SEER) database. All these datasets suffer of a time-lag between case occurrence, reporting, registration and eventually data availability for research purposes; these are serious limiting factors in the case of mesothelioma. Because of the rarity and lethality of the disease, a real-time capture registry is needed to thoroughly collect exposure data, complete data on treatments, quality of life before and after treatment, symptoms and pain management. All these elements are lacking in the existing databases.
Because the US mesothelioma incidence is not decreasing as quickly as predicted and new cases still occur as well the fact that mortality rates are steady overtime, the overall health burden due to mesothelioma in the US still remains. Although the use of asbestos has been restricted or banned since 1980, several scientific questions remain open due to the long latency period between exposure and mesothelioma clinical occurrence, and to gaps in knowledge of the carcinogenesis process. Data on occupational and environmental asbestos exposure and co-exposure to other carcinogens are needed. Certain patterns, such as differences in outcomes by gender, differences in incidence rates by race, as well as geographic clusters of increased number of cases, are hard to explain with the existing data.
Possible next steps towards a US mesothelioma registry
“Real time” enrollment is important in order to systematically collect information on asbestos and other exposures through interviews with mesothelioma patients or a close relative. Furthermore, optimal coverage, preferably population based and nation-wide, and a simplified consent process are needed in order to capture a maximum number of cases. A centralized quality control system, standardized data collection methods, and the ability to link to relevant other existing registries are important in order to integrate the registry with clinical and prognostic information. Additionally, consistency in the design and questionnaire content with other countries would be ideal, in order to conduct comparisons and possibly pool the data. The flexibility to add or modify modules to tailor to future research questions are other preferable features for a US mesothelioma registry. (Figure 1) A discrete amount of work has been devoted to molecular markers such as mesothelin and certain germline mutations as prognostic factors. The role of these biomarkers could be validated on larger populations of patients if a comprehensive registry that includes tissue is implemented.
Summary and conclusions
In conclusion, with the remaining health burden due to mesothelioma, the changing landscape of asbestos exposure, and the many unanswered scientific questions, a nation-wide, real-time US mesothelioma registry is urgently needed. Methods for data sharing, linkage to existing tissue banks, and data access should be implemented and tested on a small scale before being implemented nationwide. One of the most practical outputs of these efforts would be the ability to conduct pragmatic trials that could be built out of a “real time” case capture system.
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MA02 - Miscellaneous Topics in the Management of Early Stage Lung Cancer (ID 116)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Now Available
- Moderators:Mireia Serra-Mitjans, Thomas A. D'Amico
- Coordinates: 9/08/2019, 10:30 - 12:00, Interlaken (1988)
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MA02.09 - Prognostic Impact of Immune Cell Biomarkers in Surgically Resectable Non-Small Cell Lung Cancer (Now Available) (ID 2646)
10:30 - 12:00 | Author(s): Raja Flores
- Abstract
- Presentation
Background
Immune cells within the tumor microenvironment (TME) play an important role in the development, progression and eventual outcomes of non-small cell lung cancer (NSCLC). The relative balance of immune effector and regulatory cell subpopulations may tilt the TME to be either detrimental or supportive of tumorogenesis and will have a profound impact on the tumor’s eventual destiny. In early-stage lung cancer, the role of individual immune cell subtypes in the TME on survival outcomes following surgical resection is unknown.
Method
This project made use of The Cancer Genome Atlas (TCGA) Program data. We computed sample-specific scores for different immune cells using xCell, a new model for estimating different immune cell types from RNAseq data, for all stage I-IIIA NSCLCs. Then, we assessed the association between each cell type and survival with Cox Regression, while adjusting for important clinical variables (i.e., stage, age, gender, smoking status). We stratified the analysis according to histological subtype.
Result
There were 910 surgically resected early-stage NSCLC analyzed, of which 438 were adenocarcinomas (LUADs) and 472 were squamous cell (LUSC) samples. Higher levels of natural killer cells, neutrophils, and mast cells within tumors were associated with significantly improved survival in LUAD patients, whereas no immune cell type was associated with survival for LUSC patients or the combined analysis.
Figure 1: Adjusted Survival According to Estimated Immune Cell Infiltration
Hazard ratios are adjusted for stage, gender, age and smoking status
Conclusion
Innate and adaptive immune cells within the TME may have prognostic value in early-stage NSCLC patients undergoing surgical resection. However, the role of individual immune cells may vary according to histological subtype. Prospective research should continue to assess the association of the immune cell composition of the TME with clinical outcomes.
