EDITORIALS

Predicting Breast Cancer: the Search for a Model

Mary B. Daly, Eric A. Ross

Affiliation of authors: Division of Population Science, Fox Chase Cancer Center, Philadelphia, PA.

Correspondence to: Mary B. Daly, M.D., Ph.D., Division of Population Science, Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111 (e-mail: mb_daly{at}fccc.edu).

The recent success of the National Surgical Adjuvant Breast and Bowel Project (NSABP) tamoxifen chemoprevention trial (1) and the increasing availability of novel agents targeting the early stages of carcinogenesis have resulted in a renewed interest in chemoprevention, in general, and in the need to more accurately assess cancer risk to identify appropriate candidates for participation in cancer prevention trials and to monitor early preclinical events. In the case of breast cancer, the epidemiologic literature is replete with studies describing various demographic, reproductive, and medical factors associated with risk. These risk factors have been quantified in a mathematical model developed by Gail et al. (2), which predicts the risk for breast cancer on the basis of age, race, age at menarche, parity, family history of breast cancer, and history of breast biopsies. This model served as the basis for determining eligibility for the NSABP tamoxifen chemoprevention trial and is now being used clinically to identify women who would benefit from tamoxifen for risk reduction. Although extremely useful in clinical decision-making, the Gail model does little to elucidate the molecular events that culminate in cancer, and it is not useful in the evaluation of novel agents for their chemopreventive properties, for which we need biologic end points.

Our understanding of the biologic progression of breast epithelium from normal cells to cancer, however, has been impeded by the inaccessibility of the "at-risk" tissue for routine surveillance. Unlike the case of colon cancer, where serial sampling of the surface epithelium has produced a model of colon carcinogenesis in which the chronologic progression of molecular and genetic events has been identified, our current model of the biologic progression of breast cancer is based mainly on pathologic material from women undergoing diagnostic procedures. These studies have identified a number of histologic patterns, such as atypical hyperplasia and lobular carcinoma in situ, that predict an increased risk for breast cancer (3, 4), and a series of prognostic features, such as estrogen receptor status, that predict survival from breast cancer and/or response to therapy (5). Because access to breast tissue has been confined to the diagnostic setting, however, the full sequence and spectrum of events that accompany the carcinogenic process are still unclear, and a means of monitoring these changes has been lacking.

During the last 40 years, several groups have explored the use of nipple aspirate fluid as a means of monitoring the breast epithelium and the glandular microenvironment for early premalignant changes. The finding of cytologic epithelial hyperplasia and/or atypia in nipple aspirate fluid has been shown to increase the risk for breast cancer up to sixfold. Nipple aspirate fluid also contains a variety of biochemical components of breast tissue, including immunoglobulins, lipids, fatty acids, steroid hormones, peptide growth factors, and tumor biomarkers (68). Use of this technique has been limited in the past by failure to obtain fluid in 40%–60% of attempts and the absence of epithelial cells in some specimens. However, modifications in technique and repeated sampling have resulted more recently in yields of cellular fluid in approximately 90% of subjects (9).

In this issue of the Journal, Fabian et al. (10) report their findings on the use of a more invasive procedure, random periareolar fine-needle aspiration of the breast in high-risk premenopausal and perimenopausal women to identify surrogate end point biomarkers. Women at increased risk for breast cancer as defined by family history of breast cancer or personal history of premalignant or malignant disease of the breast underwent serial random fine-needle aspirations of the breast at the periareolar margin. The fluid obtained was pooled and examined for cytologic abnormalities and expression of a series of molecular biomarkers (estrogen receptor, p53 protein, and HER2/NEU protein). Gail model scores were also calculated from family and personal history data. The women were subsequently followed (median follow-up = 45 months) for the development of breast cancer. Fabian et al. report successful cytologic assessment of the fluid in a high percentage of women in their sample. Proliferative cytology, with or without atypia, was found in 70%. The presence of epithelial hyperplasia with atypia was associated with the expression of multiple biomarkers. However, as predictors of cancer development, only the Gail model and the presence of hyperplasia with atypia remained in multivariable analysis. The authors conclude that cytomorphology coupled with the Gail model can identify a cohort of women at high risk for breast cancer development, and they recommend the use of cytomorphology as a surrogate end point in clinical prevention trials.

