Researchers develop model to find blood biomarkers that estimate tumor size

- By Krista Conger

In any battle, size matters. Identifying cancer in its infancy, before it spreads, will increase the odds of defeating it. However, no method currently exists to reliably translate the results of common blood-screening tests meant to suss out malignancy into the size of the tumor challenging both patient and doctor.

Now researchers at the School of Medicine have begun to map out a way to correlate levels of so-called blood biomarkers with cancer volume. The effort will guide development of new tests to facilitate early detection of the disease.

'Early cancer detection is a very challenging but important goal for the cancer field,' said Sanjiv Sam Gambhir, MD, PhD, professor of radiology and senior author of the study published in the Aug. 18 issue of PLoS-Medicine. 'This modeling work enables a very deep understanding of the problems that will have to be solved for blood-based cancer biomarkers to be successful in this effort.'

Gambhir is also head of the Molecular Imaging Program at Stanford. He and radiologist Amelie Lutz, MD, developed the mathematical model using two common blood biomarkers: PSA, or prostate-specific antigen, which is often elevated in prostate cancer, and CA125, which serves as a marker for follow-up therapy in ovarian cancer. They found the minimum tumor sizes predicted by their calculations roughly matched what is found in clinical practice, indicating that they are on the right track.

'We're pretty happy that we came up with rather realistic tumor sizes,' said Lutz. 'Although this is a very basic model, it should give researchers a tool to use when deciding if a particular secreted protein would be a good biomarker.'

Good biomarkers are eagerly sought for early cancer diagnosis. Several things happen when a cell turns cancerous. It begins to divide when it shouldn't, and it may start to secrete proteins into the bloodstream that noncancerous cells nearby do not. Ideally, doctors would be able to do a simple blood test to find even minute amounts of these proteins, or biomarkers, early in the development of cancer to initiate life-saving therapy.

In reality, cancers rarely provide such a foolproof 'tell.' Because many biomarkers, including CA125 and PSA, are secreted by both healthy and cancerous cells, doctors assessing their levels in the bloodstream must make educated guesses as to where to assign the cutoff between the high end of normal and the low end of worrisome. Misjudging this number can lead either to unacceptably high numbers of false-positive results or to overlooking already dangerous disease.

Lutz used published data from cells grown in culture dishes to estimate how much CA125 or PSA is secreted into surrounding cell growth media. The team then devised a mathematical model to translate the amount secreted by the cells into levels expected to appear in the bloodstream for specific tumor volumes. If the marker is tumor-specific, the minimum detectable amount of biomarker in the blood marked the smallest tumor detected with this method. If the marker is secreted by both normal and cancerous cells, the threshold amount for suspicion is necessarily higher and the minimum detectable tumor size is larger.

The technique required many simplifications of a complex biological process. But it worked surprisingly well. Because PSA is secreted by both normal and cancerous cells, the smallest prostate tumor predicted by the method is about the size of a small pea. If it were secreted only by cancer cells, PSA could be used to detect tumors much smaller: about the size of the period at the end of this sentence.

'We're making assumptions about how tumors behave in the human body,' said Lutz. 'Although there's not always a linear relationship between tumor size and secretion levels, our model identifies some important characteristics of a good biomarker. We also try to point out additional physiological parameters and studies needed to develop more precise models.'

With this approach, a protein that is highly secreted only by cancer cells would warrant more study. Also, a panel, or group, of good cancer-specific biomarkers is likely to be more clinically useful than just one protein, since not all tumors may express the same markers.

'A lot of effort is going in to finding the perfect panel,' said Lutz, 'and we hope that this work will help researchers home in on specific candidates.'

Lutz and Gambhir's Stanford co-authors included Juergen Willmann, MD, assistant professor of radiology; Frank Cochran, PhD, postdoctoral scholar, and Pritha Ray, PhD, research associate.

The research was funded by the Canary Foundation, a nonprofit dedicated to detecting early cancer. Support also came from the National Cancer Institute, the Swiss National Science Foundation, the Holcim Foundation, the Swiss Foundation of Medical-Biological Grants and Novartis Research Foundation.

About Stanford Medicine

Stanford Medicine is an integrated academic health system comprising the Stanford School of Medicine and adult and pediatric health care delivery systems. Together, they harness the full potential of biomedicine through collaborative research, education and clinical care for patients. For more information, please visit med.stanford.edu.

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