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Biomarkers in upper aerodigestive tract tumorigenesis: a review
D M Shin1, W N Hittelman, W K Hong
1Department of Thoracic/Head and Neck Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston 77030.
Abstract:
Because therapeutic efforts such as surgery, radiotherapy, and chemotherapy have only marginally improved the 5-year survival rate from cancers of the upper aerodigestive tract (including head and neck and lung cancers) over the past 2 decades, chemoprevention has become an important strategy in reducing the rates of incidence and mortality of these cancers. However, chemoprevention trials have been hampered by serious feasibility problems; they require large numbers of subjects and long-term follow-up for accurate determination of cancer incidence and they are very costly. Because the use of intermediate end points would reduce the duration and costs of these studies, biomarkers that could serve as such end points have recently become a subject of great interest. With the strengthening of the assumption that tumorigenesis is a multistep process of transformation from normal tissues to malignant lesions, there has been a great effort to examine each of these steps for genetic and/or phenotypic alterations that might be candidates for such biomarkers. These candidates include genomic markers, certain specific gene alterations, such as tumor suppressor genes, oncogenes, growth factors and their receptors, proliferation markers, and differentiation markers. In this review, we describe several genomic markers, including micronuclei, chromosomal alterations, and specific genetic markers, e.g., the ras gene family, erb B1, int-2/hst-1, and p53 tumor suppressor gene. We also review the proliferation markers, including proliferating cell nuclear antigen, and squamous cell differentiation markers, including keratins, involucrin, and transglutaminase 1. These biomarker candidates have the potential to be important adjuncts to the development of new chemopreventive agents and to the rational design of future intervention trials. However, we can not overemphasize that these markers need to be validated in clinical trials; only then can they replace cancer incidence as the sole end point for chemoprevention trials.
Insights
Chemoprevention is crucial for reducing upper aerodigestive tract cancer rates. Biomarkers like genetic alterations and proliferation markers can improve clinical trials, but require validation.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Therapeutic advances for upper aerodigestive tract cancers show limited survival improvement.
- Chemoprevention offers a strategy to reduce cancer incidence and mortality.
- Current chemoprevention trials face feasibility issues like large cohorts and long follow-up.
Purpose of the Study:
- To explore the potential of biomarkers as intermediate endpoints in cancer chemoprevention trials.
- To identify and review candidate biomarkers for upper aerodigestive tract cancers.
- To discuss the role of these biomarkers in developing chemopreventive agents and designing trials.
Main Methods:
- Review of existing literature on biomarkers for cancer chemoprevention.
- Identification of genomic, proliferation, and differentiation markers.
- Discussion of specific genetic alterations (e.g., ras, p53) and protein markers (e.g., PCNA, keratins).
Main Results:
- Several genomic markers (micronuclei, chromosomal alterations, ras gene family, p53) show promise.
- Proliferation markers (proliferating cell nuclear antigen) and differentiation markers (keratins) are discussed.
- These biomarkers can potentially shorten and reduce the cost of chemoprevention studies.
Conclusions:
- Biomarker candidates have the potential to aid in developing chemopreventive agents.
- Validated biomarkers could serve as crucial intermediate endpoints in future intervention trials.
- Clinical validation is essential before biomarkers can replace cancer incidence as the sole trial endpoint.