Researchers have discovered for the first time that the small-molecule compound N1-N12 diacetylspermine could be a potential blood pre-diagnostic biomarker for lung cancer. Levels of the compound were elevated in blood samples of patients with non-small cell lung cancer (NSCLC) that were taken up to 12 months before their cancers were diagnosed, and there was an additive performance with pro-surfactant protein B. The study is published online ahead of print in the Journal of Clinical Oncology (DOI: 10.1200/JCO.2015.61.7779).
“We have found a new compound which has not previously been known to exist in blood, and we have shown that levels are significantly elevated in patients up to 12 months before a diagnosis of lung cancer,” lead study author William R. Wikoff, PhD, Senior Scientist at University of California Davis Genome Center and Project Coordinator for the West Coast Metabolomics Center, said via email. “Thus this is a potential biomarker for early stage lung cancer before it is diagnosed by conventional means.”
Currently the U.S. Preventive Services Task Force recommends low-dose computed tomography (LDCT) cancer screening for adults between 55 and 80 who are at high risk for developing lung cancer, based on data that such screening leads to earlier diagnoses of cases of lung cancer when the tumors are more treatable and can reduce lung cancer mortality by 20 percent, as was determined by the National Cancer Institute-funded National Lung Screening Trial (OT 11/25/10 issue).
Wikoff said that the biggest potential for testing for N1-N12 diacetylspermine is if a test can be developed that can detect cancers even earlier than the current technology does. “The earlier lung cancer is caught, the better the prognosis. Hence we need to diagnose the disease as early as possible—and we need to do it in a way that large numbers of patients can be screened routinely.”
In the study, the blood samples for the individuals with lung cancer were taken up to 12 months before their cancers were found, he said. “This is the crux of the study—that we looked at individuals before they were diagnosed with lung cancer.”
The researchers evaluated blood plasma samples collected both at zero to six months prior to lung cancer diagnosis or six to 12 months prior to diagnosis in 208 patients with lung cancer who were part of the Beta-Carotene and Retinol Efficacy Trial (CARET). Additionally 415 healthy adults' blood plasma samples were evaluated—two patients who did not have lung cancer were matched to each patient with lung cancer based on age, sex, baseline smoking status, and study enrollment phase as controls for the study (except for one of the patients with lung cancer for whom only a single control could be matched). The control patients were also part of the CARET trial.
Mass spectrometry combined with liquid chromatography was used to evaluate the blood plasma samples for the presence of thousands of small molecule compounds. And for each metabolomics compound evaluated, a total area under the receiver operating characteristic curve was calculated to evaluate the significance of that compound.
N1-N12-diecetylspermine levels were found to be significantly elevated in all subgroups of patients with NSCLC compared with the healthy controls; and the area under the curve was 0.61 for serum samples collected six to 12 months prior to lung cancer diagnosis, while the area under the curve was 0.71 for the sera collected zero to six months prior to lung cancer diagnosis.
“The N1-N12-diecetylspermine levels increased as the patients were closer to diagnosis,” Wikoff noted—“presumably as the early stage disease was progressing.”
Additionally, levels of pro-surfactant protein B (pro-SFTPB), a previously established protein biomarker for NSCLC, was measured and also found in the blood plasma to increase the predictive value of the testing assay. Pro-SFTPB levels were significantly elevated in prediagnostic sera from patients with lung cancer compared with controls—with levels of pro-SFTPB significantly increased in the samples both taken closer to diagnosis (for samples taken 0 to 6 months prior to cancer diagnosis area under the curve was 0.626) and those collected farther from diagnosis (for samples taken 6 to 12 months prior to cancer diagnosis, the area under the curve was 0.645).
The results are exciting, Wikoff noted, because they suggest that a blood test to measure the levels of N1-N12-diecetylspermine levels and pro-SFTPB could be an effective screen for lung cancer. At this point, such testing would complement LDCT screening and other tests, but if such testing were determined to be effective in detecting cancer earlier than is currently possible, such a test may be considered an effective preliminary screen for lung cancer on its own. Also significant, he added, is that the blood test has the potential to be much less expensive than a radiological scan, including LDCT.
Another factor that could make testing for N1-N12-diecetylspermine as a lung cancer screen more feasible is that N1-N12-diecetylspermine is found in urine at much higher levels than in plasma. “So we would like to follow up with a similar study in urine to find out if this could be an alternative to a blood test.”
The next step, though, before either test would be able to be used in clinical practice is validating these findings in different patient cohorts, including patients pre- and post-diagnosis to understand how N1-N12-diecetylspermine levels change in later cancer stages, Wikoff explained.
Additionally, normal population data on individuals' N1-N12-diecetylspermine levels would need to be collected and compared with patient levels. “We are very interested in obtaining access to patient cohorts and samples that would allow investigation of these questions—but the challenge is to find the samples to make that happen.”