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MA06 - Challenges in the Treatment of Early Stage NSCLC (ID 124)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Now Available
- Moderators:Florentino Hernando-Trancho, Ayten Kayi Cangir
- Coordinates: 9/08/2019, 13:30 - 15:00, Colorado Springs (1994)
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MA06.13 - Tsuguo Naruke Lectureship Award for Surgery (Now Available) (ID 3901)
13:30 - 15:00 | Presenting Author(s): Raja Flores
- Abstract
- Presentation
Abstract not provided
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MA07 - Clinical Questions and Potential Blood Markers for Immunotherapy (ID 125)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:David R Spigel, Roberto Ferrara
- Coordinates: 9/08/2019, 13:30 - 15:00, Vancouver (2003)
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MA07.10 - The Influence of Sex on Immunotherapy Efficacy in Non-Small Cell Lung Cancer (Now Available) (ID 712)
13:30 - 15:00 | Author(s): Raja Flores
- Abstract
- Presentation
Background
Patient’s sex impacts clinical outcomes for multiple cancers, including non-small cell lung cancer (NSCLC). A recent meta-analysis demonstrated sex may also impact response to novel immunotherapeutic agents, where men appear to derive greater benefit than women. However, the role of important clinical confounders of immunotherapy response that differ according to sex was not accounted for. The aim of this project was to investigate the effect of sex on immunotherapy benefit for NSCLC patients using a large, nationally representative database while adjusting for important clinical confounders.
Method
Advanced metastatic NSCLC patients diagnosed between 2013-2015 were identified in the National Cancer Database (NCDB). A Cox Proportional Hazards model was used to assess the interaction between sex and immunotherapy treatment for overall survival. This model was also adjusted for histology, stage, age, race, tumor size, comorbidities and other treatment (i.e. chemotherapy, radiation).
Result
Of 103,525 advanced NSCLC patients, 69,120 (67%) had adequate follow-up information for survival analysis. Of these, 37,423 (54.1%) were males and 31,697 (45.9%) females; 4,012 patients received immunotherapy as first-course treatment. In the adjusted model, both males (Hazard Ratio [HR]adj: 0.77, 95% Confidence Interval [CI] 0.73-0.81) and females (HRadj: 0.80, 95% CI 0.76-0.85) receiving immunotherapy had improved survival compared to those not receiving immunotherapy. The interaction between sex and immunotherapy was not significant (p=0.2539) after adjusting for clinical variables. Among the covariates, younger age, adenocarcinoma histology, Black race, smaller tumor size, lower comorbidity score and additional cancer treatment (either chemotherapy or radiation) were independently associated with better survival (p<0.0001 for all comparisons).
Conclusion
Patient sex does not appear to affect the benefit of immunotherapy in advanced NSCLC patients after adjusting for potential clinical confounders. Other clinical factors may play a role in immunotherapy response and should be explored in future research.
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P1.13 - Staging (ID 181)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Staging
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.13-01 - The Importance of Staging of Lung Cancers, 30 mm or Less, Separately for Subsolid and Solid Nodules (ID 1413)
09:45 - 18:00 | Author(s): Raja Flores
- Abstract
Background
To determine pathologic results on non-small-cell lung cancers (NSCLCs), 30 mm or less in maximum diameter, separately by tumor consistency (solid, subsolid) on CT scans as we had shown that long-term survival was significantly different by tumor consistency and by type of parenchymal invasion.
Method
We reviewed all patients enrolled in the Initiative for Early Lung Cancer Research on Treatment (IELCART), a prospective cohort study of patients with first primary T1a-T1c NSCLC between 2016 and 2018 who had surgical resection. Short-axis diameter of N1-N3 lymph node on CT and SUVmax uptake on FDG-PET, if performed, were documented with values ≥ 2.5 defined as PET positive. Pathology reports were reviewed for N1-N3 lymph nodes (LNs) metastases and parenchymal invasion.
