MOLECULAR DIAGNOSTICS :: TUMOR MARKERS
Current and future state of early cancer detection biomarkers
by Harvey W. Kaufman, MD, and Yuri A. Fesko, MD C
ancer biomarkers are important in early cancer detection when cure rates are highest. For the past several decades, we have made limited progress towards biomarker de-
velopment for early cancer diagnoses. We continue to rely on older biomarkers to screen for cancers including cervical, prostate and colon cancers. This article aims to examine some current cancer screening tests, detail barriers to progress in cancer biomarker screening, and outline what’s next for this important field of study. Currently, the Papanicolaou test, also known as “the Pap,” exists as a pillar of women’s health and an important cancer detec- tion tool. The Pap test was developed in the 1940s by Georgios Papanikolaou, MD, and it involves examination of exfoliating cells from the transformation zone of the cervix for detection of cancerous or precancerous lesions. The Pap has proven to be extremely effective at cervical cancer detection and has been critical to the dramatic decrease in cervical cancer incidence and mortality in the United States. The addition of human papil- lomavirus (HPV) with the Pap (co-testing) provides enhanced sensitivity for cervical cancer detection.1 For men, the prostate specific antigen (PSA) test was created with hopes it would have a similar impact on reducing prostate cancer. Indeed, the PSA test can detect prostate cancer approxi- mately years earlier than a digital rectal exam and years before symptoms of the disease are recognized. The prostate cancer mortality rate in the US declined more than 40% since the early 1990s, when PSA screening became widespread.2
In recent years,
concerns were raised about whether prostate cancer mortality had truly declined, and if the risks of diagnosis and treatment were substantial, relative to their benefits. These tests are examples of older screening tests to detect
cancer. Fortunately, there has been some progress with much of the most impactful recent advances supported by the National Cancer Institute (NCI). For example, a variety of projects in progress are currently evaluating liquid-based tests that could identify a variety of cancers early based on DNA fragments.3
One
example, UroSEEK, is a urine-based test that detected the most common alterations in 11 genes linked to bladder and upper tract urothelial cancers. In a study, UroSEEK identified 83% of those who developed bladder cancer.4
is similar, and aims to look at available DNA from specimens collected for Pap tests. In a study, the test was able to detect some endometrial and ovarian cancers at early, more treatable stages.5
Finally, CancerSEEK looks at circulating DNA and protein
biomarkers. In a large trial of women with no history of cancer that combined the blood test with whole-body PET imaging, 65% of cancers that were detected were at an early stage.6
Given
this information and the above projects, why has there not been more progress made in cancer biomarker screening?7
What are the primary issues? Primary issues to overcome include cost and biomarker per- formance, i.e., false positives and false negatives. False positive screening test results push patients, in the absence of having the screened condition, to obtain follow-up or confirmatory testing. Follow-up tests can have substantial costs and may
22 DECEMBER 2021
MLO-ONLINE.COM Another project, PapSEEK,
A variety of projects evaluating liquid-based tests are in progress to detect cancer early based on DNA fragments. Bladder cancer, pictured here, is the subject of one such test.
cause harm. False negative screening results leave patients with the screened condition unidentified, and the disease can progress. In addition, cost is a consideration, including the cost of the biomarker-based testing and associated costs including financial, risks of harm, time, and anxiety associated with a making the definitive diagnosis with follow-up diagnostics in both true (and any false) positives. Cancer biomarkers must be carefully selected. For instance,
CA-125 testing can help physicians in follow-up management of patients with ovarian carcinoma. Because a biomarker screening test for ovarian cancer does not exist, some providers may also use CA-125 to help screen patients. Yet, a study of 78,216 women ages 55 to 74 years of age who were randomly selected to receive either an annual CA -125 test and pelvic ultrasound screening or the usual medical care showed that CA-125 testing and ul- trasound screening failed to reduce ovarian cancer deaths.8
The
study also found that false-positive tests led to additional testing and procedures that sometimes resulted in serious complications. Biomarkers for bladder cancer screening have not proven to be successful and are not recommended by national guidelines, yet in surveillance for recurrence they have been shown to be useful.9
Cancer biomarkers can help decrease the need for an
invasive procedure such as intravesical therapy (injection for early stage bladder cancer) and detect bladder cancer recurrence. The use of a screening test using fluorescence in situ hybridiza- tion (FISH) in urine samples in conjunction with cystoscopy has been shown to help in bladder cancer diagnosis in patients with hematuria who are suspected of having bladder cancer. The test may also detect cancer recurrence when a cystoscopy and urine cytology are equivocal. In a prospective study the test was beneficial in patients who had an atypical cytology and an equivocal or negative urine cytology.10
The combination of the
procedure and the testing can help in ambiguous situations to further identify patients who truly have a recurrence from those who remain in remission.11
Photo 163942834 © Katerynakon |
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