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

Abstract

Ki-67 expression in ductal cells obtained by random periareolar fine needle aspiration (RPFNA) is currently being used as a response biomarker in phase II breast cancer chemoprevention trials; however, Ki-67 in RPFNA has not been well studied as a risk predictor for cancer, which would support its use as a response indicator. We examined the expression of Ki-67 in RPFNA specimens with hyperplasia F atypia obtained from 147 women at high risk for development of breast cancer. Median Ki-67 was 1.4% (range 0-24%). Ki-67 was higher in specimens from women <50 versus those z50 (median 2% versus 0.6%; P = 0.006) and from premenopausal women versus postmenopausal women (P = 0.037); however, hormone replacement therapy (predominately low-dose estrogen without progestins) had no effect. By univariate analysis, Ki-67 was positively correlated with ductal cell number (P = 0.001) and hyperplasia with atypia (P = 0.007). By multivariable analysis, the proportion of ductal cells expressing Ki-67 was again predicted by cell number, which, in turn, was predicted by cytologic atypia. The association of Ki-67 expression with cytologic atypia, a known risk factor for development of breast cancer, provides preliminary justification for its use as a response biomarker in phase II chemoprevention trials. (Cancer Epidemiol Biomarkers Prev 2005;14(4):786 -9)

Lipid Metabolism Genes in Contralateral Unaffected Breast and Estrogen Receptor Status of Breast Cancer

“…Until now rFNA samples have been used for immunohistochemistry (27,28) and DNA-based analyses (29)(30)(31)(32)(33)(34), although feasibility of gene expression measurement has been explored (35). Considering the topographic heterogeneity in the breast, rFNA sampling is a useful tool for the discovery of breast cancer risk biomarkers; it provides a predominantly epithelial sample from a large area of the breast and allows the evaluation of women with clinically normal breasts, therefore greatly expanding the population for study, and eventual application of results.…”

Breast-tissue sampling for risk assessment and prevention

“…A no-treatment control (either randomized or non-randomized) may be used as well to determine the effect of biopsy and other influences (such as stopping HRT) on the biomarkers being assessed. Generally, a proliferation biomarker such as Ki-67 is used as the primary endpoint and 8-12 subjects are entered at each dose level (Fabian et al 2004a(Fabian et al , 2005. In Phase IB, the dose(s) from Phase IA which have shown favorable modulation in 80% of subjects is chosen and subjects are randomized to study (Decensi et al 2003, Fabian et al 2004a.…”

“…Two models have been proposed in this regard which would facilitate sample-size estimation and statistical analysis. These have been termed the prevention-of-progression and reversal-of-atypia models , Fabian et al 2005). …”

“…7). Even if up to 25% of subjects randomized to placebo showed atypia in the follow-up sample, a 50% reduction in the incidence of hyperpalsia with atypia could be detected in 335 subjects, with 80% power and a 5% type I error rate (Fabian et al 2005). Approximately 670 high-risk subjects would have to be screened by RPNA for this type of trial design.…”

“…Detection of a 50% reduction in the proportion of cells expressing Ki-67 would require approximately 50 subjects in each arm, assuming a median Ki-67 of 3.5% at baseline and a standard deviation of a similar value, with 80% power and a 5% type I error rate. Detecting a 33% reduction in proliferation would require approximately 200 subjects (Fabian et al 2005). These are theoretical estimates as studies assessing the variability of Ki-67 in postmenopausal women or premenopausal women in the same phase of the menstrual cycle over 6-12 months have not yet been performed.…”