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Minimizing the cost effects of false positives in cancer testing
April 2010
by By Amnon Gonenne  | 
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In recent months, controversy has swirled around the proper age at which women should have their first mammograms and Pap smears. Yet even as these questions dominate the headlines, we ought not lose sight of a larger issue that affects the lives of every potential cancer patient, male and female: the emotional and economical costs associated with false positives in cancer testing. Given the profusion of tests for different types of cancers, false positives pose a substantial challenge to healthcare providers who are dedicated to ensuring the most accurate diagnoses. As we will see, however, there are solid grounds for optimism on the horizon. The key to reducing the incidence of false positives is to increase the specificity of the detection method, and there is solid evidence that this is feasible.    
 
The dictionary defines a "false positive" as a test result that shows evidence of a disease or abnormal condition, even though the condition being tested for is not actually present. To get an idea of the extent to which false positives pose a problem for cancer testing, consider the results of a study reported in Annals of Family Medicine this past June.1 Over a period of three years, 68,436 male and female subjects underwent a battery of tests for prostate, lung, colorectal and ovarian cancer. After being subjected to 14 tests, the cumulative risk of having at least one false-positive screening was found to be 60.4 percent for men and 48.8 percent for women. It has also been reported that in any given 10-year period, half of American women screened receive a false-positive mammogram; as many as 90 to 95 percent of women in the United States who get a positive mammogram do not have breast cancer. Such stark numbers must be balanced against the potential benefits of early cancer screening for those judged to be at high risk—a thriving controversy in its own right.  
 
The first of several types of cost associated with false positives in cancer screening is psychological. It is easy to envision how one could experience great mental trauma after being informed that one has tested positive for cancer; this phenomenon is doubly insidious since a heightened level of anxiety can negatively impact one's physical health. For example, a research study published in Urology in 2007 reported that men who receive false-positive prostate cancer screening results report more problems with sexual function, despite having negative biopsy findings.2 
 
A related cost can be triggered by "horror stories" in the popular media regarding false positives. Tales of unnecessary surgery can influence the general public's view of the need for cancer screening. Should such stories dissuade individuals from coming in for tests, they risk having a potentially serious condition go undiagnosed.    
 
A second major cost connected to false positives is practical in nature. When hospitals allocate their time and manpower to the performance of unnecessary invasive procedures motivated by a spurious test result, precious resources are taken away from treating those patients with genuine health issues. Perhaps even more serious is the risk of complications that can arise in the wake of such unnecessary biopsy or surgery. For example, a woman who has undergone breast cancer surgery must watch for signs of infection (including redness and swelling of the incision), lymphedema (the swelling of the arm or hand on the side of the surgery due to the removal of the lymph nodes under the arm), seroma (accumulation of fluid in the location of the surgery) and other warning signs. All of this worry could be avoided if it were known in advance that no surgery was needed and none performed.  
Perhaps the most well-publicized cost of false positives is the economic one. Not only will a patient who undergoes an unnecessary invasive procedure incur a potentially very large expense for no good reason, but also the healthcare provider that is performing the procedure must pay the surgeon for work done unnecessarily.
 
False positive mammograms are costly, with more than $100 million spent annually in the United States on follow-up testing and treatment. For a separate example, consider women who make the choice to undergo surgery to have their ovaries removed. As is now well-known, pelvic ultrasound, or sonography, has a hard time distinguishing ovarian cancer from cysts on the ovaries, which are almost always benign. These benign cysts are much more common than ovarian cancer and most of them do not need to be treated at all.
 
According to the authors of a 2005 research study,3,4 we can calculate that if all American women over the age of 50 (the authors used 43 million for this number) had a pelvic ultrasound every year, we might expect 2.5 million of them to have an abnormality detected. Let us envision the most extreme scenario: 37,000 of these women would be found to have ovarian cancer that would otherwise have not been detected so early. But, at least in theory, the other 2,463,000 women might go on to have unnecessary surgery. Of those women, 2,500 might be expected to die from the procedure, and 112,500 would suffer a serious complication. The cost of performing this number of ultrasounds would be $11.8 billion per year; the cost of the unnecessary surgeries would be about $37.5 billion per year. These extraordinary numbers starkly illustrate the need for more reliable testing that would justify surgical intervention.  
 
A related perspective on the economic costs stems from statistics linked to the use of the Prostate-Specific Antigen (PSA) test. While the false positive rate for this test is 75 percent, the rate of false negatives is around 30 percent. This means that many men who ought to be receiving treatment for early stage prostate cancer are not. When their disease subsequently makes itself evident at a later stage, the cost of treating them is greater than it otherwise would have been.    
 