Result
Among 347 patients, 280 (80.7%) and 67 (19.3%) had solid and subsolid NSCLCs, respectively; all subsolid NSCLCs were adenocarcinoma. There was FDG-PET uptake in 253 (93.3%) with solid NSCLCs and in 55 (91.7%) with subsolid NSCLCs.None of the 67 subsolid NSCLCs had N1 or N2 LN metastases (Table 1). Among the 280 solid NSCLCs, none of the 42 NSCLCs≤ 10 mm had N1 or N2 metastases, while 5 of the 238 solid NSCLCs greater than 10 mm had N2 and 14 had N1 LN metastases. None of the N2 LNs were positive on FDG-PET and only 4(28.6%) of the 14 N1 LNs were positive on FDG-PET.
Angiolymphatic invasion was most frequently, followed by pleural and major vascular invasion (Table 1). For solid NSCLCs, invasion increased with increasing tumor diameter.
Conclusion
No N1-N3 LN metastases were identified in solid NSCLCs ≤ 10 mm; none in subsolid NSCLCs ≤ 30 mm. None with N2 LN metastases were positive on FDG-PET. This suggests that for NSCLCs, 30 mm or less, clinical staging be based on solely tumor size. For pathologic staging, we recommend differentiating staging classification by tumor consistency in line with the latest recommendations for pathologic assessment.
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P1.17 - Treatment of Early Stage/Localized Disease (ID 188)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.17-14 - Prognostic Value of Immune Cell Biomarkers in Surgically Resectable Non-Small Cell Lung Cancer: A Meta-Analysis (Now Available) (ID 2658)
09:45 - 18:00 | Author(s): Raja Flores
- Abstract
Background
Immune cells within the tumor microenvironment (TME) play an important role in the development, progression and outcomes of non-small cell lung cancer (NSCLC). We conducted the first meta-analysis of studies assessing the role of individual immune cells in surgically resected stage I-III NSCLC to evaluate the prognostic value of immune cell biomarkers.
Method
PubMed was searched to identify eligible studies assessing clinical outcomes of surgically resected stage I-III NSCLC patients according to immune cell subsets: CD3+ T cells, CD4+ T Helper cells, CD8+ T cytotoxic cells, CD20+ B cells, FoxP3+T Regulatory cells, Natural Killer cells (CD56/CD57+), macrophages (CD68+), and Mast Cells. Meta-analysis was performed using a linear mixed-effects model to determine overall survival (OS) and disease free survival (DFS), and was reported according to whether or not the study adjusted for clinical covariates. I2 was used to assess heterogeneity across studies.
Result
42 articles (7,906 patients) were included in this analysis. Higher levels of CD20+ B cells were associated with better OS, while increased FoxP3+ T regulatory cells and Mast Cells were associated with worse OS in unadjusted studies. However, in studies adjusting for clinical variables, CD8+ T cytotoxic cells and Natural Killer cells were also found to be associated with improved OS, while mast cells no longer were significantly detrimental. CD20+ B cells were associated with better DFS in unadjusted studies; in adjusted studies, CD8+ T cytotoxic cells were associated with better survival and FoxP3+ T Regulatory cells were associated with worse survival, with CD20+ B cells no longer significantly associated survival. I2 did not show substantial heterogeneity between studies.
Table 1: Meta-Analysis Survival Estimates
OS
DFS
Biomarker
Unadjusted HR (95% CI)
N, Heterogeneity (%)
Adjusted HR
(95% CI)
N, Heterogeneity (%)
Unadjusted HR (95% CI)
N, Heterogeneity (%)
Adjusted HR
(95% CI)
N, Heterogeneity (%)
CD3+
T cells
0.98
(0.87-1.12)
6 articles
I2= 0.00
0.71
(0.37-1.37)
3 articles
I2= 0.00
0.98
(0.86-1.12)
5 articles
I2= 0.00%
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CD4+
T Helper cells
0.64
(0.37-1.10)
4 articles
I2= 13.65
0.80
(0.50-1.28)
4 articles
I2= 0.00
0.72
(0.39-1.32)
3 articles
I2= 0.00%
0.59
(0.11-3.12)
1 article
CD8+
T Cytotoxic cells
0.99
(0.95-1.04)
14 articles
I2= 0.00
0.71
(0.52-0.96)
12 articles
I2= 20.95
0.94
(0.77-1.16)
