Early Detection Award

Improvements in outcomes for cervix cancer and bowel cancer provide support for the concept that early diagnosis has the greatest promise to improve cancer outcomes. Unfortunately our improved understanding of the molecular basis of lung cancer has not translated into effective means for early detection. There is at the present time a substantial need for simple but accurate non-invasive tests to detect lung cancer before it is advanced to the point that treatment is rendered ineffective. Blood based biomarker tests provide an ideal approach given that asymptomatic subjects have blood drawn at the time of routine check-ups. The public health impact of the development of effective blood based tests for the detection of lung cancer are quite substantial, given the millions of subjects who are at risk for lung cancer due to current smoking or due to a past history of smoking. Additionally there is a need to develop tests to identify subjects at risk for developing lung cancer who are never-smokers given that never smokers with lung cancer represent some 15% of cases and lung cancer among never smokers is number 7 on the top ten list of cancer killers. This two-year program of research builds on the identification of candidate markers for lung cancer by a team of three PI’s at the Fred Hutchinson Cancer Research Center with expertise in Thoracic Oncology, Cancer Epidemiology and Prevention, and Molecular Diagnostics. Our goals are to develop blood tests to 1- identify never smoker subjects at increased risk of developing lung cancer (C. Li, PI); 2- detect lung cancer before onset of symptoms (G. Goodman, PI); and 3- distinguish between benign and malignant lesions identified by CT scans (S. Hanash, PI). If successful this research program will result in a paradigm shift in our approach to lung cancer screening.

Lung cancer accounts for more than 28 percent of all cancer deaths each year and is the leading cause of cancer related mortality in the United States causing more deaths than prostate, colon and breast cancers combined Despite focused research in conventional therapies, the five-year survival rate remains only 15 percent. Due to anti-tobacco initiatives the number of active smokers in the US is steadily declining, however recent studies suggest that individuals who quit smoking continue to have an elevated risk of lung cancer that may not return to baseline risk for as much as 30 years following smoking cessation. Owing to the lack of reliable early diagnostic techniques, most patients are being diagnosed with advanced stage disease that his inoperable and therefore they have a poor prognosis. Thus, there are more than 100 million current and former smokers in the US who have elevated risk for lung cancer and may benefit from a non-invasive test for early detection.

Patients at risk for lung cancer may have undetected disease for years prior to diagnosis. The clinical challenge is therefore to develop lung cancer detection methods that are effective during this window of opportunity to increase the rate of early detection and thereby spur early treatment and improve lung cancer patient outcomes. During tumorigenesis, the developing tumor forms a microenvironment that is comprised of many components and cell types. These complex cellular populations produce many soluble factors that could be important for tumor initiation and growth and thus potentially serve as lung cancer biomarkers. Small tumors, initiated in this environment, may remain undetected; however, the profile of soluble factors produced by the tumor mircorenvironment will be altered in the peripheral blood of cancer patients and could therefore have utility for the development of a diagnostic panel for early lung cancer detection. Because the blood vessels in the lungs comprise approximately 50% of the body’s total vasculature, the peripheral blood is expected to serve as a non-invasive biospecimen that reflects even small variations in lung cancer biomarkers.  We hypothesize that interactions between tumor cells and host cells recruited into the local tumor microenvironment will result in the production of a unique biomarker signature composed of proteins and microRNA (miRNA) important for cancer progression.

Over the past decade, our laboratory has gathered substantial data supporting the analysis of soluble mediators of lung carcinogenesis including inflammatory, growth and angiogenic factors and miRNA. Additionally, since our early investigations, a considerable literature has developed describing the contribution of these factors to lung carcinogenesis. Based on these findings, in our preliminary studies we have developed a plasma protein-based biomarker panel that accurately distinguishes smokers with and without lung cancer. Our predictive model provided 97% sensitivity.

Early detection of lung cancer has the potential to reduce deaths from this disease. CT scans often detect the presence of a lung nodule, the majority of which are benign. Because of the concern for lung cancer, however, almost all individuals with a lung nodule require multiple follow-up studies with resultant radiation risk, significant cost and delays in diagnosis. Our laboratory is developing a simple blood test that will be able to rapidly determine which patients with lung nodules have lung cancer and require immediate intervention, and which patients have a benign lesion and need no further evaluation.

Lung cancer is the leading cause of death for men and women in the United States. Contributing to the lethality of this disease is our inability to detect treatable early stage lung cancer resulting in the majority of lung cancer patients being diagnosed with incurable advanced disease. Computerized tomography (CT) screening has shown promising preliminary results in the detection of early stage lung cancer (with a 20% reduction in lung cancer mortality); however, it remains to be determined how it will be incorporated into standard practice. Biomarker-based screening methods that complement CT – and that are accessible to all current and former smokers – will be vital to making early lung cancer detection more attractive. Our goal at UC Davis is to combine our multidisciplinary leaders in lung cancer practice and research (Drs. Kelly, Gandara, Cooke, Yoneda and Murin) with “omics” experts (Drs. Miyamoto, Fiehn, and Lebrilla), who have developed sensitive technologies to detect and analyze sugars, lipids, and metabolites in human specimens, to identify blood biomarkers for early stage lung cancer that can be used in conjunction with CT screening. We will examine biomarker compositions of tumor tissue, non-malignant tissue, and blood in cancer patients, healthy controls and patients with benign lung nodules, to ultimately identify easily detectible blood markers that: 1) will detect early stage cancer and 2) are sensitive and specific. Such biomarkers will contribute to earlier, more informative lung cancer detection and make tailored lung cancer therapy and increased cure rates possible.