Abnormal laboratory results
- David Faulkner, Cliff Meldrum
- Aust Prescr 2012;35:125-8
- 1 August 2012
- DOI: 10.18773/austprescr.2012.052
Doctors are faced with an increasing multitude of tumour markers, biomarkers, tissue markers and genetic markers.
Some markers will make it through years of development and evaluation to clinical trial and eventual clinical use. The majority, however, will never proceed beyond the development stage.
Doctors need to be aware of the clinical use of tumour markers, but at the same time realise their limitations and the implications of inappropriate use.
Bowel (colorectal) cancer screening is recommended by the Cancer Council of Australia. The National Bowel Cancer Screening Program sends an immunochemical-based faecal occult blood test to people based on their age. However there is insufficient evidence to support any other tumour-based screening program.4
Newly developed tumour marker tests are marketed to patients and health professionals. Physicians should realise that while their well-informed patients may actively seek a particular test, it is not likely to have been validated in prospective clinical trials and is probably not available at their local pathology laboratory.
There are many different methods used to measure tumour markers, and samples analysed at different laboratories may yield different results. These discrepancies can be minimised by using the same laboratory.
The National Academy of Clinical Biochemistry (NACB) in the USA has published guidelines for the use of tumour markers in several malignancies (Table 1).5,6 Despite the numbers of proposed tumour markers under development, only the ‘traditional’ markers are used in diagnosis, prognosis and monitoring. For example in bladder cancer there are at least six urine tumour marker kits available that have been approved by the US Food and Drug Administration, yet there are no prospective clinical trial data establishing increased survival time, improved quality of life or decreased cost of treatment for any of the tests. However for testicular cancer, the measurement of beta-human chorionic gonadotrophin hormone and alpha-fetoprotein has been validated and is well established for diagnosis, prognosis and monitoring. Similarly cancer antigen 15-3 in breast cancer, cancer antigen 125 in ovarian cancer and carcinoembryonic antigen in colorectal cancer are recommended for prognosis and monitoring. Prostate specific antigen is used to monitor men treated for prostate cancer (Aust Prescr 2011;34:186-8).
The patient suspected of having multiple myeloma should have serum and urine electrophoresis screening tests along with routine biochemistry and haematology tests. If paraprotein is detected, skeletal X-ray, bone marrow and other specialised tests are needed. The serum free light chain test is a fairly new tumour marker which may become useful in multiple myeloma screening as an adjunct to serum and urine electrophoresis.7 In the rare case of non-secretory multiple myeloma, testing can detect small increases in free light chains. Currently however, there are no guidelines for its use in this role, but it is accepted for monitoring previously diagnosed patients.
Many other tumour markers exist and are used in specific clinical circumstances. However, it is doubtful if any of the following markers would be ordered outside of a specialist’s office:
A number of molecular genetic markers have become available that predict a patient’s response to targeted therapy. The most commonly used of these are mutations in the KRAS gene (Kirsten rat sarcoma-2 virus oncogene) which are indicative of lack of response to therapy with anti-epidermal growth factor receptor (EGFR) antibodies. Similarly, mutations in the EGFR gene predict sensitivity or resistance to EGFR tyrosine kinase inhibitors, and mutations in the BRAF gene (proto-oncogene B-Raf) predict response to BRAF inhibitors.
A number of international consensus groups have recommended testing for EGFR mutations in non-small cell lung cancer as a prerequisite to treatment with EGFR tyrosine kinase inhibitors, such as gefitinib or erlotinib. More than 80% of these EGFR mutations are either a single nucleotide substitution in exon 21 (p.Leu858Arg:L858R) or small deletions in exon 19.8 These mutations are termed classical activating mutations because they both activate the receptor tyrosine kinase and respond to the EGFR inhibitors gefitinib and erlotinib.
Not all EGFR gene mutations predict sensitivity to treatment. Primary and secondary resistance has been observed in non-small cell lung carcinoma, and a single mutation in exon 20 of the EGFR gene (p.Thr790Met:T790M) accounts for approximately 50% of acquired resistance to anti-EGFR therapy.9 Amplification of the MET oncogene is another common mechanism of acquired resistance and is associated with a poor prognosis.10
Importantly, high response rates to gefitinib and erlotinib can be achieved in appropriate populations of non-small cell lung cancer based on stratification by EGFR gene mutation status compared to the treatment of unselected populations with these inhibitors.
Anti-EGFR monoclonal antibodies are increasingly being used in both first- and second-line treatment of colorectal cancer.11 However, mutations in genes downstream of EGFR in the mitogen-activated protein kinase (MAPK) pathway can predict non-response to these therapies. Anti-EGFR therapy with cetuximab or panitumumab is generally not indicated if the tumour carries a mutation in exon 2 of the KRAS gene. These mutations commonly occur at codons 12 and 13. However, recent data suggest that not all KRAS mutations in these codons are equal in their prediction of response to cetuximab.12
Mutations in the BRAF gene have been identified in over 40% of melanomas, and specific inhibitors to a mutated form of the BRAF protein (BRAF V600E) have produced a clinical response in phase III trials (Aust Prescr 2012;35:134-5).13 The most prevalent mutation is a single nucleotide substitution (c.1799T>A) that results in an amino acid substitution of glutamic acid for valine in the BRAF protein. Similar to KRAS, other BRAF mutations may result in varying responses to treatment.
While cutaneous melanomas commonly harbour mutations in the BRAF gene, melanomas arising from acral and mucosal surfaces tend to harbour KIT gene mutations (8% of tumours) that predict response to another tyrosine kinase inhibitor, imatinib.
A role for BRAF mutations in the pathogenesis, diagnosis and targeted therapy of diseases beyond melanoma is also possible. In a recent report, all of 40 patients with hairy cell leukaemia carried the BRAF p.Val600Glu(V600E) mutation.14
Sturgeon CM, Lai LC, Duffy MJ. Serum tumour markers: how to order and interpret them. BMJ 2009;339:b3527.
Canil CM, Tannock IF. Doctor’s dilemma: incorporating tumour markers into clinical decision-making.
Semin Oncol 2002;29:286-93.
Kilpatrick ES, Lind MJ. Appropriate requesting of serum tumour markers. BMJ 2009;339:b3111.
Scientist in Charge, Biochemistry and Specimen Reception, Peter MacCallum Cancer Centre, Melbourne
Head, Diagnostic Molecular Pathology, Peter MacCallum Cancer Centre, Melbourne