Role of tumor markers in patients with solid cancers: A critical review

doi:10.1016/j.ejim.2006.12.001

European Journal of Internal Medicine

Volume 18, Issue 3, May 2007, Pages 175-184

https://doi.org/10.1016/j.ejim.2006.12.001 Get rights and content

Abstract

The measurement of tumor markers is currently one of the most rapidly growing areas in laboratory medicine. Lack of sensitivity and specificity preclude the use of most existing markers for the early detection of malignancy. For patients with diagnosed malignancy, however, markers are potentially useful in determining prognosis, predicting therapeutic response, maintaining surveillance following curative surgery and monitoring therapy in advanced disease. Clinically useful markers include CEA in the surveillance of patients with diagnosed colorectal cancer, AFP and HCG in the management of patients with non-seminomatous germ cell tumors, HCG in the management of patients with trophoblastic disease, CA 125 for monitoring therapy in patients with ovarian cancer, estrogen receptors for predicting response to hormone therapy in breast cancer and HER-2 for the identification of women with breast cancer likely to respond to trastuzumab (Herceptin). Although widely used, the impact of PSA screening in reducing mortality from prostate cancer remains to be shown.

Introduction

A tumor marker can be defined as a molecule that indicates the likely presence of cancer or that provides information about the likely future behaviour of a cancer (e.g., ability to metastasise or to respond to therapy). Tumor markers are potentially useful in [1], [2]:

•
screening for early malignancy,
•
acting as a diagnostic aid for malignancy,
•
determining prognosis in malignancy,
•
predicting therapeutic efficacy,
•
maintaining surveillance following surgical removal of the primary tumor and
•
monitoring therapy in advanced malignancy.

The aim of this article is to provide a short overview of the uses and limitations of tumor markers in the above settings. The article will focus on both tissue and serum markers but will be confined to patients with solid tumors.

Section snippets

Screening for early malignancy

Lack of sensitivity for early malignancy and lack of specificity, combined with the low prevalence of most cancers in the general population, preclude the use of most existing tumor markers for screening asymptomatic subjects for early malignancy [3]. Despite these limitations, a number of tumor markers have either undergone or are currently undergoing evaluation as potential cancer screening tests. These markers include the use of vanillymandelic acid and homovanillic acid in screening for

Aiding cancer diagnosis

As with screening, lack of sensitivity and specificity generally preclude the use of tumor markers for the primary diagnosis of cancer. In certain situations, however, selected markers may aid detection. One of these situations is the diagnosis of tumors of unknown primary origin. Metastasis of unknown origin is defined as a metastasis for which the primary site remains occult despite obtaining a clinical history, physical examination, chest X-ray, routine analysis of blood and urine, along

Determining prognosis

For optimum patient management, reliable prognostic and predictive factors are necessary. Prognostic markers are factors that predict the likely outcome of disease in the absence of systemic adjuvant therapy [40]. In contrast, predictive markers are factors that are associated with either response or resistance to a specific therapy [40].

Traditional prognostic factors for malignancy include tumor size, tumor grade and number of local lymph nodes with metastasis. With few exceptions, tumor

Predicting response to therapy

Predictive markers are important in oncology as cancers vary widely in their response to therapy. Thus, for most types of cancer, only a minority of patients benefit from a particular form of systemic treatment. Being able to prospectively select those patients likely to respond would both save patients from unnecessary side effects and allow them to receive therapy that is more likely to be useful [66]. Furthermore, having accurate predictive markers would result in considerable cost savings.

Post-operative surveillance

One of the main uses of tumor markers at present is in the post-operative follow-up of patients with diagnosed malignancy (Table 4). This practice is based on the assumption that the early detection of recurrent or metastatic disease enhances the chance of cure or results in an improved survival. For many cancer types, however, the evidence currently available does not support this widely held assumption. Thus, although CEA and CA 15-3 are widely used in the surveillance of newly diagnosed

Monitoring therapy in advanced disease

As with post-operative surveillance, markers are frequently used to monitor treatment in patients with advanced cancer. Generally, the same marker or markers that are used in surveillance following curative surgery for the primary cancer are used for monitoring treatment in advanced disease. Consistently increasing levels suggesting treatment failure should result in discontinuation of ineffective therapy, switch to an alternative therapy or randomisation in trials investigating new therapies.

