Affiliations of authors: Biostatistical Center, National Surgical Breast and Bowel Project and Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA (JW, JPC); Cancer Research Network, Plantation, FL (ETC); Operations Office, National Surgical Breast and Bowel Project and Department of Surgical Oncology Allegheny General Hospital, Pittsburgh, PA (DLW, NW); Division of Pathology, National Surgical Breast and Bowel Project and Department of Pathology, Allegheny General Hospital (SP)
Correspondence to: Jiping Wang, MD, PhD, Biostatistical Center, National Surgical Breast and Bowel Project, University of Pittsburgh, 201 N. Craig St., Ste. 350, Pittsburgh, PA 15213 (e-mail: wang{at}nsabp.pitt.edu)
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ABSTRACT |
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INTRODUCTION |
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In their assessment of the association between BBD and breast cancer, some authors have recognized the potential for confounding in the estimates of breast cancer risk and have adjusted for or stratified some of the key epidemiologic factors known to be associated with breast cancer risk. However, none of these authors has fully explored the independence of BBD in breast cancer risk from the known breast cancer risk factors by including adjustment for the full complement of breast cancer risk factors used in the Gail model (13) (such as age at menarche, number of first-degree relatives diagnosed with breast cancer, age at menopause, age at first live birth, and number of previous breast biopsies). Adjustment for all key risk factors is critical for determining the independent nature of BBD as a predictor of breast cancer and for estimating the magnitude of risk associated with specific pathologic diagnoses of BBD. This type of adjustment is particularly important for assessing the independent nature of the risk associated with the pathologic diagnoses of BBD that are included in the College of American Pathologists BBD categories 1 and 2 (Table 1), for which the available RR estimates are lower than for those in categories 3 and 4 (e.g., atypical hyperplasia and in situ disease).
In general, the emphasis of breast cancer risk determination associated with BBD has been on disease associated with the upper categories of BBD (i.e., categories 3 and 4). The focus of this report is both to quantify the risk of breast cancer associated with the pathologic types of BBD in the two lower categoriesto which we refer as lower-category benign breast disease (LC-BBD)and to determine whether LC-BBD is an independent predictor of breast cancer after adjustment for the full set of key epidemiologic factors known to be associated with breast cancer risk. We used data from the Breast Cancer Prevention Trial (BCPT), Protocol P-1, of the National Surgical Adjuvant Breast and Bowel Project. This trial, in which women at increased risk of breast cancer were randomly assigned to 5 years of either tamoxifen or placebo, represents one of the largest studies in recent history in which healthy women at high risk for breast cancer have been prospectively followed and the diagnosis of all breast biopsies has been systematically reported (14). Information from this study provides a prospectively collected source of data to evaluate the relationship between LC-BBD and breast cancer, while adjusting for the full compliment of key breast cancer risk factors by using the composite breast cancer risk estimates obtained for each participant from the modified Gail model (13).
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SUBJECTS AND METHODS |
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An initial analysis was performed based on a set of data that was limited to the information obtained while the participants were under blinded follow-up; that is, before the announcement of findings from the trial (through March 1998). The results of this initial analysis provided no evidence of an interaction between treatment and LC-BBD in terms of LC-BBD as a marker for breast cancer. Thus, to increase the number of LC-BBD and breast cancer events for study and to improve the statistical power of the assessment, a subsequent analysis was undertaken based on all follow-up data from the BCPT received and processed by August 31, 2002. The findings presented in this report are based on the analysis of the extended follow-up data for which the mean follow-up time is 79 months.
