Serum Metabolite Concentrations May Prove Useful for Lung Cancer Detection

October 28, 2014

Early diagnosis of lung cancer is crucial, because surgery is curative only in the early stages. However, by the time most patients experience symptoms, the cancer has already progressed beyond the point of successful surgery.

Early diagnosis of lung cancer is crucial, because surgery is curative only in the early stages. However, by the time most patients experience symptoms, the cancer has already progressed beyond the point of successful surgery.

Current strategies for lung cancer screening have limitations. Chest radiographs most often fail to detect early-stage lung cancer, and while low-dose computed tomography (CT) imaging can be effective, it is costly and exposes patients to small doses of radiation.

In the hopes of developing a simple diagnostic blood test, a new study to be presented at the CHEST 2014 conference (October 25-30, 2014) evaluated blood biomarkers that may provide an early signal for lung cancer.

Christopher Carroll, MD, chair of the CHEST scientific abstract committee, explained, “Lung cancer is difficult to diagnose and frequently requires invasive testing. It would be a huge advance if you could diagnose lung cancer noninvasively with a biomarker.”

Researchers at the Cleveland Clinic in Ohio searched for differences between patients with stage 1-3 non-small cell lung cancer (NSCLC) and matched controls in serum profiles of small molecule metabolites.1

Serum was collected from 94 biopsy-confirmed, untreated cancer patients (50 adenocarcinoma, 44 squamous cell) and 190 at-risk controls who were propensity matched for age, gender, smoking history, COPD, and chronic diseases that might affect metabolism, such as diabetes mellitus.

Chromatography analysis identified 534 metabolites in 8 metabolite super-pathways and 73 subpathways; concentrations of 149 differed significantly between the groups.

Peter J. Mazzone, MD, director of the lung cancer program for the Respiratory Institute at Cleveland Clinic and lead author of the study notes, "Patients with lung cancer have altered metabolic processes. The way that cancer cells grow and use energy is different than normal cells. The building blocks for cell formation and the by-products of growth may be altered. This information could lead to the development of a diagnostic biomarker for early detection of lung cancer."

Metabolic reprogramming, a hallmark of cancer cells, arises from mutations that alter cellular physiology to favor proliferation. Although a systematic characterization of the metabolic differences between cancer and normal cells is incomplete, specific pathways that are altered in malignant cells have been identified.

Cell proliferation requires increased amounts of fatty acids and phospholipids. Platelet activating factor (PAF), a potent phospholipid, promotes lung cancer growth, and free fatty acids have been shown to promote tumor development, progression, and metastases in lung cancer cells.

Another recent study by Mazzone and colleagues showed that the free fatty acids arachidonic acid and linoleic acid, and their metabolites, were 2- to 3-fold higher in 37 patients with adenocarcinoma compared with 111 patients without cancer.2However, phospholipid and fatty acid concentration differences in squamous cell carcinoma were less pronounced.

The current results similarly describe serum elevations of fatty acids in the cancer samples. Also noted were significant reductions in phenolic compounds as well as elevated transsulfuration pathway activity, an important contributor to cell proliferation.

Of the 149 compounds that differed significantly between groups, a subset of 36 metabolites contributed to a predictive model with sensitivity 70.2% and specificity 89.5% (area under the ROC = 0.837).

Mazzone adds that their results form the basis for future development on the idea. “We have discovered potential markers of lung cancer. We will next need to validate these markers in new patient samples. If promising, assays will need to be developed that will be easier to use clinically then the research methods that have been used to date.”

These preliminary results demonstrate that metabolite profiles can indicate altered metabolic processes characteristic of lung cancer, paving the way for a simple blood test to detect lung cancer in early stages.

References

  1. Mazzone PJ, Wang X, Beukeman M, et al. The Analysis of Small Molecule Metabolite Profiles in the Blood as a Biomarker of Lung Cancer.Chest. 2014. 146(4_MeetingAbstracts): 587A. http://journal.publications.chestnet.org/article.aspx?articleID=1912779
  2. Liu J, Mazzone PJ, Cata JP, et al. Serum free fatty acid biomarkers of lung cancer.Chest. 2014 Sep; 146(3):670-679.