In recent months, controversy has swirled around the properage at which women should have their first mammograms and Pap smears. Yet evenas these questions dominate the headlines, we ought not lose sight of a largerissue that affects the lives of every potential cancer patient, male andfemale: the emotional and economical costs associated with false positives incancer testing. Given the profusion of tests for different types of cancers,false positives pose a substantial challenge to healthcare providers who arededicated to ensuring the most accurate diagnoses. As we will see, however,there are solid grounds for optimism on the horizon. The key to reducing theincidence of false positives is to increase the specificity of the detectionmethod, and there is solid evidence that this is feasible.
The dictionary defines a "false positive" as a test resultthat shows evidence of a disease or abnormal condition, even though thecondition being tested for is not actually present. To get an idea of theextent to which false positives pose a problem for cancer testing, consider theresults of a study reported in Annals of Family Medicine this past June.1 Over a period of threeyears, 68,436 male and female subjects underwent a battery of tests forprostate, lung, colorectal and ovarian cancer. After being subjected to 14tests, the cumulative risk of having at least one false-positive screening wasfound to be 60.4 percent for men and 48.8 percent for women. It has also beenreported that in any given 10-year period, half of American women screenedreceive a false-positive mammogram; as many as 90 to 95 percent of women in theUnited States who get a positive mammogram do not have breast cancer. Suchstark numbers must be balanced against the potential benefits of early cancerscreening for those judged to be at high risk—a thriving controversy in its ownright.
The first of several types of cost associated with falsepositives in cancer screening is psychological. It is easy to envision how onecould experience great mental trauma after being informed that one has testedpositive for cancer; this phenomenon is doubly insidious since a heightenedlevel of anxiety can negatively impact one's physical health. For example, aresearch study published in Urology in2007 reported that men who receive false-positive prostate cancer screeningresults report more problems with sexual function, despite having negative biopsyfindings.2
A related cost can be triggered by "horror stories" in thepopular media regarding false positives. Tales of unnecessary surgery caninfluence the general public's view of the need for cancer screening. Shouldsuch stories dissuade individuals from coming in for tests, they risk having apotentially serious condition go undiagnosed.
A second major cost connected to false positives ispractical in nature. When hospitals allocate their time and manpower to theperformance of unnecessary invasive procedures motivated by a spurious testresult, precious resources are taken away from treating those patients withgenuine health issues. Perhaps even more serious is the risk of complicationsthat 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 ofinfection (including redness and swelling of the incision), lymphedema (theswelling of the arm or hand on the side of the surgery due to the removal ofthe lymph nodes under the arm), seroma (accumulation of fluid in the locationof the surgery) and other warning signs. All of this worry could be avoided ifit were known in advance that no surgery was needed and none performed.
Perhaps the most well-publicized cost of false positives isthe economic one. Not only will a patient who undergoes an unnecessary invasiveprocedure incur a potentially very large expense for no good reason, but alsothe healthcare provider that is performing the procedure must pay the surgeonfor work done unnecessarily.
False positive mammograms are costly, with morethan $100 million spent annually in the United States on follow-up testing andtreatment. For a separate example, consider women who make the choice toundergo surgery to have their ovaries removed. As is now well-known, pelvicultrasound, or sonography, has a hard time distinguishing ovarian cancer fromcysts on the ovaries, which are almost always benign. These benign cysts aremuch more common than ovarian cancer and most of them do not need to be treatedat all.
According to the authors of a 2005 research study,3,4we can calculate that if all American women over the age of 50 (the authorsused 43 million for this number) had a pelvic ultrasound every year, we might expect2.5 million of them to have an abnormality detected. Let us envision the mostextreme scenario: 37,000 of these women would be found to have ovarian cancerthat 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 thosewomen, 2,500 might be expected to die from the procedure, and 112,500 wouldsuffer a serious complication. The cost of performing this number ofultrasounds would be $11.8 billion per year; the cost of the unnecessarysurgeries would be about $37.5 billion per year. These extraordinary numbersstarkly illustrate the need for more reliable testing that would justifysurgical intervention.