Statistical Analysis
The primary method of analysis was Cox proportional hazard modeling of time to diagnosis of breast cancer. In this modeling, the first diagnosis of LC-BBD was incorporated as a time-dependent covariate. Women who developed atypical hyperplasia or noninvasive breast cancer were censored at the time of these events. The relative risk of breast cancer and the 95% confidence interval (CI) for the relative risk were derived from the parameter estimates of the Cox modeling. To determine whether LC-BBD is an independent marker of breast cancer, multivariable Cox modeling was performed including treatment and level of breast cancer risk as additional covariates. The proportional hazards assumption for treatment and level of breast cancer risk was verified by using Grambsch and Therneaus method (15). Adjustment for level of breast cancer risk was achieved by including each womans 5-year risk score as determined from the modified Gail model (13). The use of this score provided a parsimonious means to adjust for seven breast cancer risk factors (age, race, age at menarche, age at first live birth, family history of breast cancer, number of breast biopsies, and history of atypical hyperplasia) as one parameter in the modeling. For women who did not undergo a biopsy, the 5-year risk score that was incorporated in the modeling was that determined at randomization into the BCPT. For those who experienced a biopsy, the 5-year risk score used in the modeling was that determined at the time of the first diagnosis of LC-BBD. Average annual rates of breast cancer diagnosis were calculated by dividing the number of observed events by the number of observed event-specific person-years of follow-up. The person-years at risk for the determination of the breast cancer diagnosis rate in women with LC-BBD were calculated from time of first confirmed LC-BBD biopsy to time of developing breast cancer or to time of last follow-up. The person-years at risk for the determination of the breast cancer diagnosis rate for those without LC-BBD were calculated as the sum of the time from randomization to the time of developing breast cancer or to the time of last follow-up (for women who never developed LC-BBD) and time from randomization to time of first confirmed LC-BBD biopsy (for women who did develop LC-BBD).
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RESULTS |
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As would be expected, women in the tamoxifen group had a lower risk of breast cancer than did those in the placebo group. This difference was evident even when the women were stratified by LC-BBD status (Table 3). A statistically significant effect of LC-BBD was evident within each treatment group, and the magnitude of effect within each treatment group was similar. Among the placebo group, annual rates of breast cancer were 8.04 per 1000 for women with LC-BBD and 5.43 per 1000 among those without LC-BBD. Among the tamoxifen group, annual rates of breast cancer were 6.30 per 1000 and 3.52 per 1000 for women with and without LC-BBD, respectively. The relative risk of breast cancer for women with LC-BBD was 1.46 (95% CI = 0.97 to 2.21) in the placebo group and 1.69 (95% CI = 1.05 to 2.73) in the tamoxifen group.
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DISCUSSION |
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Our data also indicate that women diagnosed with a mammary cyst have an increased breast cancer risk. An elevated risk of breast cancer associated with a diagnosis of a cyst has been indicated by studies of case series (1618). However, these studies used rates from the general population for comparison and did not consider the confounding effect of epidemiologic factors affecting breast cancer risk. Our data, which are adjusted for confounding factors, indicate that a diagnosis of a cyst is an independent risk factor associated with breast cancer and that the risk of breast cancer in patients with cysts is about 60% higher than the risk in those who have no form of breast disease. This finding indicates that women with LC-BBD, particularly those with cysts, should be considered at increased risk for the development of breast cancer and should be followed accordingly.
Only a moderate number of breast cancer cases were diagnosed among women who developed LC-BBD during the course of follow-up in the BCPT. Additional studies on larger datasets that include the ascertainment of complete breast cancer risk factor profiles are needed to further quantify the magnitude of independent breast cancer risk associated with LC-BBD. Additional studies are also needed to separately quantify the level of breast cancer risk associated with each of the LC-BBD pathologic types. Although we had originally hoped to develop separate estimates for several other pathologic types, because the number of breast cancer events was too small for the other LC-BBD categories, we were able only to determine estimates of breast cancer risk for cysts. In addition, it was not always possible for us to determine whether the degree of hyperplasia was mild or moderate or to make a determination regarding the presence or absence of complex features with fibroadenoma (fibroadenomas with or without cysts greater than 3.0 mm, sclerosing adenosis, calcifications, or papillary apocrine changes) (2). These are limitations inherent in using data reported from multiple community pathologists without having biopsy material for central review. An additional limitation of using this type of data is that not all pathologists use standardized criteria for reviewing biopsies. However, estimating breast cancer risk on the basis of the diagnoses of community pathologists provides risk values that relate directly to the actual pathologic diagnoses that are used as the basis for decision-making in clinical practice for women at high risk of breast cancer.
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NOTES |
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REFERENCES |
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Manuscript received October 6, 2003; revised February 12, 2004; accepted February 24, 2004.
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