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Jonathan D. Spicer
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MA04 - Models and Biomarkers (ID 122)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Montse Sanchez-Cespedes, Kwok-kin Wong
- Coordinates: 9/08/2019, 13:30 - 15:00, Interlaken (1988)
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MA04.07 - Inhibition of CXCR2+ Neutrophil Migration as a Targeted Therapy in KRAS-Driven Lung Adenocarcinoma (Now Available) (ID 2914)
13:30 - 15:00 | Author(s): Jonathan D. Spicer
- Abstract
- Presentation
Background
Lung adenocarcinoma (LUAD) accounts for 40% of all lung cancer cases. Although driver mutations in the K-RAS oncogene occurs in 25% of all LUAD cases, to date, there are no available targeted therapies. Infiltrating neutrophils in LUAD are indicative of the worst survival outcomes. The C-X-C motif chemokine receptor 2 (CXCR2) mediates their recruitment to the tumour microenvironment where they promote a pro-tumorigenic environment. CXCR2 ligand expression is higher in KRAS-driven LUAD compared to the other most frequently mutated oncogenes. Therefore, we hypothesize that K-RAS-driven LUAD may be the best candidate for a CXCR2 targeted treatment strategy.
Method
The PREdiction of Clinical Outcomes from Genomic Profiles (PRECOG) is a dataset of gene expression and survival outcome. The dataset includes data from approximately 18 000 human patients with 39 different malignancies. The dataset was used to determine whether high neutrophil infiltration, CXCR2 expression and CXCR2 ligand expression were associated with poor survival outcomes in LUAD. A 100 patient LUAD tissue microarray was built and stained for neutrophil elastase and CXCR2 by immunohistochemistry. Kaplan-Meier curves were used determine the effect of high neutrophil or CXCR2+ cell infiltration in the LUAD tumour microenvironment on survival outcome. The Cancer Cell Line Encyclopedia (CCLE) is an online dataset that provides gene expression and genotype data from 947 human cancer cell lines (36 cancer types). Expression data of all LUAD cell lines (n=70) from CCLE was obtained for all known CXCR2 ligands. The expression of CXCR2 ligands in K-RAS, EGFR, ALK and ROS-1-driven LUAD cell lines was compared. Microfluidics devices were used to compare the neutrophil recruitment to K-RAS, EGFR, ALK and ROS-1-driven LUAD cell lines. The neutrophil recruitment to each of the cell lines was compared in the presence and absence of CXCR2 inhibition.
Result
Using the PRECOG dataset, we found that CXCR2 expression in neutrophils is at least 18-fold greater than its expression in other immune cell types. Using all the LUAD cell lines (n=70) available on the CCLE, we found that K-RAS-driven LUAD is the highest CXCR2 ligand expresser as compared to EGFR, ALK and ROS1-driven LUAD. Moreover, using PRECOG, we found that poorer survival outcome is associated with high expression of eight out of nine known CXCR2 ligands (p < 0.05). In addition, high neutrophil infiltration in LUAD is associated with the worst survival outcome compared to other immune cell infiltrates (p < 0.001). In accordance with the PRECOG data, the presence of infiltrating neutrophils in a 100 patient LUAD tissue microarray is associated with poorer survival outcome when compared to patients with no infiltrating neutrophils (p < 0.05). Neutrophil migration to K-RAS, EGFR, ALK and ROS1-driven LUAD cell lines was examined in microfluidics devices and found to be highest in K-RAS-driven LUAD. CXCR2 inhibition reduced neutrophil migration only in K-RAS-driven lung adenocarcinoma (p < 0.05).
Conclusion
CXCR2 inhibition could be an exciting potential targeted treatment for patients with K-RAS-driven LUAD. CXCR2 inhibition is in clinical trials for metastatic melanoma, pancreatic, breast and head and neck cancer. Current evidence suggests that CXCR2 inhibition is safe and tolerable.