8 articles
I2= 16.65%
0.60
(0.41,-0.87)
9 articles
I2= 20.43%
CD20+
B cells
0.45
(0.22-0.93)
5 articles
I2= 52.29
0.16
(0.04-0.64)
1 article
0.57
(0.33,-1.00)
4 articles
I2= 0.00%
0.51
(0.20-1.32)
1 article
FoxP3+
T Regulatory cells
1.78
(1.20-2.64)
9 articles
I2= 14.93
2.38
(1.56-3.65)
6 articles
I2= 0.00
1.45
(0.81-2.59)
3 articles
I2= 0.00%
2.07
(1.10-3.90)
3 articles
I2= 0.00%
Natural Killer cells
0.66
(0.35-1.25)
3 articles
I2= 13.63
0.50
(0.26-0.95)
4 articles
I2= 0.00
1.35
(0.39-4.66)
1 article
0.59
(0.27-1.28)
2 articles
I2= 0.00%
Macrophages
1.11
(0.65-1.90)
5 articles
I2= 18.11
1.04
(0.69-1.55)
6 articles
I2= 0.00
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1.88
(0.87-4.08)
4 articles
I2= 43.97%
Mast Cells
1.81
(1.01-3.15)
3 articles
I2=0.00
2.01
(0.88-3.92)
3 articles
I2=43.99
2.30
(1.20-4.70)
1 article
1.50
(0.60-3.60)
1article
HR= Hazard Ratio, CI = Confidence Interval
Conclusion
Immune cell subsets are able to provide prognostic information in early-stage NSCLC undergoing surgical resection. When evaluating these immune biomarkers, adjustment for clinical covariates can have a profound impact on survival estimates.
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P1.17-28 - Refusal of Surgery for Early Stage Lung Cancer: Risk Factors and Survival (ID 1395)
09:45 - 18:00 | Author(s): Raja Flores
- Abstract
Background
The standard of care for treatment of early stage non-small cell lung cancer (NSCLC) is surgical resection. However, suitable patients refuse surgery for various reasons. We characterize the clinical and sociodemographic predictors of those who refuse recommended surgery for early stage NSCLC cancers and explore the influence of surgical compliance on survival.
Method
Primary Stage I and II NSCLC cases diagnosed between 2007 and 2014 were selected from the Surveillance, Epidemiology and End Results (SEER) database (n = 36,926). All cases were recommended surgery for treatment. Predictors of surgery refusal were examined using multivariate logistic regression. The likelihood of mortality after refusing surgery and any chemotherapy/radiation and refusing surgery but receiving alternative forms of treatment was performed using a cox proportional hazards model. Propensity-matched survival analysis was then performed between those who received surgery and those who refused surgery. SAS v9.4 was used for statistical analyses.
Result
The majority of the sample was non-Hispanic White (79%), female (52%), married (57%) and Stage I (83%). Most were between 50-64 years old (31%) or 65-79 years old (55%) and had tumor sizes of 11-20 mm (32%), 21-40 mm (42%), or > 40 mm (20%); 909 cases (2.5%) refused surgical intervention. Of these, 634 (69.7%) cases underwent radiation therapy and 87 (9.6%) received chemotherapeutic treatment. At multivariable analysis, non-Hispanic blacks (ORadj 2.14, 95% CI: 1.76-2.61), increasing age (65-79 years old: ORadj 4.29, 95% CI: 2.02-9.11), increasing tumor size (21-40 mm: ORadj 2.79, 95% CI: 1.73-4.50), and single marital status (ORadj 2.14, 95% CI: 1.85-2.48) were associated with increased odds of surgical refusal. Stage II lung cancer was inversely associated (ORadj 0.75, 95% CI: 0.62-0.92) with surgical refusal. Refusing surgery and having no chemotherapy/radiation (HRadj 4.16, 95% CI: 3.48-4.96) as well as refusing surgery but undergoing alternative forms of treatment (HRadj 2.90, 95% CI: 2.55-3.29) were associated with increased mortality compared to those who received recommended surgery. After propensity matching (n = 1790), refusing surgery was associated with increased likelihood of mortality (HRadj 2.77, 95% CI: 2.22-3.46).
Conclusion
Identifiable risk factors exist for refusing recommended surgery for Stage I/II NSCLC, and refusal is associated with an increased likelihood of mortality. Recognizing that certain subgroups are more likely to refuse surgery is vital when providing treatment choices and reducing disparities in survival for early stage lung cancer.
