New Medical Tests Raise Questions

The search is always on to develop new ways of making and confirming medical diagnoses, especially if novel tests can anticipate developing a potentially life-threatening but treatable disease. Yet whenever a new test is advanced, we must ask not only if it does indeed accurately identify the disease it is after but also whether the test itself can cause a new set of problems. And fundamental to our assessment of new tests is the question about whether they are easily available and affordable. Three recent developments highlight the importance of addressing these issues, one for Alzheimer’s disease, one for breast cancer, and one for colorectal cancer.

Alzheimer’s disease is the  leading cause of dementia globally, affecting more than 50 million people in the world. Its cause is unknown, but one prominent and controversial theory involves the ubiquitous presence in the brains of people who have died with Alzheimer’s disease of abnormal protein deposits called amyloid plaques. Two drugs,  lecanemab and donanemab, recently approved by the US Food and Drug Administration (FDA) target those amyloid plaques in people with early symptoms of Alzheimer’s disease and were shown to modestly  slow progression of the disease.

Determining who has early signs of Alzheimer’s disease and therefore may be a candidate for one of these drugs is a challenge. Brain scans using the technique called positron emission tomography (PET) can identify amyloid plaques in the brain before the disease has advanced to more serious stages, but PET scans are expensive and not widely available. An analysis of cerebrospinal fluid (CSF) from a lumbar puncture or spinal tap can also be used to identify people with early onset Alzheimer’s disease, but this is an invasive test that some people are reluctant to undergo. A simple blood test for Alzheimer’s disease would be an important advance for identifying who might be eligible for treatments to delay the onset of Alzheimer’s disease and slow its progression.

A new blood test was approved in May by the FDA that seems to do just that. With the roll-off-your-tongue name Lumipulse G pTau217/ß-Amyloid 1-42 Plasma Ratio, the blood test measures the blood levels of two abnormal proteins that also appear in the brains of patients with Alzheimer’s disease, phosphorylated tau and beta-amyloid, and compares their ratio. To approve the new test, the  FDA evaluated a study comparing the results of the blood test to those of either PET scans or spinal taps in 499 adults with mild cognitive impairment. The study showed that 91.7 percent of individuals with positive results on the blood test also had the presence of amyloid plaques by PET scan or spinal tap test result, and 97.3 percent of individuals with negative results on the blood test also had a negative amyloid PET scan or spinal tap test result. This means that the blood test is highly accurate in identifying the presence of amyloid plaques in the brain.

But while this means that people over the age of 55 with memory complaints can now get a simple blood test instead of undergoing an expensive PET scan or invasive spinal tap to find out if they have amyloid plaques in their brains, the decision to do so will be challenging. There is the existential question of whether someone wants to know that they may develop a fatal disease for which there is no cure that will slowly degrade their cognitive function. Not everyone with a positive amyloid PET scan will ultimately develop Alzheimer’s disease. For people who began with mild cognitive impairment, a study found that 40 percent progressed to full Alzheimer’s disease in three years. Assuming that the blood test predicts progression at about the same rate as PET scans do, the implication is that some people who test positive will never develop Alzheimer’s disease.

Then there is the practical question of what to do if there is a positive blood test. The two newest drugs for Alzheimer’s disease, lecanemab and donanemab, do not cure the illness (i.e., experts say they are not “disease modifying”), their  ability to slow cognitive decline is very modest at best and may not even be noticeable to the patient or caregivers, and they carry some risk of adverse events like bleeding in the brain. Hence, we have a nice new blood test that may or may not be useful for a disease.

Contrast-Enhanced Mammography for Breast Cancer Detection

A different set of challenges arises with the recent report of a better way to detect some breast cancers. About 50 percent of women have what are called “dense breasts,” a situation that makes it more difficult to detect tumors with standard mammograms and increases the risk for breast cancer. A  study from the United Kingdom evaluated three different alternatives to standard mammography to see if they increased the rate of breast cancer detection in women who had negative standard mammography scans and dense breasts. The results among the 9,361 study participants showed that magnetic resonance imaging (MRI) scans and contrast-enhanced mammography “detected three times as many invasive cancers as whole breast ultrasound.” The lead author of the UK study, Dr. Fiona Gilbert of the University of Cambridge, was quoted in the New York Times stating that contrast-enhanced mammography should become the “standard of care” for women with dense breasts.

Yet, contrast-enhanced mammography is not FDA approved and is not widely available in the US. One concern is the incidence of allergic reactions to the dye used in contrast-enhanced mammography, which, according to another expert quoted in the New York Times story, are uncommon but can be severe. There is also a concern about false positives—the test may be so sensitive that it detects tumors that are not actually medically significant. This can cause a great deal of anxiety in patients and create the need for more, and sometimes invasive, testing. Once again, then, we have what at first seems like a major diagnostic breakthrough that nevertheless comes with questions and concerns.  

A Simple Blood Test for Colorectal Cancer

Our third example is blood tests to detect colorectal cancer. Two are currently approved by the FDA and last month in a paper published in the journal JAMA Network a study evaluated the ability of a novel DNA test for colorectal cancer. A total of 48,995 people aged 45 to 85 enrolled in the study, had the blood test, and then underwent colonoscopy. The blood test was very accurate in identifying cancers that were subsequently confirmed with colonoscopy. Right now, the gold standard for screening for colorectal cancer is a colonoscopy, a procedure that no one likes and therefore many people who should be screened for cancer are not. The most often recommended alternative to colonoscopy for screening is a fecal test, again something people are often averse to doing.

Given that colorectal cancer is the  second most common cause of cancer death in the US, a simple blood test that detects colorectal cancer would clearly improve screening rates, identify many cancers, and save lives. Yet  experts warn that blood tests are still not as good as colonoscopy or fecal tests for detecting colorectal cancers. And if a blood test is positive for colorectal cancer, a colonoscopy will still be needed to determine the type of cancer and to potentially remove it without the need for surgery.  The blood test may be ideal for people who refuse colonoscopy, have limited access to medical care, or are uninsured and cannot afford the procedure, but it also may not be the best approach.

These three examples highlight the challenges posed by new and often seemingly very exciting advances in diagnostic technology. New tests, like blood tests for Alzheimer’s disease and colorectal cancer and contrast-enhanced mammography for breast cancer, clearly have advantages, but each one raises difficult questions with which patients and their physicians must grapple. We need to support the science that makes these advances, but there is no substitute for individualized health plans devised by people with their own doctors.