The strengths of the study by Fabian et al. (10) are the yield of cellular specimens from more than 90% of the sample, the effort to minimize intraobserver variance in cytologic evaluation, the relatively high success rate in obtaining molecular marker assessment, and the ongoing attempt to determine clinical follow-up status. The failure to identify an independent predictive value for any of the molecular markers suggests that, although individual markers are relevant to the carcinogenic process, the final common pathway is the development of cytologic abnormalities. To abandon the search for early molecular events and to focus solely on cytologic end points, however, bypass those pieces of the puzzle most likely to improve our basic understanding of breast cancer development and most likely to provide targets for novel chemopreventive agents. Other limitations of this study include the heterogeneity of the women in the study sample, some of whom may have already been exposed to systemic hormonal and/or chemotherapeutic agents, and the absence of information on screening status, an important variable in determining the predictive value of the Gail model.

Are we ready, therefore, to adopt random periareolar fine-needle aspiration as the technology of choice for determining breast cancer risk and for monitoring response to preventive interventions? The surgical practice of mirror image random biopsies in the setting of lobular carcinoma in situ has been largely abandoned for lack of clinical usefulness. The similar concept of random periareolar fine-needle aspiration assumes that early premalignant changes in breast epithelium constitute a "field" effect, although many would argue for a process where changes are confined to a genetically altered "clone" of cells, in which case the proposed approach would lack sensitivity. As Fabian et al. (10) correctly point out, to be broadly applicable as a surrogate end point biomarker, cytologic evaluation must first be quantitated and standardized, and efforts are already under way to accomplish this. However, the question of how to manage women who exhibit suspicious cytologic changes must also be addressed and a standard clinical strategy must be developed. The authors raise caution in applying the approach beyond a young, high-risk population, thus eliminating the majority of women at risk for breast cancer. Despite these limitations, the current study provides evidence that, in the hands of experienced investigators, this may be a valuable technique in the setting of clinical chemopreventive trials for breast cancer. A direct comparison of this approach to the less invasive method of using nipple aspirate fluid to quantify their respective advantages is certainly appropriate. Perhaps more important is the need to continue to search in the context of these studies for biologically important molecular markers to fully characterize each stage of breast carcinogenesis and to provide early targets for preventive intervention.

REFERENCES

1 Fisher B, Costantino JP, Wickerham DL, Redmond CK, Kavanah M, Cronin WM, et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 1998;90:1371–88.[Abstract/Free Full Text]

2 Gail MH, Brinton LA, Byar DP, Corle DK, Green SB, Schairer C, et al. Projecting individualized probabilities of developing breast cancer for white females who are being examined annually. J Natl Cancer Inst 1989;81:1879–86.[Abstract]

3 Marshall LM, Hunter DJ, Connolly JL, Schnitt SJ, Byrne C, London SJ, et al. Risk of breast cancer associated with atypical hyperplasia of lobular and ductal types. Cancer Epidemiol Biomarkers Prev 1997;6:297–301.[Abstract]

4 Bodian CA, Perzin KH, Lattes R. Lobular neoplasia. Long term risk of breast cancer and relation to other factors. Cancer 1996;78:1024–34.[Medline]

5 Mansour EG, Ravdin PM, Dressler L. Prognostic factors in early breast carcinoma. Cancer 1994;74(1 Suppl):381–400.[Medline]

6 Petrakis NL. ASO Distinguished Achievement Award Lecture. Studies on the epidemiology and natural history of benign breast disease and breast cancer using nipple aspirate fluid. Cancer Epidemiol Biomarkers Prev 1993;2:3–10.[Abstract]

7 Foretova L, Garber JE, Sadowsky NL, Verselis SJ, Joseph DM, Andrade AF, et al. Carcinoembryonic antigen in breast nipple aspirate fluid. Cancer Epidemiol Biomarkers Prev 1998;7:195–8.[Abstract]

8 Gann P, Chatterton R, Vogelsong K, Dupuis J, Ellman A. Mitogenic growth factors in breast fluid obtained from healthy women: evaluation of biological and extraneous sources of variability. Cancer Epidemiol Biomarkers Prev 1997;6:421–8.[Abstract]

9 Sauter ER, Ross E, Daly M, Klein-Szanto A, Engstrom PF, Sorling A, et al. Nipple aspirate fluid: a promising non-invasive method to identify cellular markers of breast cancer risk. Br J Cancer 1997;76:494–501.[Medline]

10 Fabian CJ, Kimler BF, Zalles CM, Klemp JR, Kamel S, Zeiger S, et al. Short-term breast cancer prediction by random periareolar fine-needle aspiration cytology and the Gail risk model. J Natl Cancer Inst 2000;92:1217–27.[Abstract/Free Full Text]


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