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P2.04 - Immuno-oncology (ID 167)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.04-04 - CITEseq Characterization in Early Stage NSCLC Patients Identifies Distinct Patterns of Immune Infiltrate (ID 2305)
10:15 - 18:15 | Author(s): Raja Flores
- Abstract
Background
The success of immunotherapy in late-stage lung cancer patients, together with the need for novel therapies for early-stage disease, mandates an increased understanding of the immune infiltrate in early-stage lesions. Recent advances in sequencing-based single-cell technologies have enabled an unprecedented degree of resolution in the phenotypic characterization of patient tissues.
Method
Tumor and non-involved lung resection specimens were acquired from 23 early-stage NSCLC patients. Immune cells were isolated and analyzed by single-cell RNAseq (scRNAseq) using the 10X Chromium platform. Resulting expression signatures were clustered using an in-house pipeline. To validate populations and elucidate surface marker staining patterns for transcriptionally-defined cell clusters, we used cellular indexing of transcriptomes and epitopes by sequencing (CITEseq)—using oligonucleotide-conjugated antibodies to simultaneously measure expression of over 50 surface proteins along with transcriptomes of single cells—to analyze tumors from 8 additional patients. To identify T cell phenotypes that were differentially present and clonally expanded within tumor compared to non-involved lung, we paired scRNAseq with T cell receptor repertoire profiling in 3 patients. Finally, to validate the transcriptional phenotypes we detected and to extend our dataset, we incorporated 8 patients from a public dataset, totaling 39 patients included in the study. Immune signatures were correlated with presence of actionable mutations, smoking history, stage, and histology.
Result
Using these single cell analyses, all major immune cell lineages were identified within tumors, including multiple distinct myeloid and lymphoid subsets, which notably were phenotypically distinct from those isolated from uninvolved lung tissue. Existing databases of ligand-receptor pairs were leveraged to construct an interactome, implicating specific axes of cell-cell communication in driving changes common to tumors. As we hypothesized, correlative analyses across tumor samples revealed a cellular module marked by exhausted T cells, plasma cells, mature dendritic cells, and monocyte-derived macrophages that was enriched in patients with significant smoking histories and EGFRWT disease.
Conclusion
These findings indicate that strong immune differences exist between treatment-naïve lesions, and that these differences stratify with smoking history and smoking-related driver mutations. Given existing literature indicating that positive smoking history confers improved response to immune checkpoint blockade, our data suggests that this disparity may be mediated by set differences in treatment-naïve immune microenvironments. We will now apply this analysis pipeline to tumors treated in the neoadjuvant setting in an ongoing trial (submitted to WCLC in abstract form).
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P2.06 - Mesothelioma (ID 170)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Mesothelioma
- Presentations: 2
- Now Available
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.06-16 - Racial Disparities in Treatment Patterns and Survival Among Surgically Treated Malignant Pleural Mesothelioma Patients (ID 1869)
10:15 - 18:15 | Author(s): Raja Flores
- Abstract
Background
Although surgical intervention improves survival for patients with malignant pleural mesothelioma (MPM), black patients are less likely to receive surgery. It is not known what the treatment patterns in MPM surgical patients are according to race. This study sought to examine treatment patterns and survival between black and white surgical patients using a large nationwide cancer database.
Method
This study used the National Cancer Database (NCDB) to examine the subset of black and white MPM patients who received surgery, defined as pleurectomy/decortication (P/D) or extrapleural pneumonectomy (EPP). Multivariable logistic regressions were used to evaluate the racial differences in the extent of surgery, receipt of additional treatment (chemotherapy and/or radiotherapy), and 30-/90- day mortality, while accounting for clinical and demographic factors. A multivariable Cox proportional hazards model was used to assess the independent associations of race with overall survival. Association between race and survival was also analyzed using a 1:1 propensity score matching with the greedy algorithm.
Result
There were 2550 MPM patients in the NCDB who received surgery; 2462 white (96.5%) and 88 black (3.5%). Most patients received P/D (77.8%); 63.8% received additional treatment. Black patients were significantly less likely to receive EPP (ORadj: 0.36, 95% CI: 0.17-0.78). There was no significant difference with race in the receipt of additional treatment (ORadj: 0.79, 95% CI: 0.46-1.34); EPP patients were significantly more likely to receive additional treatment (ORadj: 1.34, 95% CI: 1.02-1.74). Black patients tended to have worse 30- and 90- day mortality than white patients (ORadj: 1.52, 95% CI: 0.58-4.01; ORadj: 1.50, 95% CI: 0.75-3.01, respectively). There was no significant difference in overall survival between black and white patients (HRadj: 0.96, 95% CI: 0.72-1.27); patients who had treatment in addition to surgery had significantly better survival (HRadj: 0.71, 95% CI: 0.64-0.80). Results remained similar after propensity matching.
