Serum tumour markers: how to order and interpret them

Which are the most clinically useful serum tumour markers and how should they be used?

Serum tumour markers may be used in screening, to help in diagnosis, or to monitor response to treatment. Although routinely available, tumour markers are specialised tests, ideally measured only after consideration of the likelihood that results will improve patient outcome, increase quality of life, or reduce overall cost of care.5 Table 1⇓ lists the 10 serum tumour markers most likely to be requested by non-specialists, with current recommendations for their use. PSA (prostate specific antigen) is the marker most often requested, and the increased incidence of prostate cancer in the United States during the past two decades is attributed largely to its widespread measurement.6

When are tumour markers helpful for diagnosis?

With a few important exceptions (such as α fetoprotein and human chorionic gonadotrophin in germ cell tumours), measuring more than one serum tumour marker is unlikely to be helpful when trying to establish a diagnosis. Table 2⇓ outlines typical clinical presentations that would prompt requests for each of the seven most commonly requested tumour markers. The National Academy of Clinical Biochemistry recommends that requests for panels of tumour markers are actively discouraged, as are requests for prostate specific antigen in women or CA125 in men.1 The likely benefit of the result to the individual patient must be considered before requesting any tumour marker. If decisions about treatment depend solely on the result of a single tumour marker, the result should be confirmed on a repeat specimen.

In carefully selected undiagnosed patients who are at medium to high risk of malignancy, highly raised levels of the appropriate tumour marker may provide helpful information—for example, in a patient unable or unwilling to have further, invasive investigations such as colonoscopy. Major recent improvements in the speed of access to ultrasonography in UK general practice may reduce the number of unfocused requests for tumour markers, which previously may have been made pragmatically while awaiting more definitive radiological testing.

Together with radiological testing, measurement of both human chorionic gonadotrophin and α fetoprotein is mandatory in patients in whom testicular or other germ cell cancers are strongly suspected, although these markers are not raised in all such patients.6

A recently developed UK consensus statement on ovarian cancer recommends measurement of CA125 and pelvic ultrasonography in women aged over 50 years presenting with persistent, continuous, or worsening unexplained abdominal or urinary symptoms and in whom abdominal palpation gives cause for concern.9 The rationale is to reduce the risk of delaying diagnosis if women with ovarian cancer are referred to non-gynaecological specialists.

Inadequate sensitivity and specificity limit the use of CA 19-9 measurement in the early diagnosis of pancreatic cancer.10 In patients without jaundice, however, CA19-9 measurement may complement other diagnostic procedures, especially in the absence of cholestasis.

In conjunction with abdominal ultrasonography, the National Comprehensive Cancer Network, like other expert groups, recommends α fetoprotein measurements at six-monthly intervals in patients at high risk of hepatocellular carcinoma (especially those with liver cirrhosis related to hepatitis B or hepatitis C) and further investigation if increases in α fetoprotein persist.11 The effectiveness of such testing will reflect prevalence of disease in the screened population.

Although PSA is essentially organ specific (table 2⇑), it is not cancer specific (box). Sustained high levels of PSA occur in benign prostatic hyperplasia, and transient increases may occur in some patients with urinary tract infections, in prostatitis, and after catheterisation (table 3⇓). Provided these latter conditions are excluded, the higher the PSA level, the greater the probability of prostate cancer. About 15% of men with a PSA <4 μg/l will have cancer on biopsy, as will about 25% with a PSA 4-10 μg/l and 50% with a PSA >10 μg/l.13 Confirmed levels >100 μg/l are usually consistent with metastatic disease. Prostatic biopsy or radiological evidence of bone metastases is generally required for definitive diagnosis.

Are tumour markers helpful for diagnosis in patients with non-specific symptoms?

Tumour markers are not helpful for diagnosis in patients with non-specific symptoms. Many tumour markers (particularly carcinoembryonic antigen (CEA), CA125, CA15-3, and CA19-9) are raised in several cancers (table 2⇑) but may also be raised in certain benign diseases (box). They therefore cannot either identify or exclude suspected malignancy (especially early stage disease) reliably, owing to low diagnostic sensitivity (the ability to identify the true cases of a particular cancer type) and low specificity (the ability not to identify people as having a particular cancer type when they do not have it).

For example, the proportion of patients with early stage (Dukes’s type A) colorectal cancer who have CEA levels >5 μg/l is only 3%, compared with 25%, 45%, and 65% for Dukes’s type B, C, and D respectively.14 Measurement of these markers is therefore not recommended in patients with non-specific symptoms (a presentation most likely to be encountered in primary care) before imaging or a definitive diagnosis of malignancy by biopsy.

Are tumour markers effective for screening asymptomatic populations?

Population based screening of asymptomatic people with most serum tumour markers is not recommended owing to low diagnostic sensitivity and specificity. Screening for prostate cancer with PSA has the potential to detect malignancy at least five years before clinical evidence of disease but remains controversial, with some expert groups in favour and others not.6 Interim results of two large prospective trials of PSA screening are contradictory, one suggesting no mortality benefit15 and the other concluding that 1410 men would need to be offered screening and 48 men treated to prevent one death from prostate cancer during a 10 year period,16 a benefit achieved only at the cost of substantial overdiagnosis and overtreatment.17 Until these studies finally report their findings, asymptomatic men should be informed of the benefits and limitations of PSA screening before deciding whether to have the test.6 18 The Prostate Cancer Risk Management Programme (part of the NHS Cancer Screening Programmes) provides helpful information packs intended for distribution through primary care (www.cancerscreening.nhs.uk/prostate/informationpack.html).

