Abstract

The fundamental understanding of carcinogenesis has increased thanks to our 10-year translational study using the oral premalignant lesion (OPL) model. Despite the fact that retinoids have demonstrated effectiveness in this paradigm,a significant portion of our OPL patients develop malignancy, particularly after treatment is stopped. We have created the first complete method for determining the cancer risk of OPL patients based on our 10-year OPL study. Cellular and molecular biomarkers, epidemiological parameters and medical/demographic factors are all included in this method for assessing cancer risk.

Seventy patients with advanced OPL were enrolled in a chemoprevention trial between 1988 and 1991 that involved an induction with high dose isotretinoin (1.5 mg/kg/day for three months), followed by nine months of maintenance treatment with either low dose isotretinoin (0.5 mg/kg/day) or -carotene (30 mg/d; total treatment time, one year).Using exploratory data analysis,logrank testing,Cox proportional hazard modelling,and recursive partitioning,we evaluated the connection between cancer risk variables and time to cancer development.

After treatment, upper aerodigestive tract malignancies appeared in 22 of our 70 patients (31.4%), with a median follow-up of 7 years. The annual incidence of cancer was 5.7%. OPL histology, cancer history, and three of the five biomarkers we evaluated are the most effective predictors of cancer risk (chromosomal polysomy, p53 protein expression, and loss of heterozygosity at chromosome 3p or 9p). The best predictors of the development of cancer in the multivariable Cox model are histology (P = 0.0003) and the combined biomarker score of chromosomal polysomy,p53, and loss of heterozygosity (P = 0.0008). Micronuclei and the retinoic acid receptor were not linked to an increased risk of developing cancer.

We have successfully illustrated a method for thoroughly evaluating cancer risk in OPL patients. A panel of three biomarkers and traditional medical/demographic factors can be combined to identify high risk patients in our sample.Future research will be required to confirm this finding. It is possible to develop more effective chemoprevention trials and molecular targeting studies with the identification of high risk patients.