Conclusion
Among MPM patients receiving surgery, black patients received less extensive surgery, and are less likely to receive additional treatment, indicating less aggressive treatment overall. Although overall survival was similar, black patients tended to have worse short term outcomes after surgery. Racial disparities in treatment and short term outcomes need to be better addressed.
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P2.06-19 - A Meta-Analysis of Mesothelin, Osteopontin, and Fibulin-3 as Biomarkers of Malignant Pleural Mesothelioma (Now Available) (ID 1729)
10:15 - 18:15 | Author(s): Raja Flores
- Abstract
Background
Malignant Pleural Mesothelioma (MPM) is a rare and aggressive cancer; the use of mesothelin, fibulin-3, and osteopontin as biomarkers has been proposed as a screening tool. The following meta-analysis examines average levels of these biomarkers in blood and pleura in comparison to several control groups.
Method
A PubMed search was conducted for studies that measured the levels of mesothelin, osteopontin, and fibulin-3 in patients with MPM compared to several control groups (other malignancies, benign lung disease, or healthy participants).
Result
Thirty two studies with 28 distinct datasets were identified as reporting mesothelin levels. Statistically significant mean differences (MD) were observed between mesothelin in the blood of MPM patients and each of the control groups. The overall MD (95% confidence interval) between MPM and non-MPM controls was 3.88 (2.73-5.05) nM/L (nMPM=455). Statistically significant MDs in pleural levels of mesothelin were also seen between MPM patients and non-MPM cancers and benign lung diseases. The overall MD (95%CI) was 31.45 (23.63-39.27) nM/L (nMPM=571). Twelve articles with 10 distinct datasets reported the mean level of osteopontin in MPM cases and controls. Statistically significant MDs in blood levels of osteopontin were seen between MPM patients and benign lung diseases or healthy controls (overall MD (95% CI) 103.75 (54.77-152.72) ng/mL (nMPM=504)), but not with other cancers. Studies on pleural levels of osteopontin were too scarce to conduct a meta-analysis. Nine articles measured fibulin-3 in blood or pleura of MPM patients compared to controls. There was a statistically significant MD in blood levels of fibulin-3 between MPM and each of the control groups. The overall MD (95%CI) was 46.52 (34.04-59.00) ng/mL (nMPM=330). There was also a statistically significant MD in the pleural levels of fibulin-3 between MPM and the cancer and benign lung disease groups. The overall MD (95% CI) was 385.35 (287.98-482.73)ng/mL (nMPM=137).
Conclusion
This meta-analysis supports the concept that mesothelin and fibulin-3 in control groups are significantly lower than in MPM, and thus they might be useful as screening biomarkers. Further studies are necessary to better assess the value of these promising biomarkers.
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P2.16 - Treatment in the Real World - Support, Survivorship, Systems Research (ID 187)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment in the Real World - Support, Survivorship, Systems Research
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.16-01 - Risk Factors for Short-Term Post-Operative Events Following Lung Cancer Resection (ID 1381)
10:15 - 18:15 | Author(s): Raja Flores
- Abstract
Background
Lung cancer represents 13% of all newly diagnosed US cancers and is the leading cause of all cancer deaths (25%). Reducing postoperative complications and improving quality of life following surgery remains central when providing treatment. We examined risk factors for short-term post-opeartive complications following lung cancer resection in patients treated at Mount Sinai, New York City.
Method
Data was selected from the General Thoracic Surgery Database (2012-2018). Patients with a primary diagnosis of lung cancer who underwent a Lobectomy (n = 603) or a Wedge resection (n = 659) were included. Preoperative assessments of health, including the Zubrod Performance Score, % predicted FEV1, heart (congestive heart failure, coronary artery disease, peripheral vascular disease) lung (pulmonary hypertension, chronic obstructive pulmonary disease, and interstitial fibrosis) comorbidities, diabetes, and smoking status were measured for each patient. The primary outcome was the occurence of at least one post-operative event (pulmonary/ cardiovascular/gastrointestinal/neurological complications, infections, and unexpected readmissions to the operating room or intensive care unit) during their hospital stay or within 30 days of their surgery; SAS v9.4 was used for statistical analyses.