New technologies for the measurement of tumor markers

The traditional assays used for the measurement of tumor markers have been ELISA-type assays for serum markers and immunohistochemistry for tissue markers. With these techniques, only single or small numbers of markers can be detected simultaneously. Two new technologies, i.e., gene expression microarray and proteomics, however, have the potential to detect hundreds or thousands of markers simultaneously. Although these individual markers may be less sensitive and specific than existing

Conclusion

For the optimum management of patients with specific cancers, the use of tumor markers is now mandatory. Mandatory markers include ER and PR for predicting response to hormone therapy in breast cancer, HER-2 for identifying patients with breast cancer for treatment with trastuzumab, AFP and HCG in determining prognosis, surveillance and monitoring treatment in patients with non-seminomatous germ cell tumors, CEA in post-operative surveillance in patients with colorectal cancer, CA 125 in

Acknowledgement

This work was supported by grants from the Health Research Board of Ireland (Programme Grant, Breast Cancer Metastasis: Biomarkers and Functional Mediators) and the Irish Cancer Society.

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Review articleRole of tumor markers in patients with solid cancers: A critical review

Abstract

Introduction

Section snippets

Screening for early malignancy

Aiding cancer diagnosis

Determining prognosis

Predicting response to therapy

Post-operative surveillance

Monitoring therapy in advanced disease

New technologies for the measurement of tumor markers

Conclusion

Acknowledgement

Lancet

Gastroenterology

Lancet

Ann Oncol

J Urol

Clin Chim Acta

Ann Oncol

Eur Urol

Ann Oncol

Am J Med

Crit Rev Oncol Haematol

Urology

Clin Chim Acta

Urol Clin North Am

Ann Oncol

Eur J Cancer

Semin Oncol

Cancer Treat Rev

J Urol

Eur J Cancer

Clinical uses of tumor markers: a critical review

Crit Rev Clin Lab Sci

Serum tumor markers: past, state of the art and future

Int J Biol Markers

Limitations of tumor markers in screening

Br J Surg

Screening for hepatocellular carcinoma in high-risk individuals, a clinical review

Arch Intern Med

The performance of screening tests for ovarian cancer: results of a systematic review

Br J Obstet Gynaecol

Prostate-specific antigen: a review of the validation of the most commonly used cancer biomarker

Cancer

Estimation of prostatic growth using serial prostate-specific antigen measurements in men with and without prostate disease

Cancer Res

PSA as a marker for prostate cancer

Ann Clin Biochem

Effect of false-positive prostate cancer screening results on subsequent positive cancer screening behavior

Cancer Epidemiol Biomarkers Prev

Prevalence of prostate cancer among men with a prostate-specific antigen level < 4 ng per millilitre

N Engl J Med

Prostate cancers in men with low PSA levels, must we find them?

N Engl J Med

Pre- and post-analytical factors that may influence use of serum prostate specific antigen and its isoforms in a screening programme for prostate cancer

Ann Clin Biochem

Screening for prostate cancer (Review). The Cochrane Collaboration

Large-scale randomised prostate cancer screening trials: program performances in the European randomised screening for prostate cancer trial and the prostate, lung, colorectal and ovary cancer trial

Int J Cancer

The prostate, lung, colorectal and ovarian cancer screening trial of the National Cancer Institute

Cancer

American Cancer Society Guidelines for the Early Detection of Cancer

CA Cancer J Clin

Screening for prostate cancer: recommendations and rationale

Ann Intern Med

Tumor markers in prostate cancer: EGTM recommendations

Anticancer Res

Use of tumor markers to identify primary site of metastatic cancer

Br Med J

Tumor markers of unknown primary origin: a clinical perspective

Ann Clin Biochem

Differential diagnosis of ovarian cancer with tumour markers CA 125, CA 15-3, and TAG-72-3

Br J Obstet Gynaecol

Diagnostic value of pelvic examination,ultrasound and serum CA 125 in post-menopausal women with a pelvic mass

Cancer

CA 125 in ovarian cancer: European Group on Tumor Markers (EGTM) guidelines for clinical use

Int J Gynecol Cancer

Effect of surgeon specialty on processes of care and outcome for ovarian cancer patients

J Natl Cancer Inst

Review article
Role of tumor markers in patients with solid cancers: A critical review