Faced with this challenge, there have been a number of attempts made to reduce the rate of false positives in cancer screening, including the creation of unique and highly specific monoclonal antibodies (Mabs) targeted against several cancers (e.g. ovarian and prostate carcinomas) that that could potentially identify these diseases in their earliest stages. The development of diagnostic tests harnessing this technology could lead to far earlier and more reliable diagnoses than has ever been possible, as well as reduce the incidence of false positives.  
 
A second approach that could help reduce the incidence of false positives was reported by a research team at Johns Hopkins University last year.5 Using tiny crystals called quantum dots, the JHU team has developed a highly sensitive test to look for DNA modifications that often are early warning signs of cancer. The target of their test is a biochemical change called DNA methylation. When this change occurs at critical gene locations, it can halt the release of proteins that suppress tumors. When this takes place, it is easier for cancer cells to form and multiply. The team engineered quantum dots that attract methylated DNA strands. When the dots are exposed to certain types of light, they transfer the energy to fluorescent molecules that emit a glow. This enables researchers to detect and count the DNA strands linked to cancer.  
 
Nanotechnology is also the key to an approach, pioneered in 2009 at Yale University, for improving the sensitivity of detecting very small quantities of an antigen in physiological fluids.6
 
The Yale team used nanowire sensors to detect and measure the concentrations of two specific cancer biomarkers in whole blood—one for prostate cancer and the other for breast cancer. The researchers developed a novel device that acts as a filter, catching the biomarkers (in this case, antigens specific to prostate and breast cancer) on a chip while washing away the rest of the blood. Creating a buildup of the antigens on the chip allows for detection down to extremely small concentrations, on the order of picograms per milliliter, with 10 percent accuracy. This is the equivalent of being able to detect the concentration of a single grain of salt dissolved in a large swimming pool.     
 
Another study released last year7 focuses on detecting the presence of microRNAs in saliva—a method that could aid in the detection of oral cancer. MicroRNAs are molecules produced in cells that have the ability to simultaneously control activity and assess the behavior of multiple genes. They are a thriving research topic right now, and researchers believe they could hold the key to early detection of cancer. The emergence of a microRNA profile in saliva represents a major step forward in the early detection of oral cancer. The team measured microRNA levels in the saliva of 50 patients with oral squamous cell carcinoma and 50 healthy control patients. They detected approximately 50 microRNAs, two of which were present at significantly lower levels in patients with oral cancer than in the healthier controls.  
 
As we have seen above, there is a variety of promising leads on the road toward minimizing the costs—psychological, practical, and economic—of false positives in cancer testing. And although there are no guarantees that any specific method (or combination of methods) will eradicate the problem completely, the widespread awareness of a need to resolve this issue, coupled with exciting advances on the frontiers of medical research, contribute to the expectation of a brighter future.  
 
Dr. Amnon Gonenne is president, CEO and director of MabCure Inc. Gonenne has more than 20 years experience in the United States biotechnology field and has held a number of top executive positions in regulatory affairs and supervision of international clinical trials. He served as vice president of corporate development at BioTechnology General Corp., CEO of Immunotherapy Inc. and CEO of venture capital fund Elscint Biomedical Investment in Israel. Gonenne holds a doctoral degree in biochemistry and biophysics from Syracuse University and completed his postdoctoral training at the University of California San Diego, School of Medicine.
References:   1. Croswell, JM, et al. "Cumulative incidence of false-positive results in repeated, multimodal cancer screening." Ann Fam Med., 2009.   2. Katz DA, et al. "Health perceptions in patients who undergo screening and workup for prostate cancer." Urology, 2007.   3. Parker, WH, et al. "Ovarian conservation at the time of hysterectomy for benign disease." Obstet Gynecol, 2005.   4. Parker, WH, et al. "Are there any good tests for ovarian cancer?" Available at: http://www.ovaryresearch.com/screening.htm.   5. Bailey, VJ, et al. "MS-qFRET: a quantum dot-based method for analysis of DNA methylation." Genome Res. 2009.   6. Stern, E, et al. "Label-free biomarker detection from whole blood." Nature Nanotech. Available at: http://www.nature.com/nnano/journal/vaop/ncurrent/abs/nnano.2009.353.html.   7. Park, NJ, et al. "Salivary microRNA: discovery, characterization and clinical utility for oral cancer detection." Clin Cancer Res. 2009.
 

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