To whatever extent the oft-troubled waters of breast cancer screening had cleared since the last salient controversy, they have been stirred up again by a study just published in the New England Journal of Medicine. The paper, which has received widespread media attention, suggests in essence that mammography routinely finds cancers that would be better left unfound -- cancers that would not progress, and do not need treatment.
The authors assert that 1.3 million women in the U.S. over the past 30 years have been diagnosed with breast cancer that would have remained latent without treatment. In 2008, the most recent year for which data are included in their analysis, such unnecessary diagnoses affected 70,000 women, or just over 30 percent of all breast cancers diagnosed that year.
The authors make this case by examining time trends in the frequency with which both early-stage and late-stage breast cancer is diagnosed. They argue, reasonably, that the benefit of screening is finding early-stage cancers that would progress to late-stage cancers if not detected. And so, each early-stage cancer found through screening should -- they tell us -- be one less late-stage cancer. Over the past several decades, that has not been the case; the rise in incidence of early-stage cancers is much larger than the fall in incidence of late-stage cancers.
On this basis, the authors conclude: The discrepancy between the two represents over-diagnosis. They go on to suggest that the decisive decline in breast cancer mortality over recent years is due entirely to better treatments, not to the early detection offered by screening.
The researchers in this case may be right, which is why their paper was published in the New England Journal. But there are important ways in which they may be wrong.
Some early-stage cancers may progress despite treatment. Many late-stage cancers may be treated effectively -- but the treatments required may be far more onerous than treatment at earlier stages. Mortality is an important measure -- but so is survivable misery.
Rather than revisit the particulars of the mammography debate -- which are receiving abundant attention already -- my intent here is to address why cancer screening, which is quite literally looking for trouble, can at times seem to be so in the figurative sense as well. Then, I'll suggest what we can do about it, individually, and collectively.
There are two basic problems with cancer screening in general -- problems that pertain as much or more to prostate cancer as to breast cancer. The first is the challenge of accurate detection, and the second is the challenge of accurate prediction. Let's deal with them in turn.
The very point of screening is to find cancers when they are tiny and subtle, not when they are large, obvious masses eroding through other body parts. The earlier a cancer is found, the harder it is to see both because it's tiny, and because it may look a whole lot like the healthy tissue around it.
The challenge of finding something tiny and subtle is met, in statistical parlance, with sensitivity. Sensitivity is the ability, in this context, for a medical test to find what's there.
But there is a problem with extreme sensitivity -- and one not limited to medical testing. Imagine you drop a contact lens in a large room with a multicolored floor and dim light. As you search for it, you are apt to react with a moment of excited hope to any glint off the floor. In order not to miss your contact lens, you will be highly sensitive to any such glint.
But you will, in all probability, get excited by a whole batch of glints that are not your contact lens. These are called "false positives" in statistical parlance, and they are one form of over-diagnosis to which screening programs are subject.
But unless you have a perfect ability to detect the glint off of a contact lens without fail, and never mistake it for any other kind of glint -- these false positives are the price you pay for any hope of finding that lens. In cancer screening, they are the price paid for finding the cancers that are truly there, and need to be found.
The other goal of cancer screening is to rule out disease when it's absent. In statistical terms, specificity is the tendency for a test to give a negative result when disease is truly absent. But here, too, there is a price to pay. If in the case of your missing contact lens you never want the rush of false hope, there is a good chance you will ignore the subtle clues emitted by the lens. In order to avoid false hope, you may lose your real chance. This is called a false negative, and in cancer screening, it's a test that says there is no cancer -- when, in fact, there is.
The solution to this problem is improved technology. Ideally, we would devise a perfect test: one that unfailingly finds what it needs to find, and never mistakes anything else for it. But tests that produce no false positives, nor false negatives are vanishingly rare in medicine.
The next-best thing is enhanced technology that produces very high levels of specificity and sensitivity. In the case of mammograms, this would mean enhanced imaging, or computer-aided interpretation of the images. It might mean alternatives to mammography -- such as ultrasound, or thermography. Or combinations.
A combination of screening tests is used routinely for HIV, for example. The initial screening test, called an ELISA, is very sensitive, but not very specific. That makes it good for ruling out HIV, but not reliable for ruling it in. A highly-sensitive test will very reliably be positive when disease is present -- and thus a negative result on a highly-sensitive test tells you with a high level of confidence that disease is, in fact, absent. A negative ELISA is taken to mean no HIV.
But since the ELISA is so sensitive, it can be positive even when HIV is not there. So a second test, a Western Blot, is used. This test is highly specific. Since a specific test will reliably be negative when disease is absent, a positive result on a highly-specific test tells you with a high level of confidence that disease is, in fact, present. A positive Western Blot means, alas, that HIV has been found.
Enhanced technologies for breast cancer screening are in various stages of development and testing. So are combinations of tests. One of the limiting factors, of course, is cost. Better technology usually costs more. Our society must confront the challenge of best-possible breast cancer screening at a price the system is able and willing to bear.
The second challenge is prediction. The new study doesn't really highlight the flaws in mammography. Rather, it suggests we don't know what to do with the information the test gives us. Some early-stage breast cancers, in particular ductal carcinomas in situ, are destined never to progress. This is true of many prostate cancers as well, and the reason for formal recommendations against routine prostate cancer screening.
We don't want just to find cancer early; we want to change health outcomes for the better by finding cancer early. That doesn't happen when cancer is found that would never have progressed if left alone.
The solution here is deeper knowledge at the cellular level. Gene variants can help anticipate cancer behavior. A combination of reliable detection through better technology, and then better information from biopsy specimens, should lead us in the direction of treatment when it's needed -- away from it when it isn't.
In the interim, I think we all need to suppress our passions so we can work through the challenge of decisions that are far from easy. Advocates of cancer screening tend, on the basis of emotion rather than evidence, to dismiss studies that argue against overwhelming benefits of screening. Therapeutic nihilists who think screening is just a money-making gimmick tend to have equally passionate reactions in the opposite direction. Browse cyberspace and you will readily find a motherlode of both.
But these really are tough calls. Any given individual woman is more likely to have a false positive mammogram at some point, than to have her life saved by one. Ditto for prostate cancer screening in men. But some women will indeed have their lives saved by mammography, just as some men will have their lives saved by PSA testing. We just have trouble knowing who's who.
And therein lies the trouble with the kind of looking for trouble cancer screening requires. You may be the one helped; you may be the one harmed.
I favor access to and reimbursement for mammography until or unless we have truly decisive evidence of more harm from it than benefit. I do not think that will happen. Even though the argument for prostate cancer screening is weaker, I favor access to and reimbursement for that as well. Individual choice should be informed by personal preference, family history, and customized guidance from a health-care professional you trust.
Mammography specifically, and cancer screening in general, is often something of a muddle. It doesn't help us to refute this, or simply rant in favor of our preconceived notions. We should acknowledge the trade-offs, work toward better screening methods, and in the interim -- muddle through.
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