Result
There were 1262 patients (age 18-95 years); 60% were female, 64% were White, and 55% were Stage 1a / 1b. More patients underwent surgery with a Video-Assisted Thoracoscopic Surgery (VATS) approach (58%) rather than an Open approach (42%). The majority of patients was classified as past smokers (58%), while the remainder were never (27%) and current (15%) smokers. 17% of patients presented with at least one heart comorbidity, while 21% with at least one lung comorbidity. At multivariable analysis, female gender (ORadj 0.64, 95% CI: 0.49-0.96), Wedge resection (ORadj 0.64, 95% CI: 0.44-0.92 compared to Lobectomy), VATS (ORadj 0.54, 95% CI: 0.38-0.77 compared to an OPEN approach), and an increasing % predicted FEV1 were inversely associated with the occurence of a post-operative event. Increasing age (ORadj 1.03, 95% CI: 1.01-1.04), Zubrod performance score (ORadj 1.53, 95% CI: 1.21-1.93), duration of surgery in hours (ORadj 1.10, 95% CI: 1.01-1.21), and currently smoking (ORadj 1.97, 95% CI: 1.14-3.40) were associated with increased odds of a post-operative event.
Conclusion
Significant risk factors exist for the occurence of a short-term post-operative event following lung cancer resection, which should be recognized to improve post-surgery quality of life. A VATS wedge resection should be utilized whenever appropriate to reduce the likelihood of post-operative complications.
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P2.17 - Treatment of Early Stage/Localized Disease (ID 189)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Treatment of Early Stage/Localized Disease
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.17-11 - Evaluating PD-L1 as a Prognostic Biomarker in Surgically Resectable Non-Small Cell Lung Cancer (ID 1959)
10:15 - 18:15 | Author(s): Raja Flores
- Abstract
Background
Identifying biomarkers that can predict which early stage non-small cell lung cancers (NSCLCs) are likely to recur following surgical resection is critical to improving survival outcomes. Programmed Cell Death Ligand-1 (PD-L1) is an immune regulatory protein expressed on tumor cells that inhibits T effector response against tumors. Therefore, high PDL-1 expression on tumor cells may enable evasion of the anti-tumor response and be associated with worst outcomes. We conducted a meta-analysis to determine if PDL-1 expression is associated with survival in surgically resected early stage NSCLCs.
Method
PubMed was searched to identify eligible studies comparing survival of surgically resected stage I-III NSCLC patients according to PD-L1 tumor expression. Included studies were grouped according to measurement criteria of PDL-1 expression: 1%, 5%, 50% cutoffs or as a continuous variable expressed as H-score. The latter is calculated from the percentage of cells expressing PDL1 multiplied by the intensity of staining. Meta-analysis was performed using a linear mixed-effects model to determine overall survival (OS). I2 was used as a measure of heterogeneity across studies.
Result
Of the 519 articles queried, 31 articles met eligibility criteria, accounting for 6,713 patients. Nine studies (n=2,407) used H score, where higher PD-L1 expression was associated with worse OS (hazard ratio [HR]meta: 1.68, 95% confidence interval [CI]: 1.17-2.41, I2= 15.45%). Five studies used a 1% cutoff (n=1,073), 14 studies reported using a 5% value (n=2,310) and 6 studies (n=1,572) used a 50% cutoff for evaluating high vs. low PD-L1 expression. PD-L1 expression was not statistically significantly associated with survival according to these cutoffs and there was high inter-study heterogeneity (HRmeta: 1.47, 95% CI 0.89-2.41; I2= 17.57%; HRmeta: 1.09, 95% CI 0.79-1.52; I2= 35.49%; HRmeta: 1.21, 95% CI 0.61-2.40; I2= 58.26% for 1%, 5%, 50%, respectively).
Conclusion
Higher PD-L1 expression in early stage NSCLCs as measured by H scores was associated with worse post-surgical survival. The measurement of PD-L1 expression as a continuous variable (i.e. H score) may provide more accuracy for predicting survival outcomes over percentage cutoffs. Future research is needed to validate PD-L1 expression as a predictive biomarker of survival for early-stage NSCLCs undergoing surgical resection.
