Appropriate use of tumour markers

Key practice points:

• Tumours markers have an increasing role in primary care as more evidence and guidance becomes available for their use. For example, the role of CA 125 has changed over time; testing serum CA 125 levels is now indicated in primary care as part of the diagnostic workup of a patient with suspected ovarian cancer.
• There are currently no tumour markers that have high enough sensitivity or specificity to be used alone as screening tests for malignancy in asymptomatic patients. Instead, specific tumour markers may be requested to determine which patients presenting with symptoms should be prioritised for further assessment.
• The main role for a tumour marker test is in the management of a patient with established malignancy, e.g. to assess response to treatment or to monitor for any secondary cancer or recurrence
• A tumour marker test should only be requested based on a specific clinical indication for investigating that parameter. Using these tests for general screening in asymptomatic patients can result in unnecessary follow-up and anxiety due to an abnormal test result, which turns out not to be cancer. Conversely, relying on tumour markers alone to rule out cancer in a symptomatic patient, can result in false reassurance.

Tumour markers generally make poor screening tests

The term “tumour marker” encompasses a spectrum of molecules that are produced either by, or in response to, a tumour that contributes to the clinical detection, management or prognosis of a patient with cancer.^{1, 2}

The clinical use of a tumour marker largely depends on its sensitivity, specificity and positive and negative predictive value for a particular cancer.^{2, 3} An ideal tumour marker is one that is highly sensitive and specific.³ Many of the currently available and frequently requested serum tumour markers (Table 1) can be produced by normal tissues and levels can be elevated in non-malignant conditions.^{2, 3} They are also not always site- or organ-specific.^{2, 4} In addition, not all people with a particular cancer have raised levels of the corresponding tumour marker(s).^{2, 3} Therefore, clinical utility is currently limited.

Under certain clinical scenarios, testing specific serum tumour markers may be indicated in primary care as part of the diagnostic workup of a patient with suspected cancer, e.g. CA 125 for ovarian cancer.⁵ Tumour markers are not appropriate to be used as screening tests for malignancy in patients who are asymptomatic due to low sensitivity and specificity.^{1, 5} Instead they can be used to determine which patients presenting with symptoms should be prioritised for further assessment.

In general, the main role of a tumour marker test is in the management of a patient after diagnosis of a particular cancer, where it is used to assess response to treatment or to monitor for any secondary cancer or recurrence.^3–5 A rising tumour marker level usually requires further investigation, while an undetectable, low or falling level tends to be reassuring.¹

Only request laboratory testing for a tumour marker when it is clinically indicated.^{2, 5} If a tumour marker is inappropriately requested there is a higher risk of false positive and false negative results, e.g. as a screening test in an asymptomatic patient, as a diagnostic test in a patient with non-specific symptoms, for a suspected cancer that is not known to produce the marker. An elevated result may be due to reasons other than malignancy which can cause the patient anxiety and distress, lead to unnecessary investigations and a delay in reaching the correct diagnosis.^{3, 4} Conversely, false reassurance is possible if normal/negative results are returned (and it is the only test used to exclude malignancy). In rare cases, requesting serum tumour markers when not clinically indicated may detect cancer, but this is likely to be outweighed by the potential for harm.

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Table 1. Commonly requested tumour markers.

Tumour markers in ovarian cancer

Ovarian cancer is the second most common gynaecological cancer in New Zealand after endometrial cancer, and has a higher mortality than all other gynaecological cancers combined.¹⁶

Cancer antigen 125 (CA 125) is a cell-surface glycoprotein that is raised in more than 80% of people with advanced epithelial ovarian cancer, and in half of those with early-stage disease.^{8, 9} It is less commonly raised in people with non-epithelial ovarian cancers.⁸ Some non-malignant conditions are also associated with elevated CA 125 levels. These may include conditions involving or inflaming the peritoneum, pericardium or pleura, e.g. endometriosis, pelvic inflammatory disease, ascites, recent abdominal surgery, pleuritis, pericarditis or congestive heart failure with pleural effusion.^{8, 9} Menstruation and first-trimester pregnancy can also cause up to three-fold elevations in CA 125.⁸

The role of CA 125 has changed over time, and testing serum CA 125 levels is now indicated in primary care as part of the diagnostic workup of a patient with suspected ovarian cancer.¹⁷ CA 125 is not used as a screening test for ovarian cancer in asymptomatic people (including those at high-risk) due to low sensitivity and specificity.^{8, 9} Instead, it is used to determine which females presenting with symptoms suggestive of ovarian cancer should be prioritised for further assessment.

