New Diagnostic Test for the Early Detection of Lung Cancer

I was invited to discuss a new diagnostic test for the early detection of lung cancer by Gerri Willis of Fox Business News’ Willis Report.
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An Italian clinical study presented at the September 2014 European Respiratory Society described 82 patients with abnormal chest x-rays. Patients breathed into a machine that measured the temperature of the exhaled air. Forty of the patients ultimately proved to have cancer and 42 did not, as confirmed by subsequent biopsy. They found a correlation between the temperature of the exhaled breath and presence of lung cancer. They also found that long term smokers had higher breath temperatures, as did those with higher stage disease.

For a variety of reasons, a test as simple as breath temperature seems unlikely to be highly specific. After all, the temperature of the exhaled breath could reflect infection, inflammation, or even activity level, as vigorous exercise can raise the body’s core temperature. Nonetheless, the fact that there is any correlation at all is of interest.

PET scan lung cancerWhat might underlie these findings? Accepting the shortfalls of this small study, it is an interesting point of discussion. First, cancer is a hyper metabolic state. Cancers consume increased quantities of glucose, proteins, and lipids. PET scans measure these phenomena every day. Second, cancer is associated with hyper vascularity. Up-regulation of VEGF could cause hyperemia (increased capillary blood flow) in the airways of lung cancer patients, resulting in the finding. Finally, cancer, in and of itself, is an inflammatory state. Inflammation reflects increased metabolic activity that could manifest as a whole body change in basal temperature.

Lung cancer is the leading cause of cancer death in the US, constituting 27% of all cancer deaths. Despite the over 224,000 new diagnoses and 160,000 deaths, the five-year survival for lung cancer today at 17% has not changed in several decades. Nonetheless patients who are detected early (Stage I) have a greater than 50% five-year survival.

We know from the National Lung Cancer Screening Trial published in 2010, that early detection by CT scans can reduce mortality from this disease by 20%. In the cancer literature, that is huge. The problem is that screening CTs are comparatively expensive, inconvenient, expose patients to radiation and are themselves fraught with false positives and false negatives. Furthermore, it is estimated that that broad application of spiral CT’s could cost over $9 billion a year. Thus, simple, non-invasive screening techniques are sorely needed.

The use of exhaled breath to diagnose cancers has been under in development for decades. Recently, investigators from The Cleveland Clinic and others from Israel have reported good results with a microchip that measures the concentration of volatile organic compounds in the breath and provides a colorimetric score. With several hundred patients the receiver-operating curves (ROC, a technique that gauges the sensitivity and specificity of a test) in the range of 0.85 (1.0 is perfect) are quite favorable. Although these techniques have not yet gained broad application, they are extremely interesting from the standpoint of what it is they are actually measuring.

For decades, the principal focus of scientific exploration in cancer has been genomic. Investigators at Boston University and others at MD Anderson in Texas have used genomic and methylation status of oro-and naso-pharyngeal swabs to identify the earliest hallmarks of malignant transformation. To the contrary, the breath tests described above measure phenomena that fall more in the realm of metabolomics. After all, these are measures of cellular biochemical reactions and identify the transformed state at a metabolic level.

Though still in its infancy, metabolomics reflects the most appealing of all cancer analyses. Examining cancer for what it is, rather than how it came to be, uses biochemistry, enzymology and quantitative analyses. These profile the tumor at the level of cellular function. Like the platforms that I utilize (EVA-PCD), these metabolic analyses examine the tumor phenotype.

I applaud these Italian investigators for using a functional approach to cancer biology. This is a highly productive direction and fertile ground for future research. Will breath temperature measurement prove sensitive and specific enough to diagnose cancer at early stage? It is much too early to say, but at least for now, I wouldn’t hold my breath.

About Dr. Robert A. Nagourney
Dr. Nagourney received his undergraduate degree in chemistry from Boston University and his doctor of medicine at McGill University in Montreal, where he was a University Scholar. After a residency in internal medicine at the University of California, Irvine, he went on to complete fellowship training in medical oncology at Georgetown University, as well as in hematology at the Scripps Institute in La Jolla. During his fellowship at Georgetown University, Dr. Nagourney confronted aggressive malignancies for which the standard therapies remained mostly ineffective. No matter what he did, all of his patients died. While he found this “standard of care” to be unacceptable, it inspired him to return to the laboratory where he eventually developed “personalized cancer therapy.” In 1986, Dr. Nagourney, along with colleague Larry Weisenthal, MD, PhD, received a Phase I grant from a federally funded program and launched Oncotech, Inc. They began conducting experiments to prove that human tumors resistant to chemotherapeutics could be re-sensitized by pre-incubation with calcium channel blockers, glutathione depletors and protein kinase C inhibitors. The original research was a success. Oncotech grew with financial backing from investors who ultimately changed the direction of the company’s research. The changes proved untenable to Dr. Nagourney and in 1991, he left the company he co-founded. He then returned to the laboratory, and developed the Ex-vivo Analysis - Programmed Cell Death ® (EVA-PCD) test to identify the treatments that would induce programmed cell death, or “apoptosis.” He soon took a position as Director of Experimental Therapeutics at the Cancer Institute of Long Beach Memorial Medical Center. His primary research project during this time was chronic lymphocytic leukemia. He remained in this position until the basic research program funding was cut, at which time he founded Rational Therapeutics in 1995. It is here where the EVA-PCD test is used to identity the drug, combinations of drugs or targeted therapies that will kill a patient's tumor - thus providing patients with truly personalized cancer treatment plans. With the desire to change how cancer care is delivered, he became Medical Director of the Todd Cancer Institute at Long Beach Memorial in 2003. In 2008, he returned to Rational Therapeutics full time to rededicate his time and expertise to expand the research opportunities available through the laboratory. He is a frequently invited lecturer for numerous professional organizations and universities, and has served as a reviewer and on the editorial boards of several journals including Clinical Cancer Research, British Journal of Cancer, Gynecologic Oncology, Cancer Research and the Journal of Medicinal Food.

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