A Q&A with Rama Gullapalli, MD, PhD; a a physician-scientist in the departments of Pathology, Chemical and Biological Engineering at the University of New Mexico. His research lab focuses on the role of the environment in hepatobiliary cancers. He is also a practicing molecular pathologist with an interest in emerging molecular diagnostics, next generation sequencing and bioinformatics. Email: rgullapalli@salud.unm.edu 
Q: A recent New York Times op-ed piece from an NYU Langone Health professor urged an aggressive approach to screening for early-stage pancreatic cancer. Despite optimism, the history of cancer screening is rife with trouble, the harms often exceeding the benefits. What do you think is the best way to proceed?
A: Imagine a scenario.
A new cancer test hits the market with some impressive characteristics: a detection sensitivity of 95% and a specificity of an equally impressive 95%. If you were asked the question, “Given a positive test result, what are your chances of actually having cancer?” and you guessed a number of 80 or 90%, you would not be alone. But you’d be wrong.
The key missing information necessary to answer this question is the disease probability among the general population. The number of new cases of cancer detected every year in the U.S. is about 462 cases per 100,000 people. This means that the probability of a new cancer being detected in a member of the U.S. population annually is roughly 0.00462%. Incorporating this information leads to only an 8.1% chance of having cancer for a test that is positive! This is what is called an inverse probability problem.
Puzzled? Let me explain it in a different way. Statistics show that, in the U.S., about 462 people are newly diagnosed with cancer for every 100,000 people among the general population each year. The new test will correctly pick up 95% of these new cancer patients (i.e., about 439 patients). Of the remaining 99,538 people who do not have cancer, the test will incorrectly diagnose cancer in about 4,977 individuals! This is what pathologists would refer to as a “false-positive” diagnosis. The key point to remember is that cancer is a relatively rare disease. This basic fact enormously influences the value of any given cancer-screening test available in the market.
There has been much optimism and hype associated with cancer screening. Some cancer screening tests, such as tests for colorectal cancer or cervical cancer, have indeed made a dent in our ability to detect and treat the disease at an earlier stage. But in other cancers, such as breast cancer and prostate cancer, the results have been a mixed bag. For instance, screening for cancer in hard-to-access organs, such as ovarian cancer, led to an increase in complications due to surgery with no difference in the cancer outcomes.
A screening test with an increased false-positive rate (think of the 4,977 people in our imagined scenario who had a false-positive test result, but no real cancer), results in unnecessary and invasive testing that is ultimately of no clinical value. However, the societal costs of following up false-positive test results are enormous and include increased downstream testing and increased patient interventions. For patients, an enormous amount of anxiety and stress is expended in resolving false-positive screening test outcomes.
A recent New York Times op-ed piece discussed the issue of cancer screening in one such hard-to-treat disease: pancreatic cancer. In response to beloved TV host Alex Trebek’s diagnosis of stage 4 pancreatic cancer, author Diane Simeone, MD, suggests DNA testing as a first step to identify high-risk BRCA gene mutations in potential pancreatic cancer patients. BRCA gene mutations are associated with a higher risk of some types of cancer, including breast, ovarian, and pancreatic cancers. In her op-ed, Dr. Simeone reports that her clinic identified BRCA gene mutations in roughly 15% of the pancreatic cancer patients treated there. The key point is that these mutations were detected in patients who already had pancreatic cancer.
The op-ed piece correctly states the importance of identifying individuals at a higher risk for pancreatic cancer. While it is indeed optimal to screen for these high-risk pancreatic cancer patients, the means by which we can identify these patients beforehand is unresolved and very much a work in progress. One must be especially careful in the context of hard-to-diagnose and hard-to-treat diseases, such as pancreatic, liver, and ovarian cancers.
With the dramatically falling costs of DNA testing, one may be tempted to view it as the silver bullet for early cancer detection. However, the utility of DNA testing for screening purposes in different cancers is unproven currently and needs further research. Patients and physicians must be fully aware of the potential harms of unnecessary downstream testing due to the false positive outcomes of DNA testing. DNA testing may be cheap, but the consequences of DNA testing may prove to be very costly.
Caveat emptor!
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