Tumor markers

ALSO KNOWN AS: Biomarkers, cancer markers, tumor-associated antigens, tumor-specific antigens

DEFINITION: Tumor markers are molecules whose presence or abnormal concentration in body fluids or tissue samples is associated with malignancy. They are most often individual, well-characterized proteins or nucleic acids. Increasingly, multiple tumor markers are interpreted in combination.

Cancers identified: Many, notably prostate, ovarian, and gastrointestinal cancers

How tumor markers are used: Tumor markers have been sought for every type of cancer, and tumor-marker determinations can be used in several contexts. In risk assessment, mutations in the BRCA1 and BRCA2 genes confer an increased risk of breast and ovarian cancer, and mutations in the APC gene are associated with increased colorectal cancer risk. Knowledge of increased risk can motivate more frequent screening procedures or more aggressive treatment decisions if cancer is eventually diagnosed.

In early detection efforts, several serum tumor markers are widely used:

• Cancer antigens 125 (CA-125), CA 72-4, and CA15-3 for ovarian and breast cancer
• Carcinoembryonic antigen (CEA) and CA19-9 for gastrointestinal cancer
• Prostate-specific antigen (PSA) and Prostatic acid phosphatase (PAP) for prostate cancer
• Beta Subunit HCG (human chorionic gonadotropin) and Alpha-fetoprotein (AFP) serum test for testicular carcinoma
• Neuron-specific enolase (NSE) and chromogranin A (ChgA) for neuroendocrine tumors

Because of the need for very high specificity, only one tumor marker (PSA) is recommended to screen asymptomatic individuals. Most early detection efforts focus on clinical and radiological findings. In diagnostic confirmation procedures, markers, such as alpha-methyl acyl-CoA racemase (AMACR), can be interrogated on biopsy specimens. AMACR in prostate tissue helps rule out benign mimickers of prostate cancer. In molecular classification efforts, tumor markers can resolve different types of cancer that might otherwise be misdiagnosed. Four malignancies appearing histologically as small round blue cell tumors—neuroblastoma, non-Hodgkin lymphoma, rhabdomyosarcoma, and Ewing sarcoma—fall into this category. Tumor markers are needed to distinguish among them.

Therapy selection can also be guided by tumor markers, such as the ABCB1 (MDR1) protein and the estrogen and progesterone receptors (ER/PR). Low levels of MDR1 correlate with better response to treatment in ovary and lung cancer patients, whereas the presence of the ER/PR tumor marker in advanced breast cancer patients correlates with a high response rate to endocrine ablation. Breast cancer patients whose tumors overexpress the HER2/neu (also known as ERBB2, c-erb-B2) protein are another important subgroup identified by tumor-marker analysis since these patients are uniquely appropriate for therapy with anti-HER2-based therapies such as trastuzumab. Tumor-marker concentrations often correlate with tumor burden or activity, providing information on the effectiveness of treatment. For example, rapid normalization of serum CA 125 levels following ovarian cancer treatment has favorable prognostic significance.

The next important application of tumor markers is in long-term follow-up of patients with previously diagnosed and treated cancer. Early detection of recurrent or metastatic disease can hasten intervention and improve outcomes. The tumor markers CA 15-3 (breast), CEA (colorectal), CA 125 (ovary), and PSA (prostate) are used in this context.

Finally, cancer research scientists seek improved diagnostic assays and clues to novel therapies. Tumor markers are an integral part of these efforts. For example, overexpression of fatty acid synthase was noted in several types of tumors. Subsequent efforts to inhibit the enzyme demonstrated this as a promising therapeutic modality.

Significant barriers exist to more extensive use of tumor markers in oncology. Primarily, the clinical value of the marker must be proven; that is, the result should trigger or remand a treatment decision that benefits patients, this benefit must be demonstrated in a large and rigorous trial, and the benefits must outweigh the costs of implementation and follow-up. After this is accomplished, oncologists must be convinced of the need to change their established practices by incorporating the marker.

