Seventy-eight examples of intraductal carcinoma (DCIS) were identified after pathologic review of 2072 specimens obtained from National Surgical Adjuvant Breast Project protocol 6. This randomized clinical trial compares the therapeutic merit of total mastectomy (TM) with lumpectomy (L), with (LX) and without (LO) postoperative irradiation. All patients were subjected to axillary lymph node dissection. Seven (14%) of the 51 patients with DCIS treated by L exhibited breast recurrence within or close to the site of the initial lesion 4 to 53 months (average, 16 months) after L. Only 2 (7%) of these events occurred in the 29 women treated by LX, as opposed to 23% in the LO group. No pathologic features were noticed that might have been considered predictive of local breast recurrence. The three DCIS recurrences and the four invasive forms noted are considered to represent overlooked or incompletely excised foci of cancer because of the multifocality (not multicentricity) of some breast cancers. The possibility that DCIS may represent a marker of risk for the development of cancer rather than a precursor lesion per se is suggested. Despite apparent difficulties in the pathologic diagnosis of DCIS as well as uncertainty concerning its natural history, no evidence was found to indicate that it represents a more ominous disease than invasive cancer. Indeed, treatment failure occurred in only one patient treated by LX and a similar number subjected to TM (4% versus 2%). Although these observations are short term (average follow-up, 39 months), estimates of the probability of local recurrence or survival suggest that they will not be significantly altered after longer periods of surveillance. Thus, there are no compelling reasons why DCIS may not be treated in a cosmetically acceptable manner by LX. A randomized clinical trial addressing this issue is now in progress.

Pathologic findings from the National Surgical Adjuvant Breast Project (protocol 6). I. Intraductal carcinoma (DCIS)

Background: Biomarkers are needed to refine short-term breast cancer risk estimates from epidemiologic models and to measure response to prevention interventions. The purpose of our study was to determine whether the cytologic appearance of epithelial cells obtained from breast random periareolar fine-needle aspirates or molecular marker expression in these cells was associated with later breast cancer development. Methods: Four hundred eighty women who were eligible on the basis of a family history of breast cancer, prior precancerous biopsy, and/or prior invasive cancer were enrolled in a single-institution, prospective trial. Their risk of breast cancer according to the Gail model was calculated, and random periareolar fine-needle aspiration was performed at study entry. Cells were characterized morphologically and analyzed for DNA aneuploidy by image analysis and for the expression of epidermal growth factor receptor, estrogen receptor, p53 protein, and HER2/NEU protein by immunocytochemistry. All statistical tests are two-sided. Results: At a median follow-up time of 45 months after initial aspiration, 20 women have developed breast cancer (invasive disease in 13 and ductal carcinoma in situ in seven). With the use of multiple logistic regression and Cox proportional hazards analysis, subsequent cancer was predicted by evidence of hyperplasia with atypia in the initial fine-needle aspirate and a 10-year Gail projected probability of developing breast cancer. Although expression of epidermal growth factor receptor, estrogen receptor, p53, and HER2/NEU was statistically significantly associated with hyperplasia with atypia, it did not predict the development of breast cancer in multivariable analysis. Conclusion: Cytomorphology from breast random periareolar fine-needle aspirates can be used with the Gail risk model to identify a cohort of women at very high short-term risk for developing breast cancer. We recommend that cytomorphology be studied for use as a potential surrogate end point in prevention trials. [J Natl Cancer Inst 2000;92:1217–27]

/pdf/short-term-breast-cancer-prediction-by-random-periareolar-23i9jx5ndz.pdf

Short-Term Breast Cancer Prediction by Random Periareolar Fine-Needle Aspiration Cytology and the Gail Risk Model

Among the most important targets for chemopreventive intervention and drug development are deregulated signal transduction pathways, and protein tyrosine kinases are key components of these pathways. Loss of tyrosine kinase regulatory mechanisms has been implicated in neoplastic growth; indeed, many oncogenes code for either receptor or cellular tyrosine kinases. Because of its deregulation in many cancers (bladder, breast, cervix, colon, esophagus, head and neck, lung, and prostate), the epidermal growth factor receptor (EGFR) has been selected as a potential target for chemoprevention. Because growth factor networks are redundant, selective inhibition of signaling pathways activated in precancerous and cancerous cells should be possible. Requirements for specific EGFR inhibitors include specificity for EGFR, high potency, activity in intact cells, and activity in vivo. Inhibition of autophosphorylation is preferred, because it should result in total blockade of the signaling pathway. Inhibitors that compete with substrate rather than at the ATP-binding site are also preferable, because they are not as likely to inhibit other ATP-using cellular enzymes. Several classes of specific EGFR inhibitors have been synthesized recently, including structures such as benzylidene malononitriles, dianilinophthalimides, quinazolines, pyrimidines, [(alkylamino)methyl]-acrylophenones, enollactones, dihydroxybenzylaminosalicylates, 2-thioindoles, aminoflavones, and tyrosine analogue-containing peptides. A possible testing strategy for the development of these and other EGFR inhibitors as chemopreventive agents includes the following steps: (a) determine EGFR tyrosine kinase inhibitory activity in vitro; (b) evaluate EGFR specificity and selectivity (relative to other tyrosine kinases and other protein kinases); (c) determine inhibition of EGFR-mediated effects in intact cells; (d) determine inhibition of EGFR-mediated effects in vivo (e.g., in nude mouse tumor xenografts); and (e) determine chemopreventive efficacy in vivo (e.g., in the hamster buccal pouch or mouse or rat bladder).

