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MS 10 - Management of Screening Detected Lung Cancer (ID 28)
- Event: WCLC 2015
- Type: Mini Symposium
- Track: Treatment of Localized Disease - NSCLC
- Presentations: 1
- Moderators:N. Ikeda, B. Park, P. Goldstraw, L.E. Raez
- Coordinates: 9/07/2015, 14:15 - 15:45, Mile High Ballroom 2c-3c
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MS10.01 - Epidemiology of Lung Cancer and Smoking (ID 1889)
14:20 - 14:30 | Author(s): P. Yang
- Abstract
- Presentation
Abstract:
As of 2014, use of low-dose computed tomography (LDCT) screening for lung cancer was recommended by the U.S. Preventive Services Task Force (USPSTF), i.e., to annually screen people aged 55-80 years of age who have smoked 30 or more pack-years of cigarettes and are either current smokers or have quit within 15 years recommend. From the perspective of epidemiology of lung cancer and smoking, the USPSTF criteria target precisely on the population at the highest risk: peak age range and the heaviest cumulative exposure to cigarette smoking. On the other hand, through closely following the dynamic trends of tobacco smoking and lung cancer incidence and mortality, updating and improving the eligibility criteria for lung cancer screening should be a continuing effort. Reported in 2015 from the Global Adult Tobacco Survey (GATS), current tobacco use prevalence ranges from 43% in Bangladesh to 6% in Panama and Nigeria. Based on a WHO 2015 report, lung cancer remains as the most common cancer in men worldwide with the highest estimated age-standardized incidence rates in Central and Eastern Europe and Eastern Asia (>50.4 per 100,000); in women, the highest estimated rates are in Northern America (33.8) and Northern Europe (23.7). In United States, during 2005-2012, the proportion of heavy smokers who smoked ≥30 cigarettes per day declined significantly, from 12.6% to 7.0%. With the declining percentage of the population who smoke, lung cancer incidence and mortality have been decreasing among men in the past three decades, and only recently, has shown decrease among women. A similar trend has been observed in Olmsted County population, Minnesota (Figure). Meanwhile, former cigarette smokers remain at a high risk for lung cancer although at lower risk than they would have been had they continued smoking. As a consequence, more people with lung cancers are now identified in former smokers rather than in current smokers. Specifically, less than 18% of United States adults are current smokers and more than 30% are former smokers. Intriguingly, our recent report showed that approximately two thirds of newly diagnosed lung cancer patients would not have met the current USPSTF high-risk criteria for LDCT screening. Particularly, we found a 24% offal in screening-eligibility (from 57% in 1984-1990 to 43% in 2005-2011) which exceeded the 17% decline in incidence in lung cancer (from 53 to 44/1000000) over the same time intervals. We have conducted further investigations to delineate the high-risk subpopulations based on evidence from two prospective lung cancer patient cohorts and a retrospective community cohort. Our goal was to improve the identification of individuals at high-risk for lung cancer by (1) demonstrating the chronological patterns of patients who would have been the beneficiaries or missed-outs under USPSTF criteria for lung cancer screening in two contrasting cohorts, and (2) provide strong evidence of a new subpopulation that should be added to the definition of high risk and the public health impact of this subgroup on smoking cessation effort. Two prospective cohorts are primary lung cancer patients diagnosed between 1997-2011 from referral patients (Hospital) and defined-community residents (Community); the retrospective cohort is the Olmsted County population (Minnesota, USA) followed for 28 years (1984-2011). Hospital and Community cohorts include 5988 and 850 patients, respectively; the Olmsted County population is approximately 140,000. Between 1997 and 2011, former smokers with 15-30 quit-years age 55-80 formed the largest subgroup not meeting current USPSTF screening criteria. This subgroup constituted 12% of the hospital cohort and 17% of community cohort of patients with lung cancer. Between 1984 and 2011, using current screening criteria, the age- and sex-adjusted lung cancer incidence rates in Olmsted County decreased significantly from 1.5/1000 to 0.6/1000 person-years; when adding former smoker cases with 15-30 quit-years to the high risk group, the incidence rate was doubled by 2011. Evidence from both Community and Hospital cohorts in this study suggest that former smokers with 30+ pack-years and 15-30 quit-years of cigarettes remain at high risk and should be considered as eligible for lung cancer screening. These individuals may perceive the USPSTF’s requirement to stop screening after 15 years as an indication they are no longer at high risk for lung cancer or as a pass not to quit smoking. These results may impact smoking cessation and optimize the effectiveness of screening program, and demand more effective criteria to define high-risk for lung cancer. Individuals who are under 81 years, had 30 or more pack-year smoking history, and had quit for 15-30 years should also be considered as eligible for lung cancer screening. Figure 1 References: 1. Moyer VA, US Preventive Services Task Force. Screening for Lung Cancer: USPSTF Recommendation Statement. Ann Intern Med. Mar 4 2014;160(5):330-338. 