Letters to the Editor Ki-67 Expression in Benign Breast Ductal Cells Obtained by Random Periareolar Fine Needle Aspiration

To the Editors: Robust and reversible biomarkers are needed for the successful completion of phase II prevention trials, an area where Fabian and colleagues have made enormous contributions. One potential marker is cell proliferation, measured by Ki-67 labeling; Khan et al. present data obtained by random periareolar fine-needle aspiration in 147 women at high-risk, which they interpret as providing preliminary support for use of Ki-67 as a response biomarker in prevention trials (1). They base this on an association between morphologically defined hyperplasia with atypia, and Ki-67 labeling index. These results are based on a single random periareolar fine-needle aspiration procedure, so that a key attribute of a useful biomarker (reproducibility; ref. 2) remains untested. Our experience at Northwestern University using ductal lavage for similar analyses has both similarities and differences to these data. In an ongoing phase II chemoprevention study with tamoxifen as the intervention agent, we found a mean Ki67 labeling index in ductal lavage samples of 0.72% (based on results from 117 women with >100 cells at baseline lavage). Although we observed a good correlation of Ki-67 labeling index with total epithelial cell yield (P = 0.001), no correlation was seen with cytological atypia. In agreement with Khan et al., we see a very strong correlation between cytology and total cell number, and note with interest that when Khan et al. performed a multivariate analysis to predict Ki-67 expression, a significant correlation of Ki-67 with cytomorphology was seen only after cell number was excluded from the analysis. This, together with our own findings in relation to the correlation of cell number with biomarkers such as endoplasmic reticulum, cyclooxygenase-2, and Ki-67 expression, suggests that epithelial cell yield is at least as good a biomarker of response to preventive intervention as Ki-67 labeling. We have compared the mean Ki-67 labeling index in women who did not take tamoxifen with those who accepted tamoxifen therapy, at baseline and 6 months later. In the no-intervention group, Ki-67 labeling index dropped from 0.73 to 0.27 (P = 0.003) while in the tamoxifen group, comparable values were 0.55 and 0.37 (P = 0.35; ref. 3). In phase Ia and Ib studies of women with hormone receptor– positive breast cancer, Fabian et al. found no significant difference in Ki-67 labeling, although proliferating cell nuclear antigen–labeled cells decreased significantly following arzoxifene intervention (4). Considering these results together, we remain skeptical whether parameters such as Ki-67 labeling and morphological atypia are robust and reproducible indicators of response.