Print

Motivation

Early detection of lethal forms of lung cancer represents a tremendous opportunity to save lives.

Lung cancer is the world's top cancer killer, claiming more than 1.3 million lives per year.¹ Lung cancer was once thought to be a smokers' disease, but global statistics show that 25% of all cases are not attributable to tobacco use, making lung cancer in never smokers the seventh leading cause of cancer death worldwide (Figure 1).^1-3 As more people quit smoking, lung cancer is progressively becoming a disease of former smokers and never smokers; already over half of cases in North America are in never or former smokers.^3,4

Figure 1: Annual Worldwide Deaths by Cancer Type

In North America, cancer of the lung & bronchus is the third most common cancer and is responsible for the most cancer deaths.¹ Over 40% of cases are diagnosed at an advanced stage (Stage IV) when the cancer has already spread widely beyond the lung (Figure 2) and survival outcomes are extremely poor.⁵ As is the case for many other cancers, early detection of pre-metastatic lung cancer promises to save many lives, as chances of survival are greatest when cancer is diagnosed at a stage when it is still confined to the lung (Figure 3).⁵

Figure 2: Stage of Diagnosis

Figure 3: Survival by Stage of Diagnosis

Canary Foundation and The Thomas G. Labrecque Foundation formed a partnership because of a shared recognition of the tremendous opportunity to save many thousands of lives through early detection of lethal lung cancers.

Research

Canary researchers apply a collaborative approach to blood and imaging biomarker discovery, validation, and translation into diagnostic tests for early detection of lethal lung cancers.

Canary is focused on developing diagnostics with high sensitivity and specificity to detect otherwise lethal lung cancers at a stage when they are readily curable. To this end, Canary has assembled a team of experts who are collaborating to discover and validate biomarkers for blood and imaging tests that together will identify individuals harboring lethal lung cancers so that they can be removed. We plan to follow up our research by rapidly propelling effective early detection cancer tests into the hands of clinical providers so that patients can begin to benefit as soon as possible.

Currently, lung cancer is tested for with an imaging test, such as a chest X-ray (image A, left) or a specialized X-ray like the computed tomography (CT) scan or the spiral CT scan (image B, left).⁴ The imaging test may be given to people who have symptoms of lung cancer, or to people who are thought to be at high risk for lung cancer. However, aggressive tumors are not always found soon enough, and many people die despite annual CT scans. Furthermore, even with the most advanced CT scanning, it is difficult to differentiate benign from cancerous nodules, as suspicious lesions are evaluated based on size and shape, and critical parameters like degree of aggressiveness cannot be determined. In these examples from the same patient, the chest X-ray (A) did not detect a nodule, while the spiral CT scan detected a nodule (boxed in image B). Upon examination of the nodule following surgery, it was found to be benign.⁴

Blood-Based Biomarkers

Discovery

• Under the direction of Dr. Gary Goodman and Dr. Mark Thornquist, the Carotene and Retinol Efficacy Trial (CARET) repository provides a specimen resource for discovery and validation of new serum biomarkers. CARET contains prospectively collected serum, plasma, and DNA from more than 1400 individuals who developed lung cancer.
• Dr. Samir Hanash is using proteomics to see what proteins are in the blood or other body fluids in lung cancer versus baseline. Initially his laboratory will discover proteins that are present uniquely in human blood samples prior to lung cancer diagnosis.
• Dr. Harold Varmus and colleagues are using mouse models carrying mutations that have been shown to cause lung cancer in humans. Tumors in these mutant mice can be followed from initiation through progression and during tumor regression. Serum samples from these mutant mice at various stages will be analyzed using advanced proteomics techniques in order to identify potential biomarkers of early cancer development.
• Dr. Jason Chien is identifying epidemiologic factors associated with an increased risk for developing lung cancer among women who never smoked. His study will comprehensively compare lung cancer risk factors among never, former, and current smokers to aid in designing screening strategies for never smokers and to indicate candidate lung cancer biomarkers for blood and imaging tests.

Validation

• Dr. Ite Laird-Offringa has found promising candidate genes that are modified by methylation in tumors of lung cancer patients but not in corresponding normal lung tissues. Her lab will further assess the performance of these candidate biomarkers in additional paired tissue and blood samples. Biomarkers that perform well in those tests will be tested on precious prospectively collected blood samples.
• Development of assays to measure protein biomarkers is a major bottleneck in accelerating biomarkers through the pipeline to a blood test. Canary has addressed this bottleneck by funding a dedicated team to rapidly develop serum-based assays and validate candidate biomarkers. Promising biomarkers will be used in combination to provide the basis for tests using patient blood or body fluids.

Implementation

• Dr. Sylvia Plevritis will use modeling to determine the required sensitivity and specificity of each component of combined blood-based and imaging-based tests in order to be both effective and cost-effective.

Imaging Biomarkers

Discovery

• Dr. Sanjiv Gambhir and Dr. Jürgen Willmann are developing an advanced imaging technique that will light up lung cancer cells but not normal lung cells based on their unique molecular characteristics. This technique will not only have the resolution power to show extremely small lung lesions, but will also help to indicate whether the lung lesions identified show lethal, non-lethal, or benign characteristics.

Validation

• Future work will involve moving promising molecular imaging biomarkers into safety and efficacy studies in preparation for FDA-approved Investigational New Drug (IND) clinical trials.

Implementation

• Dr. Peter Bach will examine cases of patients who died despite yearly CT screening to determine whether the window of opportunity is smaller than that interval to catch aggressive tumors.
• In order to stimulate interest in screening for lung cancer at the public health level, we must show that screening would be effective and also cost-effective. Dr. Sylvia Plevritis will develop models to find out whether current imaging-based screening is effective and cost-effective using data from clinical trials.

Together these studies will leave Canary investigators poised for further work, aimed toward additional biomarker discovery, further validation of combinations of biomarkers, and validation of imaging techniques. It will be critical to validate our biomarkers in patients or in samples from patients prior to cancer development, a true test of a marker for early detection. Ultimately these biomarkers-both imaging and blood tests-will be used for earliest detection of otherwise lethal lung cancer in smokers, non-smokers, and former smokers.

View Canary Funded Projects

Citations

1. Parkin, DM, Bray, F, Ferlay, J, Pisani, P. 2005. Global cancer statistics, 2002. CA Cancer J. Clin. 55: 74-108.
2. Garcia M, Jemal A, Ward EM, Center MM, Hao Y, Siegel RL, Thun MJ. 2007. Global Cancer Facts & Figures 2007. Atlanta, GA: American Cancer Society.
3. Sun, S, Schiller, JH, Gazdar, AF. 2007. Lung cancer in never smokers - a different disease. Nature Reviews Cancer 7: 778-790.
4. Mulshine JL, 2003. Screening for lung cancer: in pursuit of pre-metastatic disease. Nature Reviews Cancer 3: 65-73.
5. Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat Database: Incidence - SEER 9 Regs Limited-Use, Nov 2006 Sub (1973-2004 varying) - Linked To County Attributes - Total U.S., 1969-2004 Counties, National Cancer Institute, DCCPS, Surveillance Research Program, Cancer Statistics Branch, released April 2007, based on the November 2006 submission.