Serial measurements of CA125 are included in a UK collaborative trial of ovarian cancer screening involving 208 638 women aged 50-74 years.19 The final results of this trial will not be known until 2015, and in the meantime the National Academy of Clinical Biochemistry does not recommend opportunistic screening of asymptomatic women with CA125.6

What are the pros and cons of monitoring response to treatment?

Serial monitoring of patients after treatment is the most appropriate use of tumour markers (table 1⇑), but its effect on outcome varies. In patients with a diagnosis of cancer, measurement of markers before and after treatment can provide evidence of efficacy of treatment and identify recurrence some months before clinically evident. Whether the latter benefits an individual patient depends on the availability of further treatment (such as chemotherapy or resection).

For patients with germ cell tumours, all guidelines recommend measurement of α fetoprotein and human chorionic gonadotrophin according to well established protocols,20 as further treatment can be started after a confirmed increase in markers even without radiological evidence of progression.

Similar benefit in monitoring can be achieved in patients with colorectal cancer by measuring CEA; serial measurement as part of an intensive surveillance programme improves survival when compared with less intensive follow-up.6 Most expert groups recommend measurement of CEA at three-monthly intervals for at least three years in patients with stage II or III colorectal cancer who are candidates for surgery or systemic treatment of metastatic disease.6 Current trials are investigating whether intervention (such as chemotherapy) is similarly beneficial after a rise in CA125 in patients with ovarian cancer. Results of one such trial suggest not, probably reflecting the current lack of curative treatments.7

The National Academy of Clinical Biochemistry recommends monitoring with PSA measurements after treatment for prostate cancer but cautions that the clinical utility varies depending on the disease stage of the individual patient.6 Importantly, cancer progression may occur without increases in the concentration of the relevant tumour marker, and a tumour may occasionally lose its ability to produce a marker, perhaps as a result of dedifferentiation.

Sustained decreases in marker concentrations provide reassuring and objective evidence of tumour regression. However, as rising levels provide early evidence of progression, if alternative treatment is not available then monitoring with marker measurements can cause psychological distress without much clinical benefit. The ultimate decision about whether to monitor with tumour markers requires close cooperation between clinicians and patients.6 A recent article provides insight into these issues from the perspective of a patient with ovarian cancer monitored with CA125 measurement.21

Why is non-selective requesting of tumour markers undesirable?

If they are inappropriately requested, tumour marker measurements may lead to additional and unnecessary investigations, as recently illustrated for a cirrhotic patient extensively investigated for ovarian cancer because her serum CA125 was raised.22 Raised markers may lead to suspicion of disease in organs not relevant to the patient’s presentation, potentially causing undue alarm, while normal levels may provide false reassurance. Either scenario can result in additional cost (such as admission to hospital), risk of side effects (such as endoscopy, which carries a small risk of mortality), and/or delayed diagnosis.

What evidence exists that tumour markers are often requested inappropriately?

A recent audit of practice in Northern Ireland found that, although 80% of tumour marker requests were associated with the relevant organ, 54% of clinicians used tumour markers to screen for malignancy, with a low index of suspicion in 35% of these requests.23 Another audit in a single UK hospital found that 26% of all tests for the marker of breast cancer CA15-3 were for men—even though none of these men had breast biopsies in the year of the study or in the two years before—as were 17% of requests for the marker of ovarian cancer CA125.24 In the Greek study mentioned earlier, only 20% of 10 291 retrospectively reviewed tumour marker results for 1944 patients were for patients with cancer.4 The lowest level of appropriate requesting was for the pancreatic marker CA19-9 (1.9%), and 26% of CA125 requests were for men.4 The colorectal cancer marker CEA was most often correctly requested (27%).4

Is the method by which tumour markers are measured important?

When interpreting results, particularly serial results, clinicians need to be aware that results obtained using different methods are not necessarily comparable.25 The National Academy of Clinical Biochemistry recommends that laboratories indicate the method used when reporting the results for tumour markers, provide cumulative (ideally graphical) reporting, and append an interpretative comment, especially if there have been intervening method changes (figure⇓).1 Early discussion with laboratory staff about any results that do not accord with the clinical picture facilitates early identification of analytical errors.1 12 Such identification is helped by the provision of relevant clinical information when tests are ordered, which is strongly recommended by the National Academy of Clinical Biochemistry.1

Possible template for a clinical laboratory report for tumour markers that fulfils current reporting recommendations.1 Close collaboration between clinical and laboratory staff together with provision of relevant clinical details allows laboratory staff to provide advice on further action (such as referral) on the basis of the most recent result and/or on the rate at which marker level is increasing

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How can the process of requesting tumour markers be improved?

Guidelines provide a helpful framework for initiatives to promote best practice, with local ownership being essential for successful implementation.26 Encouraging effective communication between clinical and laboratory staff—such as through laboratory provision of more informative reports (figure⇑)—is likely to improve test requesting, particularly if underpinned by audit.

What new tumour markers are emerging?

New tumour markers may complement existing markers.6 The gene product human epididymis 4 protein has been cleared by the US Food and Drug Administration as an aid for monitoring patients with ovarian cancer.27 Measurement of PCA-3 in urine may help to stratify patients according to their risk of prostate cancer before biopsy, although large scale validation studies are needed.28 Similar studies are needed to assess the utility of methylated genes in the management of patients with cancer.29

Serum tumour markers currently contribute relatively little to treatment decisions, often owing to the lack of effective second line treatment. As treatments improve, predictive serum tests may help to identify patients most likely to benefit from new and expensive drugs. Personalised treatment is most advanced for breast cancer, with tissue markers such as oestrogen receptor and HER-2 (human epidermal growth factor receptor 2) predicting response to endocrine therapy and trastuzumab respectively.30