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MA08 - Pawing the Way to Improve Outcomes in Stage III NSCLC (ID 127)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Treatment of Locoregional Disease - NSCLC
- Presentations: 1
- Now Available
- Moderators:Simon Ekman, Helena A Yu
- Coordinates: 9/08/2019, 15:15 - 16:45, Tokyo (1982)
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MA08.10 - Early and Late Outcomes After Surgery for pT4 NSCLC Reclassified by AJCC 8<sup>th</sup> Edition Criteria (Now Available) (ID 2941)
15:15 - 16:45 | Author(s): Jonathan D. Spicer
- Abstract
- Presentation
Background
Classically, T4 non-small cell lung cancers (NSCLC) are tumors of any size that have features of local extension often precluding surgical resection or necessitating complex extended pulmonary surgery. However, the new AJCC 8thedition includes tumors greater than 7cm regardless of adjacent organ extension. The early perioperative outcomes from T4 resections must be contextualized to the increasingly heterogeneous classification offered by the new staging system. Our goal was to examine perioperative and long-term outcomes from pT4 resections based on the AJCC 7thedition versus those of the expanded criteria of the 8thedition.
Method
This is a retrospective study of pT4 surgical resections at the Montreal General Hospital from 2011-2018. Data was analyzed using GraphPad Prism and SPSS.
Result
We identified 158 patients with pT4 tumors based on AJCC-8: 40 by AJCC-7 criteria (Group1) and 118 with tumors >7cm considered pT4 in AJCC-8 (Group2). Demographics and clinical characteristics are detailed in Table 1. The incidence of major complications (grade 3 or 4) was similar in both cohorts (17.5% in Group1 and 13.6% in Group2; p=0.37), with 3.8% in-hospital mortality (7.5% in Group1 and 2.5% in Group2; p=0.16). Overall survival was 76% at 1 year, 44% at 3 years and 34% at 5 years. Median overall survival was 27 months and was similar between Group1 and Group2 (25.8 and 27.4 months, respectively p=0.7). Nevertheless, Group2 had better peri-operative survival than Group1: 99% vs 92% 90-day mortality (p=0.02) and 95% vs 83% 6-month mortality (p<0.01). Finally, Kaplan-Meier curves adjusted for predictors of survival with Cox regression analysis show early mortality in Group 1 with equalization of the curves at 1 year (Figure 1).
Conclusion
While long-term oncological outcomes are similar for pT4 >7cm to those of AJCC-7 pT4 patients, differences in perioperative outcomes point to the heterogeneity of the new AJCC-8 classification with regards to surgical management.
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OA01 - Advanced Diagnostic Approaches for Intrathoracic Lymph Nodes and Peripheral Lung Tumors (ID 117)
- Event: WCLC 2019
- Type: Oral Session
- Track: Interventional Diagnostics/Pulmonology
- Presentations: 1
- Now Available
- Moderators:Marioara Simon, Tim Murgu
- Coordinates: 9/08/2019, 10:30 - 12:00, Melbourne (1991)
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OA01.02 - Endobronchial Ultrasound Staging of Operable NSCLC: Triple Negative Lymph Nodes May Not Require Routine Biopsy (Now Available) (ID 2621)
10:30 - 12:00 | Author(s): Jonathan D. Spicer
- Abstract
- Presentation
Background
Current staging guidelines with endobronchial ultrasound (EBUS) still recommend systematic biopsy of at least 3 mediastinal stations prior to surgical resection. Recently, a 4-point ultrasonographic score (Canada Lymph Node Score- CLNS) was developed to determine the probability of nodal metastasis in any given lymph node. A LN with CLNS<2 is considered very low probability for malignancy. We hypothesized that, during EBUS assessment of patients with cN0 non-small cell lung cancer, individual nodal stations that have CLNS<2 do not require routine biopsy because they are likely to represent true pN0 disease.