Data analysis: After the patient obtains the appropriate material, several tumor-marker determination and data analysis options exist. The tumor-marker quantification method depends on the marker and the specimen, and the analysis method primarily depends on the form and amount of data present.

Serum protein markers are typically measured with specific antibody-based assays. The enzyme-linked immunosorbent assay (ELISA) is a popular immunoassay format that provides a numerical readout of the marker’s concentration. Protein markers can also be determined in tissue biopsy slices or individual cells by immunohistochemistry (IHC) or immunocytochemistry (ICC). In contrast to the ELISA, samples analyzed by IHC or ICC must be assessed visually to estimate tumor-marker abundance. However, IHC and ICC allow precise localization of the tumor marker within the cell. IHC and ICC are appropriate for tumor markers not shed into the extracellular space. Enzymes such as lactate dehydrogenase are sometimes employed as tumor markers. Their concentration is inferred from their catalytic activity. Highly complex protein mixtures in body fluids such as serum or urine can be analyzed by protein chips coupled with surface-enhanced laser desorption ionization/time-of-flight mass spectrometry (SELDI/TOF-MS). In this case, the relative abundance of hundreds to thousands of proteins in a sample is determined in a single run.

Tumor markers that are products expressed by genes (messenger ribonucleic acid, (mRNA) molecules) can be measured by the reverse transcriptase polymerase chain reaction (RT-PCR) or on a larger scale by oligonucleotide microarrays. In reverse transcriptase polymerase chain reaction, the mRNA sample is first reverse-transcribed into deoxyribonucleic acid (DNA), then amplified by standard polymerase chain reaction. Relative quantification is achieved by monitoring the abundance of the polymerase chain reaction products spectrophotometrically during the thermal cycling process. Messenger RNA-based tumor-marker assays can estimate the risk of breast cancer recurrence in women who are diagnosed with Stage I or II hormone-responsive cancer that has not spread to the surrounding lymph nodes. In this setting, the abundance of multiple transcripts in breast tumor tissue is determined by reverse transcriptase polymerase chain reaction.

Several methods can analyze tumor markers that exist as mutated or disrupted genes. Chromosomes can be inspected microscopically to confirm changes in genomic DNA. For example, abnormal amplification of MYCB (also known as N-myc) in neuroblastoma can be visualized as a homogenous staining region on chromosome 2p. Other tumor risk markers, such as mutated APC, can be detected through DNA sequencing or single-strand conformational polymorphism.

Tumor markers that exist as small organic compounds, such as 5-hydroxyindoleacetic acid (carcinoid tumors), are measured with chemical techniques such as high-performance liquid chromatography.

Results: Numerical results (concentrations) for single tumor markers can be interpreted only with knowledge of their normal concentration range and its sensitivity, specificity, and positive and negative predictive value for the tumor type. Also essential is knowledge of the tumor’s prevalence and the patient’s clinical history. Serial tumor-marker determinations offer additional information by demonstrating the tumor marker’s increase or decrease rate. In the case of PSA, a short time to doubling may prompt more concern than higher levels that remain steady. No single tumor marker reaches the ideal 100 percent sensitivity and specificity standards. Practitioners ultimately reject many proposed tumor markers because of unacceptably low sensitivity or specificity.

Results from multiplexed assays consist of patterns of individual data points that can yield more biologically relevant and clinically useful information than single markers. Analysis requires sophisticated and sometimes proprietary pattern-matching algorithms. For example, protein chips coupled with SELDI/TOF-MS have identified tumor-marker patterns that correctly classified individuals with and without early-stage ovarian cancer with high sensitivity and specificity. Gene expression chips (oligonucleotide microarrays) have also shown remarkable accuracy in identifying the primary sites of poorly differentiated metastatic lesions. Test results are highly reproducible and provide information to aid the physician and patient in making treatment decisions.

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