The promise and the challenges

There is growing interest in tumour markers as aids for the diagnosis, staging and management of cancer. Some are expected to succeed, after several years of evaluation to trials and eventual clinical use. A large number, however, are not likely to make it beyond development. On their part, physicians need to be aware of both opportunities and limitations in the clinical use of tumour markers.
Tumour markers are substances (antigens, proteins, enzymes or hormones) which indicate the presence of cancer or provide information about its likely course of development. They are present in cancerous tissue as well as in the bodily fluids of cancer patients.

Range of applications
Tumour markers have shown their potential for several applications. These range from the differential diagnosis of benign and malignant conditions to prognostic assessments, postoperative surveillance, the prediction of drug response or resistance, and the monitoring of therapy in
advanced disease.
The key advantage of tumour markers in the above applications is convenience. Inexpensive automated assays allow for fast processing of samples.

The case for tumour markers
The best known tumour markers include Her2/neu for breast cancer, which has an established economic case. Her-2/neu is a target for trastuzumab, whose use as an adjuvant has been shown to decrease cancer recurrence rates by 50%. However, up to one in 20 trastuzumab recipients develop cardiac dysfunction. Given that the cost of one year of therapy is close to 100,000 Euros, the need for accurately and precisely assaying every tissue sample is evidently strong.

Work in progress
Tumour markers are, however, still a work in progress and expected to remain so. In the US, the National Cancer Institute (NCI) states that “more than 20 tumour markers are currently in use.” It however lists over 30. The European Group on TumoUr Markers (EGTM) has a list of 16.
Despite the number of tumour markers in development, only ‘traditional’ markers are used in diagnosis, prognosis and monitoring. For example, at least six urine tumour marker kits are approved by the US Food and Drug Administration for bladder cancer. However, none are backed by data from clinical trials that increased survival time, improved quality of life or decreased cost of treatment.

Appropriate use, caution urged
Many experts urge caution with respect to tumour markers. Inappropriate use, according to an article in the ‘British Medical Journal’, can cause patients unnecessary anxiety and distress, and may also delay correct diagnosis and treatment. The authors cite one hospital audit which found “that only about 10% of requests for tumour markers were appropriate.”
The European Group on Tumor Markers attributes part of this problem to the growing availability of automated immunoassays. This makes tumour marker tests available in routine rather than specialist laboratories. “Results are consequently more readily available to non-specialist clinicians, who may be less familiar with their interpretation.”

Challenges of sensitivity and specificity
Only some markers, known as tumour-specific markers, are produced exclusively by a particular tumour As a result, most tumours cannot be detected by a single test, and tests for multiple markers are often required.
Tests are therefore often accompanied by the risk of both false positives and false negatives. The Cancer Information & Support Network (CISN) sums up the picture: False positives may occur because most tumour markers “can be made by normal cells, as well as cancer cells,” and markers “can be associated with noncancerous conditions.” On the other hand, the reason for false negatives is that “tumour markers are not always present in early stage cancers” and because “people with cancer may never have elevated tumour markers.”
For example, the level of CA-125, a marker for ovarian cancer, is also elevated in a variety of non-malignant disorders such as cirrhosis, pancreatitis, endometriosis, and pelvic inflammatory disease. In addition, medications appear to alter the results of a varied range of tests. So too do pregnancy, menstruation, cigarette smoking and various benign disorders.

Biopsy remains only definitive way for diagnosis
The above lack of sensitivity and specificity has been a major limitation facing the use of tumour markers in clinical practice. As with imaging, the use of tumour markers has been limited to supporting the diagnostic process, and the gold standard for diagnosis still remains a biopsy.
Although difficult to access areas such as the brain are likely to result in more use of tumour markers, a biopsy remains “the only definitive way” for diagnosis of a tumour” even in the brain.

NACB Guidelines
In 2008, the National Academy of Clinical Biochemistry (NACB) in the US released updated Laboratory Medicine Practice Guidelines for the use of tumour markers.

The guidelines made cross-referrals to efforts by numerous professional and regulatory best-practices bodies, including the American Society of Clinical Oncology (ASCO) and the National Comprehensive Cancer Network (NCCN), Britain’s National Institute for Health and Clinical Excellence (NICE), the European Group on Tumor Markers (EGTM), the International Federation of Gynecology and Obstetrics (FIGO) and the Gynecologic Cancer Intergroup (GCIG).
The NACB guidelines cover five cancer sites: testicular, prostate, colorectal, breast, and ovarian.

