Fabian C J, Kamel S, Zalles C, Kimler B F
Division of Clinical Oncology, University of Kansas Medical Center, Kansas City 66160-7820, USA.
J Cell Biochem Suppl. 1996;25:112-22.
In a prospective pilot study, we performed breast fine needle aspirations (FNAs) on 213 high-risk and 30 low-risk women and analyzed these aspirates for cytologic changes and biomarker abnormalities of aneuploidy and overexpressed estrogen receptor (ER), epidermal growth factor receptor (EGFR), p53 and HER-2/neu. High-risk women were those with a first degree relative with breast cancer (73%), prior biopsy indicating premalignant breast disease (26%), a history of breast cancer (13%), or some multiple of these risk factors (11%). Median ages of the high-risk and low-risk groups were 44 and 42, respectively. Sixty-three percent of the high-risk and 73% of the low-risk group were premenopausal. Sixty-eight percent of the high-risk and 17% of low-risk women had cytologic evidence of hyperplasia with or without atypia (P < .0001). Aneuploidy and overexpression of EGFR and p53 occurred in 25%, 36%, and 28% of high-risk subjects but in less than 4% of low-risk subjects (P < .0002). Overexpression of ER and HER-2/neu occurred in 8% and 19%, respectively of high-risk women; nc low-risk women had these abnormalities. Sixty-eight percent of high-risk women and 7% of low-risk women had abnormalities of one or more of these biomarkers exclusive of cytology. Thirty-one percent of high-risk women, but no low-risk women had abnormalities of two or more biomarkers (P = .0004). Biomarker abnormalities were more frequent with increasing cytologic abnormality. Eighteen percent of women with normal cytology, 29% of women with epithelial hyperplasia and 60% of women with hyperplasia with atypia had abnormalities of two or more biomarkers (P = .048 and < .0001, respectively). Restricting the analysis to those three biomarkers most frequently overexpressed in the high-risk group (ploidy, EGFR, p53), 13% of high-risk women with normal cytology, 20% of high-risk women with epithelial hyperplasia and 51% of high-risk women with atypical hyperplasia had abnormalities of 2 or more of these 3 biomarkers. At a median follow up of two years, 8 of 213 women have been diagnosed with in situ (n = 5) or invasive (n = 3) cancer. Later detection of neoplasia was associated with prior FNA evidence of atypical hyperplasia (P < .0001) and multiple biomarker abnormalities in the 5 test battery (P = .006) by univariate analysis. By multivariate analysis, development and/or detection of cancer was primarily predicted by atypical hyperplasia (P = .0047) and secondarily by multiple biomarker abnormalities (P = 0.021). Atypical hyperplasia, EGFR, and p53 in breast FNAs have promise as risk markers and as surrogate endpoint biomarkers for breast cancer chemoprevention trials.
在一项前瞻性试点研究中，我们对213名高危女性和30名低危女性进行了乳房细针穿刺抽吸术（FNA），并分析这些抽吸物的细胞变化以及非整倍体和雌激素受体（ER）、表皮生长因子受体（EGFR）、p53和HER-2/neu过表达的生物标志物异常情况。高危女性为有乳腺癌一级亲属的女性（73%）、先前活检显示为癌前乳腺疾病的女性（26%）、有乳腺癌病史的女性（13%）或具有这些风险因素中某些组合的女性（11%）。高危组和低危组的中位年龄分别为44岁和42岁。高危组63%的女性和低危组73%的女性处于绝经前。高危组68%的女性和低危组17%的女性有细胞学证据显示有增生，伴或不伴异型性（P <.0001）。高危组中25%、36%和28%的女性出现非整倍体以及EGFR和p53过表达，但低危组中出现这些情况的女性不到4%（P <.0002）。高危组女性中ER和HER-2/neu过表达的发生率分别为8%和19%；低危组女性无这些异常情况。68%的高危女性和7%的低危女性有这些生物标志物中一种或多种的异常情况（不包括细胞学异常）。31%的高危女性有两种或更多生物标志物异常，但低危组女性无此情况（P =.0004）。随着细胞学异常程度增加，生物标志物异常情况更常见。细胞学正常的女性中有18%、上皮增生的女性中有29%以及伴有异型性增生的女性中有60%有两种或更多生物标志物异常（P分别为.048和<.0001）。将分析局限于高危组中最常出现过表达的三种生物标志物（倍体、EGFR、p53），细胞学正常的高危女性中有13%、上皮增生的高危女性中有20%以及非典型增生的高危女性中有51%有这三种生物标志物中两种或更多的异常情况。在中位随访两年时，213名女性中有8名被诊断为原位癌（n = 5）或浸润癌（n = 3）。通过单因素分析，肿瘤的较晚发现与先前FNA显示的非典型增生证据（P <.0001）以及五项检测指标中多种生物标志物异常（P =.006）相关。通过多因素分析，癌症的发生和/或发现主要由非典型增生预测（P =.0047），其次由多种生物标志物异常预测（P = 0.021）。乳房FNA中的非典型增生、EGFR和p53有望作为风险标志物以及乳腺癌化学预防试验的替代终点生物标志物。
