Nuclear morphometry as an intermediate endpoint biomarker in chemoprevention of cervical carcinoma using alpha-difluoromethylornithine

The use of nuclear morphometry as an intermediate endpoint biomarker is des cribed in a Phase I, dose-seeking trial of chemoprevention of cervical canc er, using the agent alpha-difluoromethylornithine (DFMO). Thirty patients w ith grade ill cervical intraepithelial neoplasia (CIN III) were enrolled, a nd these received daily doses of DFMO at 0.06-1.0 mg/m(2) for a period of 1 month. Fifteen patients were observed to have a complete or partial regres sive response to the agent, as assessed by histopathology. No significant d ifferences in cell feature measurements were found between responders and n onresponders in specimens obtained before treatment, indicating that it may be difficult to predict response on the basis of these measurements. In sp ecimens collected after treatment, large differences in morphometric featur es were observed between responders and nonresponders, indicating a differe ntial effect of DFMO. Significantly modulated features were considered in t erms of their correlations with CIN grade, which was determined from an ind ependent set of measurements from archival tissue. Differences between feat ures were consistent with a deletion of cells with high grade nuclei in the responders, and with the persistence of a more heterogeneous population of high grade cells in the nonresponders. Based on an independent set of meas urements from archival material, a morphometric index of progression was de rived, yielding a quantitative measure of the degree of nuclear atypia in t hese lesions. When applied to this trial, the morphometric index was seen t o be specifically and consistently decreased in responsive lesions, and unc hanged in nonresponders. The study indicates that morphometric features ful fill the requirements for an intermediate endpoint biomarker of cervical, c ancer chemoprevention. (C) 1999 Wiley-Liss, Inc.