Testicular cancer
For testicular cancer, α-fetoprotein (AFP), human chorionic gonadotropin and lactate dehydrogenase are recommended for diagnosis, staging, prognosis determination, recurrence detection and the monitoring of therapy. AFP is also recommended for the differential diagnosis of tumours

Prostate cancer
Prostate-specific antigen (PSA) is considered to be potentially useful for detecting prostate cancer recurrence and monitoring therapy. Free PSA is considered useful for distinguishing malignant from benign prostatic disease.

Colorectal cancer
In colorectal cancer, carcinoembryonic antigen is recommended (with some caveats) for prognosis determination, post-operative surveillance, and therapy monitoring in advanced disease. Fecal occult blood testing is considered useful for screening asymptomatic adults who are older than 50 years.

Breast cancer
For breast cancer, estrogen and progesterone receptors predict response to hormone therapy, human epidermal growth factor receptor-2 predicts response to trastuzumab, while urokinase plasminogen activator/ plasminogen activator inhibitor 1 is used for determining prognosis in lymph node-negative patients. CA15-3/BR27–29 or carcinoembryonic antigen can be used for therapy monitoring in advanced disease.

Ovarian cancer
CA125 is recommended (with transvaginal ultrasound) for early detection of ovarian cancer in women at high risk for this disease. CA125 is also recommended for differential diagnosis of suspicious pelvic masses in post-menopausal women, as well as for detection of recurrence, monitoring of therapy, and determination of prognosis in women with ovarian cancer.

Future research to target higher specificity and sensitivity
In the future, research is expected to focus on finding markers which are specific of one pathology, have higher sensitivity with a low cut-off and deliver results which correlate to tumour mass and growth potential. Ideal candidates would also have a short life duration to permit efficient follow-up; in other words, their presence should decrease during treatment and increase before a relapse.

The promise and challenges of screening
Given that tumour markers can aid in assessing the response to cancer treatment and making prognoses, many public health professionals have hoped they might also be used for screening tests which would detect cancer before the presence of symptoms.
Indeed, many tests have both screening and diagnostic uses, with only the context of use determining whether the test is one or the other. “A screening test is done on asymptomatic individuals who receive the test principally because they are of the age or sex at risk for the cancer. A diagnostic test is done on an individual because of clinical suspicion of disease.”

However, no tumour marker identified to date is sufficiently sensitive or specific to be used on its own for screening, demonstrating a survival benefit in randomized controlled trials in the general population.

One of the best known examples is the prostate-specific antigen (PSA) test. Although it is now accepted that most men with elevated PSA levels do not have prostate cancer, the implications of this remain mired in controversy and also illustrate the kind of limitations which other tumour biomarkers may face in the future for use in screening.
PSA screening has been the subject of two large randomized controlled trials in the US and Europe in the 2000s. However, as the Mayo Clinic notes, in spite of the size of the trials, there were “no clear conclusions.” This is because their diversity of methodology allows for significant flexibility in interpretation. As a result, “the decision of whether to screen or not screen – using PSA testing or other means or both – is a decision best made between physicians and their individual patients.”

The two trials were PLCO (Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial) conducted by the National Cancer Institute in the US, and the European Randomized Study of Screening for Prostate Cancer (ERSPC), billed as “the largest randomized trial of screening for prostate cancer” with 162,388 subjects.
In 2011, a US government task-force concluded that healthy men should not be screened for prostate cancer. The finding, which “drastically changed the standard of care for middle-age American men who had grown accustomed to annual screenings,” was largely based on 10 years data from the two studies, which found risk of over-diagnosis and over-treatment.

Problems began when follow-on data from ERSPC two years later showed screening was associated “with a 21% reduction in risk of prostate cancer mortality.” However, this was accompanied by a still-sizeable risk of over-diagnosis and over-treatment. As a result, the authors said that “population-based screening could not yet be recommended.
In April 2015, an article in ‘The Lancet’ re-confirmed “a substantial 21% reduction” from PSA screening. However, due to access restrictions to the ERSPC trial data, the authors called this figure into serious question.

The controversy is unlikely to go away for some time. An Op Ed in The New York Times called the PSA test “hardly more effective than a coin toss.” Although the date of publication was 2010, the author of the commentary was Dr. Richard Ablin, who discovered PSA in 1970.
Such challenges are also likely to accompany screening for other conditions. For instance, data from the PLCO trial show that screening for CA-125 (recommended by the National Academy of Clinical Biochemistry for women with ovarian cancer, along with transvaginal ultrasound), does not reduce ovarian cancer mortality. Instead, false-positive screening test results have been associated with complications.