2. The GATS Atlas. Global Adult Tobacco Survey. Global Tobacco Surveillance System. Published by CDC 2015. 3. GLOBOCAN 2012 (IARC) , Section of Cancer Surveillance. July 23, 2015 4. Centers for Disease Control and Prevention. Behavioral Risk Factor Surveillance System Prevalence and Trends Data, 2013. Atlanta: U.S. DHHS, CDC, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, 2013 [accessed January 2015]. 5. Lung Cancer Incidence Trends in U.S.A. SEER Program: http://surveillance.cancer.gov/. April 2015. 6. St Sauver JL, Grossardt BR, Yawn BP, et al. Data resource profile: the Rochester Epidemiology Project medical records-linkage system. Int J Epidemiol. Dec 2012;41(6):1614-1624. 7. Wang Y, Midthun DE, Wampfler JA, Deng B, Stoddard SM, Zhang S, Yang P. Trends in the proportion of patients with lung cancer meeting screening criteria. JAMA. 2015; 313(8):853-5. 8. Yang P, Allen MS, Aubry MC, et al. Clinical features of 5,628 primary lung cancer patients: experience at Mayo Clinic from 1997 to 2003. Chest. Jul 2005;128(1):452-462.
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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
- Moderators:
- Coordinates: 9/07/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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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 - 09:30 | Author(s): P. Yang
- Abstract
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
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P3.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 235)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P3.04-055 - Accurate Strategies to Detect Clinical Important Long Indels from RNA-Seq Data: EGFR as Example (ID 2506)
09:30 - 09:30 | Author(s): P. Yang
- Abstract
Background:
Somatic mutations are driver for tumor development and tumor characteristics that can be used for diagnosis and targeted therapy. These mutations are mostly detected from tumor DNA. As dynamic molecules of gene activities, transcriptome by RNA-seq is increasingly popular, which not only measures gene expression but also structural variants such as alternative splicing, fusion products or mutations. The full utilization of the multi-level information will facilitate personalized medicine. Although single nucleotide mutations (SNVs) can be more easily identified from RNA-seq, intermediate insertions/deletions (indels) exert significant bioinformatics challenges as RNA-seq data is much more complex as a result splicing and most RNA-seq alignment programs do not align reads with gap well and variant callers designed for DNA-seq are not adequate for RNA-seq, which leaves most of important indels undetected.
Methods:
We evaluated commonly used RNA-seq analysis programs TopHat, BWA, BWA-MEM, STAR, and GSNAP along with single sample variant and paired tumor/normal somatic mutation callers GATK, VarScan, MuTect, JointSNVmix, SomaticSniper in a set of lung adenocarcinomas with known single nucleotide and indel (from 15 to 19 bases) mutations from exome-seq data. We aimed to develop highly sensitive and specific strategies for both single nucleotide and longer indel mutations that are important to clinical actions.
Results:
The alignment is the critical step for longer indel identification and the evaluated programs had a wide range of sensitivity to map sequence reads with indels, ranging from not at all (TopHat with either Bowtie 1 or 2) to a decent number of reads mapped if sequence reads are long (GSNAP). The sensitivity was significantly impacted by sequence lengths (50bp vs 100bp) or if gapped alignment was explicitly used. When sufficient reads with indels were aligned, most variant calling programs were able to detect the indels with varied sensitivities except MuTect which only single nucleotide mutations were reported. Specificity was highly filtering criteria dependent. We implemented and recommended different strategies for the indel detection depending upon which alignment program was used. For TopHat alignment, unmapped reads were realigned with BWA-MEM; alignments from STAR or GSNAP were further processed following RNA-seq variant detection best practice. With these strategies, we demonstrated high accuracy in SNV or somatic mutation detections in RNA-seq data compared with exome-seq data and known mutations validated from other technologies in lung adenocarcinoma datasets. With the information, a more comprehensive genomic aberration characterization can be made to each individual tumor for clinical decision making.
Conclusion:
With careful modifications and customization to bioinformatics algorithms, RNA-seq data can be reliably used for both single nucleotide and long indel detection that can be used for treatment selection and outcome prediction.
