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ORAL 24 - CT Detected Nodules - Predicting Biological Outcome (ID 122)
- Event: WCLC 2015
- Type: Oral Session
- Track: Screening and Early Detection
- Presentations: 1
ORAL24.06 - Stratification of Lung Adenocarcinomas in the National Lung Screening Trial (ID 102)
10:45 - 12:15 | Author(s): T. Peikert
Screening for lung cancer with low-dose computed tomography (LDCT) was shown to reduce lung cancer mortality. However, lung cancer screening also detects indolent cancers of unclear clinical significance, which generally belong to the adenocarcinoma spectrum. The individualized management of these more indolent cancers may be facilitated by non-invasive risk stratification. We present our validation study of CANARY (Computer-Aided Nodule Assessment and Risk Yield), a novel LDCT-based software, used to stratify adenocarcinoma nodules in three groups with distinct outcomes.
All individuals in the LDCT arm of the National Lung Screening Trial (NLST) with adenocarcinoma were identified. The last LDCT data available were analyzed blinded to clinical data. Using CANARY, all lung adenocarcinoma nodules were classified as Good (G), Intermediate (I) and Poor (P) based on previously established radiologic signatures. This classification was then used for survival analysis using progression-free survival
LDCT datasets of 294 patients with resected adenocarcinomas with available outcome data were included in the blinded CANARY analysis. Kaplan-Meier analysis of all the 294 adenocarcinoma nodules stratified into G, I and P CANARY classes yielded distinct progression-free survival curves (P < 0.0001). A similar separation was seen with adjusted progression-free survival curves, after adjustment for, age, gender, race and smoking status for all pathological stage I cases.
CANARY allows the non-invasive risk stratification of lung adenocarcinomas into three groups with distinct post-surgical disease-free survival. Our results suggest that CANARY could facilitate individualized management of incidentally- or screen-detected lung adenocarcinomas.
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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
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
P1.04-086 - Dopamine D2 Receptor Agonists Inhibit Lung Cancer Progression by Reducing Angiogenesis and Tumor Infiltrating Myeloid Derived Suppressor Cells (ID 2922)
09:30 - 17:00 | Author(s): T. Peikert
Lung cancer remains the leading cancer related cause of death in the United States and worldwide. Non-small cell lung cancer (NSCLC), the most common subtype (85%) of lung cancer, continues to be associated with a very poor 5-year survival rate of less than 15%. Despite the recent advances in systemic lung cancer treatment due to the introduction new therapies targeting angiogenesis, epidermal growth factor receptor (EGFR), and activin receptor-like kinase-1 (ALK1) in selected patient subgroups, the overall mortality of patients with advanced stage disease remains high. The development of new biomarkers and individualized therapies is needed to overcome these challenges and make significant strides towards improving the care of lung cancer patients. Dopamine (DA) has long been used in the treatment of Parkinson's disease and acute cardiac dysfunction. Given that DA is produced by the sympathetic nerves ending in blood vessels, we originally postulated and later revealed that DA and its dopamine D2 receptor (D~2~R) agonists inhibit VEGF-mediated angiogenesis and also completely block accumulation of tumor ascites and tumor growth in mice. Specifically, we demonstrated that DA stimulates endocytosis of VEGFR-2 via D~2~R thereby preventing angiogenesis by inhibiting VEGF binding, receptor phosphorylation and subsequent downstream signaling. These observations define a possible link between DA and vascular biology. Subsequent studies by numerous investigators clearly demonstrate that this strategy can be successfully applied to various diseases including cancer . Correspondingly, we observed significantly more angiogenesis, tumor growth, and VEGFR-2 phosphorylation in D~2~R knockout mice. We documented D~2~R colocalization with VEGFR-2 and described the molecular mechanism through which D~2~R/VEGFR-2 crosstalk can mediate the dephosphorylation of VEGFR-2. D~2~R agonists have been shown to increase the efficacy of anti-cancer drugs in preclinical models of breast and colon cancer. Here we show that D~2~R agonists inhibit tumor growth in orthotopic murine lung cancer models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells.
We utilize syngeneic (LLC1) and human xenograft (A549) orthotopic murine lung cancer models as well as pathological examination of human lung cancer tissue to describe D~2~R agonist-mediated inhibition of lung tumor growth.
We sought to determine whether Dopamine D2 Receptor (D~2~R) agonists inhibit lung tumor progression and identify subpopulations of lung cancer patients that benefit most from D~2~R agonist therapy. We demonstrate D~2~R agonists abrogate lung tumor progression in syngeneic (LLC1) and human xenograft (A549) orthotopic murine models through inhibition of tumor angiogenesis and reduction of tumor infiltrating myeloid derived suppressor cells. Pathological examination of human lung cancer tissue revealed a positive correlation between endothelial D~2~R expression and tumor stage. Lung cancer patients with a smoking history exhibited greater levels of D~2~R in lung endothelium.
Our results suggest D~2~R agonists may represent a promising individualized therapy for lung cancer patients with high levels of endothelial D~2~R expression and a smoking history.