Identification of a chemoprevention cohort from a population of women at high risk for breast cancer

Abstract

In a prospective pilot study, we performed breast fine needle aspirations (FNAs) on 21 3 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 (ECFR), p53 and HER-2lneu. 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 (1 3%), or some multiple of these risk factors (1 1 %). 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 1 7% 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-2lneuoccurred in 8% and 1 respectively of high-risk women; no 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 cytcilogy. Thirty-one percent of high-risk women, but no low-risk women had abnormalities of two or more biomarkers IP = ,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 atypi,] 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, ECFR, p53), 13% of high-risk women with normal cytology, 20% of high-risk women with epithelial hyperplasia and 51 YO 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 21 3 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 biornarker abnormalities in the 5 test battery ( P = ,006) by univariate analysis. By multivariate analysis, development andlor 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 kireast cancer chemoprevention trials.

p53 Alterations and Protein Accumulation in Benign Breast Tissue and Breast Cancer Risk: A Cohort Study

“…There have been three previous follow-up studies of p53 protein accumulation in benign breast tissue in relation to risk of subsequent breast cancer: one showed no association between p53 protein accumulation and risk of breast cancer (20); another (42) suggested that p53, when evaluated as part of a group of biomarkers, might be associated with risk; and in a previous study based on a subset of the subjects included in the present report, we showed that p53 protein accumulation in benign breast tissue was associated with a 2.5-fold increase in the risk of subsequent breast cancer (28). However, the first two of these studies were small and adjusted for confounding either incompletely (42) or not at all (20).…”

“…However, the first two of these studies were small and adjusted for confounding either incompletely (42) or not at all (20). Furthermore, all of these studies used immunohistochemistry to detect p53 protein accumulation, which may have resulted in underascertainment of p53 changes.…”

“…Future studies should be large (which would allow assessment of effect modification by factors, such as menopausal status), should assess both p53 immunopositivity and mutation status, and should use state-of-the-art methods for p53 mutation detection. Although the present report involved the use of paraffin-embedded breast tissue, the analyses described herein can also be done on tissue obtained from needle biopsies and on cells obtained from fine-needle aspirates of the breast, both of which are done increasingly commonly nowadays (42,(51)(52)(53). If confirmed, the findings reported here might facilitate the development of new approaches both to the detection of women at increased risk of breast cancer and to their clinical management [e.g., by enabling chemoprevention or therapy to restore p53 function (54) to be targeted to specific subgroups of women].…”

14-3-3ζ Down-regulates p53 in Mammary Epithelial Cells and Confers Luminal Filling

“…Accumulation of p53, which typically indicates a loss of p53 function due to p53 mutation, is associated with increased risk of progression of early-stage, benign breast disease to breast cancer (21,22), and mutations that compromise p53 function are found in f50% of human cancers (23). p53 is up-regulated during cellular stress and induces expression of genes that control cell cycle progression and programmed cell death.…”

CREB-binding protein regulates apoptosis and growth of HMECs grown in reconstituted ECM via laminin-5

“…Carcinogenesis is hypothesized to be a multistep process resulting from the progressive accumulation of genetic damage. Although loss or mutation of specific tumor suppressor genes such as TP53 promotes mammary carcinogenesis (Fabian et al, 1996;Rohan et al, 1998), not all damaged epithelial cells progress to malignancy and many are thought to be eliminated by apoptosis (Thompson, 1995). Mammary gland homeostasis requires a coordinated balanced between proliferation and programmed cell death.…”