A related perspective on the economic costs stems from statisticslinked to the use of the Prostate-Specific Antigen (PSA) test. While the falsepositive rate for this test is 75 percent, the rate of false negatives isaround 30 percent. This means that many men who ought to be receiving treatmentfor early stage prostate cancer are not. When their disease subsequently makesitself evident at a later stage, the cost of treating them is greater than itotherwise would have been.
Faced with this challenge, there have been a number ofattempts 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 tofar earlier and more reliable diagnoses than has ever been possible, as well asreduce the incidence of false positives.
A second approach that could help reduce the incidence offalse positives was reported by a research team at Johns Hopkins Universitylast year.5 Using tiny crystals called quantum dots, the JHU teamhas developed a highly sensitive test to look for DNA modifications that oftenare early warning signs of cancer. The target of their test is a biochemicalchange called DNA methylation. When this change occurs at critical genelocations, it can halt the release of proteins that suppress tumors. When thistakes place, it is easier for cancer cells to form and multiply. The teamengineered quantum dots that attract methylated DNA strands. When the dots areexposed to certain types of light, they transfer the energy to fluorescentmolecules that emit a glow. This enables researchers to detect and count theDNA strands linked to cancer.
Nanotechnology is also the key to an approach, pioneered in2009 at Yale University, for improving the sensitivity of detecting very smallquantities of an antigen in physiological fluids.6
The Yale teamused nanowire sensors to detect and measure the concentrations of two specificcancer biomarkers in whole blood—one for prostate cancer and the other forbreast cancer. The researchers developed a novel device that acts as a filter,catching the biomarkers (in this case, antigens specific to prostate and breastcancer) on a chip while washing away the rest of the blood. Creating a buildupof the antigens on the chip allows for detection down to extremely smallconcentrations, on the order of picograms per milliliter, with 10 percentaccuracy. This is the equivalent of being able to detect the concentration of asingle grain of salt dissolved in a large swimming pool.
Another study released last year7 focuses ondetecting the presence of microRNAs in saliva—a method that could aid in thedetection of oral cancer. MicroRNAs are molecules produced in cells that havethe ability to simultaneously control activity and assess the behavior ofmultiple genes. They are a thriving research topic right now, and researchers believethey could hold the key to early detection of cancer. The emergence of amicroRNA profile in saliva represents a major step forward in the earlydetection of oral cancer. The team measured microRNA levels in the saliva of 50patients with oral squamous cell carcinoma and 50 healthy control patients.They detected approximately 50 microRNAs, two of which were present atsignificantly lower levels in patients with oral cancer than in the healthiercontrols.
As we have seen above, there is a variety of promising leadson the road toward minimizing the costs—psychological, practical, andeconomic—of false positives in cancer testing. And although there are noguarantees that any specific method (or combination of methods) will eradicatethe problem completely, the widespread awareness of a need to resolve thisissue, 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 ofMabCure Inc. Gonenne has more than 20 years experience in the United Statesbiotechnology field and has held a number of top executive positions inregulatory affairs and supervision of international clinical trials. He servedas vice president of corporate development at BioTechnology General Corp., CEOof Immunotherapy Inc. and CEO of venture capital fund Elscint BiomedicalInvestment in Israel. Gonenne holds a doctoral degree in biochemistry andbiophysics from Syracuse University and completed his postdoctoral training atthe University of California San Diego, School of Medicine.
1. Croswell, JM, et al."Cumulative incidence of false-positive results in repeated, multimodal cancerscreening." Ann Fam Med., 2009.
2. Katz DA, et al."Health perceptions in patients who undergo screening and workup for prostatecancer." Urology, 2007.
3. Parker, WH, et al."Ovarian conservation at the time of hysterectomy for benign disease." ObstetGynecol, 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." GenomeRes. 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 oralcancer detection." Clin Cancer Res.2009.