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Biomarker end-points in cancer chemoprevention trials
1Chemoprevention Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Abstract:
Over the last decade, the Chemoprevention Branch, Division of Cancer Prevention and Control, National Cancer Institute, USA, has been developing drugs that will slow or stop the progression to invasive cancer of precancerous (pre-invasive) lesions generally termed 'intraepithelial dysplasia' or 'dysplasia'. Over 40 short-term clinical trials are in progress, testing the following classes of agents on precancerous lesions in the different major organ systems: antimutagens (N-acetylcysteine, oltipraz), antiproliferatives (difluoromethylornithine, dehydroepiandrosterone, selenomethionine), antioxidants (vitamin E, curcumin), anti-inflammatories (aspirin, piroxicam, ibuprofen, sulindac sulfone) and hormonally active agents (tamoxifen in breast ductal carcinoma in situ and finasteride in prostatic intraepithelial neoplasia). Because of the strong practical need to keep so many clinical trials as short-term as possible, certain tissue changes known to be associated with high cancer risk were selected for use as biomarker end-points in the trials, such changes being quantitatively assayed by computer-assisted image analysis. These 'surrogate end-point biomarkers' (SEBs) are based on the individual cellular morphological and functional changes universally used by histopathologists to diagnose the lesion of intraepithelial neoplasia (Riddell, 1984; Boone et al., 1992; Wright et al., 1994). High grades of this lesion precede invasive cancer in the great majority of cases, and therefore SEBs based on them are linked to high cancer risk. Table 1 summarizes some of the short-term clinical trials now being monitored by the Chemoprevention Branch. The SEBs abbreviated 'PPNN' in the figure are: proliferative index (P); ploidy (DNA histogram) (P); nuclear morphometry and chromatin texture (N); and nucleolar size and frequency (N). Computer-assisted image analysis is used to assay these features quantitatively, which gives the SEBs increased objectivity, reproducibility and sensitivity. Further details concerned with cancer chemoprevention trials using SEBs, and their relation to the field of cancer epidemiology, are given below.
Insights
Cancer chemoprevention trials are developing drugs to prevent invasive cancer from precancerous lesions. Surrogate end-point biomarkers (SEBs) like proliferative index and ploidy are used for rapid assessment in short-term clinical trials.
Area of Science:
- Oncology
- Preventive Medicine
- Biomarker Research
Background:
- Precancerous lesions, termed intraepithelial neoplasia, often precede invasive cancer.
- The National Cancer Institute's Chemoprevention Branch is developing drugs to halt cancer progression.
- Over 40 short-term clinical trials are underway to test various chemopreventive agents.
Purpose of the Study:
- To develop drugs that slow or stop the progression of pre-invasive lesions to invasive cancer.
- To utilize surrogate end-point biomarkers (SEBs) for efficient monitoring of short-term clinical trials.
- To validate computer-assisted image analysis for quantitative assessment of SEBs.
Main Methods:
- Testing diverse drug classes including antimutagens, antiproliferatives, antioxidants, anti-inflammatories, and hormonal agents.
- Employing computer-assisted image analysis to quantitatively assay cellular morphological and functional changes.
- Utilizing surrogate end-point biomarkers (SEBs) based on established histopathological criteria for intraepithelial neoplasia.
Main Results:
- Over 40 short-term clinical trials are actively monitoring precancerous lesions.
- SEBs, including proliferative index, ploidy, nuclear morphometry, chromatin texture, and nucleolar characteristics, are being quantitatively assayed.
- Computer-assisted analysis enhances objectivity, reproducibility, and sensitivity of SEB measurements.
Conclusions:
- SEBs provide a reliable method for assessing the efficacy of chemopreventive agents in short-term trials.
- Quantitative analysis of SEBs linked to high cancer risk aids in cancer prevention research.
- This approach facilitates the rapid development of drugs targeting precancerous lesions.