/pdf/epidermal-growth-factor-receptor-tyrosine-kinase-inhibitors-3ubs7vfswk.pdf

Epidermal growth factor receptor tyrosine kinase inhibitors as potential cancer chemopreventives.

Breast tissue and duct fluid provide a rich source of biomarkers to both aid in the assessment of shortterm risk of developing breast cancer and predict and assess responses to prevention interventions. There are three methods currently being utilized to sample breast tissue in asymptomatic women for risk assessment: nipple-aspirate fluid (NAF), random periareolar fine-needle aspiration (RPFNA) and ductal lavage. Prospective single-institution trials have shown that the presence of atypical cells in NAF fluid or RPFNA specimens is associated with an increased risk of breast cancer. Furthermore, RPFNA-detected atypia has been observed to further stratify risk based on the commonly used Gail risk-assessment model. A prospective trial evaluating risk prediction on the basis of atypical cells in ductal-lavage fluid is ongoing. The ability of other established non-genetic biomarkers (mammographic breast density; serum levels of bioavailable estradiol, testosterone, insulin-like growth factor1 and its insulin like growth factor binding protein-3) to stratify risk based on the Gail model is as yet incompletely defined. Modulation of breast intra-epithelial neoplasia (i.e. hyperplasia with or without atypia) with or without associated breast-tissue molecular markers, such as proliferation, is currently being used to evaluate response in Phase II chemoprevention trials. RPFNA has been the method most frequently used for Phase II studies of 6‐12months duration. However, ductal lavage, RPFNA and random and directed core needle biopsies are all being utilized in ongoing multi-institutional Phase II studies. The strengths and weaknesses of each method are reviewed.

/pdf/breast-tissue-sampling-for-risk-assessment-and-prevention-dhtvhms5n0.pdf

Breast-tissue sampling for risk assessment and prevention

The role of estrogen and the estrogen receptor (ER) in the induction and promotion of tumors was investigated by using transgenic MT-mER mice, which overexpress the ER. It was hypothesized that because of this abnormal expression of the ER, the reproductive-tract tissues of the MT-mER mice may be more susceptible to tumors after neonatal exposure to the potent synthetic estrogen diethylstilbestrol (DES). Normally non-estrogen responsive tissues that may have expressed ER as a result of the transgene were also studied for DES-induced tumors. Wild-type and MT-mER littermates were treated with 2 micrograms/pup/d DES 1-5 d after birth and then killed at 4, 8, 12, and 18 mo of age. The DES-treated MT-mER mice demonstrated a significantly higher incidence of uterine adenocarcinoma at 8 mo (73%) than the DES-treated wild-type mice (46%). The tumors of the MT-mER mice were often more aggressive than those in the wild-type animals. These tumors were also preceeded at 4 mo by a significantly higher incidence of the preneoplastic lesion atypical hyperplasia in the MT-mER mice (26% compared with 0% in the wild-type mice). Other DES-induced abnormalities were observed at equal rates in the wild-type and MT-mER mice. Although no tumors were observed in untreated wild-type females, a single untreated MT-mER female had uterine adenocarcinoma at 18 mo. These data indicate that the level of ER present in a tissue may also be a determining factor in development of estrogen-responsive tumors.

Accelerated onset of uterine tumors in transgenic mice with aberrant expression of the estrogen receptor after neonatal exposure to diethylstilbestrol

Breast tissue biomarkers which accurately predict breast cancer development within a 10 year period in high risk women are needed but currently not available. We initiated this study to determine 1) the prevalence of one or more breast tissue abnormalities in a group of women at high risk for breast cancer, and 2) if the prevalence of biomarker abnormalities is greater in high risk than in low risk women. Eligible high risk women were those with a first degree relative with breast cancer, prior breast cancer, or precancerous mastopathy. Low risk women were those without these or other major identifiable risk factors. Ductal cells were obtained via random fine needle aspirations and cytologically classified. Biomarkers included DNA ploidy, estrogen receptor (ER), and epidermal growth factor receptor (EGFR). The prevalence of DNA aneuploidy was 30%, overexpression of ER 10%, and overexpression of EGFR 35%, in the 206 high risk women whose median 10 year Gail risk (projected probability) of developing breast cancer was 4.5%. The prevalence of aneuploidy and overexpressed EGFR was significantly higher in the high risk women than in the 25 low risk controls (p < 0.002), whose median 10 year Gail risk was 0.7%. The difference in the prevalence of ER overexpression between high and low risk groups was not statistically significant (p = 0.095). This may be due to the low prevalence of overexpressed ER and the small number of controls. A significant difference was noted in the prevalence of one or more abnormal biomarkers between the high risk and low risk women (p < 0.001). A large prospective trial is needed to determine if one or more of these biomarkers, is predictive of breast cancer development.

Prevalence of aneuploidy, overexpressed ER, and overexpressed EGFR in random breast aspirates of women at high and low risk for breast cancer.

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Prevalence of aneuploidy, overexpressed ER, and overexpressed EGFR in random breast aspirates of women at high and low risk for breast cancer.