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Lorenzo E. Ferri



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    MA04 - Models and Biomarkers (ID 122)

    • Event: WCLC 2019
    • Type: Mini Oral Session
    • Track: Biology
    • Presentations: 1
    • Now Available
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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): Lorenzo E. Ferri

      • Abstract
      • Presentation
      • Slides

      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
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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): Lorenzo E. Ferri

      • Abstract
      • Presentation
      • Slides

      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).

      table 1.jpg

      figure 1.png

      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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