BREAST CYTOLOGY AND BIOMARKERS OBTAINED BY RANDOM FINE-NEEDLE ASPIRATION - USE IN RISK ASSESSMENT AND EARLY CHEMOPREVENTION TRIALS

In a prospective pilot study, we performed breast fine needle aspirati ons (FNAs) on 224 high-risk and 30 low-risk women and analyzed these a spirates for cytologic changes and biomarker abnormalities of aneuploi dy and overexpressed estrogen receptor (ER), epidermal growth factor r eceptor (EGFR), p53 and HER-2/neu. High-risk women had a first-degree relative with breast cancer (74%), prior biopsy indicating premalignan t breast disease (25%), a history of breast cancer (13%), or some mult iple of these risk factors (12%). Median ages of the high-and low-risk groups were 44 and 42, respectively. Seventy percent of high-risk and 17% of low-risk women had cytologic evidence of hyperplasia with or w ithout atypia (P < .0001). Aneuploidy and overexpression of EGFR and p 53 occurred in 27, 37, and 29% of high-risk subjects but only 0, 3, an d 3% of low-risk subjects (P < .0023). Overexpression of ER and HER-2/ neu occurred in 7 and 20% of high-risk women but in none of the low-ri sk subjects. Biomarker abnormalities were more frequent with increasin g cytologic abnormality. Restricting the analysis to those 3 biomarker s most frequently overexpressed in the high-risk group (ploidy, EGFR, p53), 13% of high-risk women with normal cytology, 19% of high-risk wo men with epithelial hyperplasia, and 49% of high-risk women with hyper plasia with atypia had abnormalities of 2 or more of these 3 biomarker s (P = .00004). At a median follow-up of 32 months, four women have be en diagnosed with invasive cancer and two with ductal carcinoma in sit u (DCIS). Later detection of these neoplastic conditions was associate d (P less than or equal to .016) by univariate analysis with prior FNA evidence of hyperplasia with atypia; overexpression of p53 and EGFR; the modified Gall risk of breast cancer development at 10 years; and m ultiple biomarker abnormalities. By multivariate analysis, later detec tion of cancer was primarily predicted by the number of biomarker abno rmalities in the S-test battery (P = .0005) and secondarily by the cal l risk at 10 years (P = .0049). In turn, hyperplasia with atypia was a ssociated with multiple biomarker abnormalities, particularly p53 and EGFR overexpression. Thus, hyperplasia with atypia and cytologic marke rs in breast FNAs have promise as risk predictors and as surrogate end point biomarkers for breast cancer chemoprevention trials. (C) 1998 Wi ley-Liss, Inc.