Higher levels of CA 125 should increase suspicion of malignancy and patients with elevated levels will generally require referral for a pelvic ultrasound. Malignancy is suggestive at a CA 125 level of > 200 U/mL, or at a level of > 65 U/mL in patients with an ovarian mass, but there is no level that is exclusively associated with cancer.⁸

The specificity and positive predictive value of CA 125 is higher in females who are post-menopausal, compared to those who are pre-menopausal; an elevated serum CA 125 level in younger females is less likely to be due to epithelial ovarian cancer.^17–19

Occasionally after a diagnosis of ovarian cancer, CA 125 is used to monitor response to treatment.⁸

Other tumour markers in ovarian cancer

Human chorionic gonadotrophin (hCG), lactate dehydrogenase (LDH) and alpha fetoprotein (AFP) may be elevated in pre-menopausal females with a non-epithelial ovarian cancer.¹⁷ Other tumour markers, such as human epididymis protein 4 (HE4) show potential for the detection of ovarian cancer in international studies, but are not yet available in New Zealand and further research is needed.¹⁷

For information on the diagnosis of ovarian cancer, see: bpac.org.nz/2023/ovarian-cancer.aspx

Tumour markers in bowel cancer

Bowel cancer is the most commonly diagnosed cancer in New Zealand, and is the second leading cause of cancer mortality after lung cancer.¹⁶

Carcinoembryonic antigen (CEA) is the tumour marker most commonly used, along with clinical review and other appropriate investigations, to detect bowel cancer recurrence.¹³ It is not recommended as a screening or diagnostic test for bowel cancer due to low sensitivity and specificity.^{13, 14}

Production of CEA begins and peaks during fetal development; then declines with age and is found in low levels in healthy adults.¹⁴ Bowel cancer may increase CEA levels; however it is non-specific and levels can be raised in people with other malignancies including ovarian, gastric, pancreatic, lung and breast cancer.^{13, 14} In addition, not all people with bowel cancer have raised CEA levels.¹³ CEA may also be elevated in other conditions including inflammatory bowel disease, pancreatitis and cirrhosis, and in people who smoke.^{13, 14}

Very high CEA levels are usually associated with metastatic disease.¹³ However, tumour differentiation also influences CEA levels but in an inverse relationship; CEA is more likely to be produced by a well differentiated bowel cancer than a poorly differentiated tumour.¹³

In general, the main application of CEA is for the monitoring of patients after surgical resection for bowel cancer to detect recurrence. However, pre-operative and early post-operative results do have prognostic significance. People with higher pre-operative levels tend to have a poorer prognosis as they are often diagnosed with more advanced bowel cancer.^{13, 14} A pre-operative level > 5 micrograms/L is associated with a higher rate of recurrence and cancer-related mortality.¹³

A reduction in CEA levels post-operatively is associated with a good prognosis. In contrast, a CEA level that does not return to normal (e.g. within one month) following surgical resection, is associated with poorer survival and suggests residual or recurrent disease.^{13, 14} Levels that are increasing or > 10 micrograms/L should prompt more urgent clinical review and investigations for recurrence.¹³

Recommendations for how frequently patients should have a CEA level requested post-operatively vary between international guidelines. The testing frequency will usually be determined for each patient by their secondary care specialist based on their specific clinical circumstances.

For further information on the follow-up and surveillance for patients after treatment for bowel cancer, see: bpac.org.nz/2021/bowel-cancer.aspx

Tumour markers in testicular cancer

Testicular cancer accounts for a small proportion of the total cancer diagnoses in New Zealand; in 2020, 1.4% of all cancer diagnoses in males were testicular.¹⁶ However, it is the most common solid tumour in younger males, and incidence is increasing.^{20, 21}

Approximately 95% of testicular cancers originate in primordial germ cells and are classified into two main types: seminomas or non-seminomas.^{20, 21} Most non-seminomatous tumours are associated with elevated levels of one or more of serum AFP, beta hCG and LDH, while only beta hCG and LDH are useful markers in people with seminomas.^{6, 20} These tumour markers are non-specific and may also be raised in conditions other than testicular cancer, e.g.:^{6, 7, 15}

• AFP: liver cancer, cirrhosis
• hCG: ovarian germ cell tumour, gastrointestinal cancer
• LDH: lymphoma, germ cell tumours, hepatitis

As part of the diagnostic workup of a patient with suspected testicular cancer, international guidelines and some local HealthPathways recommend testing AFP, beta hCG and LDH.²¹ These results also help to inform staging, prognosis and management decisions in a patient with testicular cancer.^{20, 21}