Method
The CLNS is a prospectively validated score that uses four ultrasonographic features to accurately predict LN malignancy. LNs were evaluated for ultrasonographic features at the time of EBUS and the CLNS was applied. “Triple Negative” LNs were defined as cN0 on CT (LN≤1cm), PET (no hypermetabolic activity) and EBUS (CLNS<2). Specificity, NPV, and false-negative rates were calculated against the gold-standard pathological diagnosis from surgically excised specimens.
Result
In total, 122 LNs in 58 cN0 patients were assessed. Triple Negative LNs were associated with the following T-stage distribution (T1a=12.07%, T1b=24.14%, T2a=34.38%, T2b=10.34%, T3=17.24%, T4=1.72%). Triple Negative LNs had a specificity, NPV, and false-negative rate of 86.10% (95%CI: 78.40-91.80%), 93.40% (95%CI: 86.90-97.30%), and 6.60%, respectively when using <2 as the CLNS malignancy cut-off. In total, only 5.74%(n=7) Triple Negative nodes were actually proven to be malignant, 6/7 (85.71%) on EBUS-TBNA, and 1/7 (14.29%) only after surgical resection.
Conclusion
Triple Negative LNs have a high NPV for malignancy. At the time of EBUS in cN0 patients, it may be possible that Triple Negative LNs do not require tissue sampling, thereby saving procedural time, cost, and discomfort. Findings also suggest that Triple Negative LNs with inconclusive biopsy results may not require repeat sampling. A prospective comparative trial is required to confirm these findings.
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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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P2.04-28 - NeoCOAST: Neoadjuvant Durvalumab Alone or with Novel Agents for Resectable, Early-Stage (I–IIIA) Non‑Small Cell Lung Cancer (ID 56)
10:15 - 18:15 | Author(s): Jonathan D. Spicer
- Abstract
Background
Resectable, early‑stage non‑small cell lung cancer (NSCLC) is a potentially curable disease.The current standard of care is surgery with or without adjuvant or neoadjuvant platinum‑based doublet chemotherapy. However, over half of patients eventually relapse after surgery and die from NSCLC. Clinical studies have shown that neoadjuvant programmed cell death-1/programmed cell death ligand-1 (PD-1/PD-L1) checkpoint inhibitors may yield clinically meaningful pathological responses in patients with resectable NSCLC.1–3 The NeoCOAST trial is a multidrug platform study to assess the PD-L1 checkpoint inhibitor durvalumab alone or in combination with novel agents, with the goal of identifying new treatment strategies to improve clinical outcomes of patients with resectable, early-stage NSCLC.
Method
NeoCOAST (NCT03794544) is a phase 2, open-label, randomized trial that will initially evaluate the clinical activity and safety of neoadjuvant durvalumab alone or in combination with the novel agents oleclumab (MEDI9447), monalizumab (IPH2201) and danvatirsen (AZD9150), in patients with resectable, stage I (>2 cm) to IIIA NSCLC. New treatment arms evaluating other durvalumab combinations may be added based on emerging preclinical and clinical data. The primary endpoint is major pathological response rate in the resected tumor specimen after treatment with neoadjuvant durvalumab alone or in combination with novel agents. Secondary objectives include feasibility of tumor resection surgery within 14 days of the end of the 4-week treatment period, safety, pathological complete response rate, pharmacokinetics and immunogenicity. Correlative translational analyses include tumor genomics, changes in the tumor microenvironment, and T cell populations. NeoCOAST is open for accrual with an estimated total target enrollment of up to 40 patients per treatment arm.
References
1Forde PM, et al. N Engl J Med. 2018;378:1976–86.
2Rusch V, et al. MA04.09. Presented at IASLC 19th World Conference on Lung Cancer, 23–26 September 2018, Toronto, Canada.
3Cascone T, et al. LBA49. Presented at European Society of Medical Oncology Congress, 19–23 October 2018, Munich, Germany 2018.
Result
Section not applicable
Conclusion
Section not applicable
