Affiliations of authors: E. B. Claus (Departments of Epidemiology and Public Health and Neurosurgery), M. Stowe (Department of Epidemiology and Public Health), D. Carter (Department of Pathology), Yale University School of Medicine, New Haven, CT.
Correspondence to: Elizabeth B. Claus, Ph.D., M.D., Department of Epidemiology and Public Health, Yale University, 60 College St., P.O. Box 208034, New Haven, CT 06520-8034 (e-mail: claus{at}biomed.med.yale.edu).
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ABSTRACT |
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INTRODUCTION |
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Although many risk factors associated with invasive breast cancer may also play a role in the development of breast carcinoma in situ, the results are not consistent, in part because small sample sizes do not allow for precise estimates of risk. Information on screening variables is often not available (4,6,8,9) or is available only on specific populations. The one study to collect information on screening (3) included only case patients under age 45 years.
Here, we undertook a large, population-based study specifically designed to examine the association between breast cancer risk factor history and a diagnosis of breast carcinoma in situ across a spectrum of ages and histologies and incorporating cancer-screening data.
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PATIENTS AND METHODS |
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All case patients with breast carcinoma in situ diagnosed among female residents of Connecticut from September 15, 1994, through March 14, 1998, were included in this study. Case patients, aged 2079 years at the time of diagnosis, were identified through the rapid-case-ascertainment shared resource of the Yale Cancer Center (Yale University, New Haven, CT). Control subjects were female Connecticut residents selected by random-digit-dialing methods by an outside consulting firm (Northeast Research, Oreno, ME). Control subjects were frequency matched by 5-year age groups to the case patients. The study, consent forms, and questionnaire were approved by the Human Investigation Committee of Yale University School of Medicine. All subjects provided verbal consent to be interviewed over the telephone. Medical records and pathology slides were reviewed only after the participants had provided written, informed consent.
We contacted the physician of each eligible case patient to request permission to approach the case patient. After receiving consent from the physicians, we sent case patients and control subjects, identified by Northeast Research, a letter of introduction describing the study and inviting them to participate. Before the interview, potential study subjects were sent an oral contraceptive picture booklet developed for the Harvard University Nurses' Health Study (16) to allow them to review products used in the past. Approximately 12 weeks after the letter of introduction and the booklet were sent, a trained interviewer contacted the potential study subject by telephone to conduct the interview. For this study, the majority of case patients were interviewed within 6 months of the date of diagnosis. Subjects were interviewed for an average of 43 minutes. The questionnaire included detailed questions on family history of cancer, pregnancy and menstrual histories, exogenous hormone history, demographics, medical and screening histories, and smoking and alcohol consumption.
Eligible case patients and control subjects were 2079 years old, were residents of Connecticut, were English speaking, and did not have a history of breast cancer or breast biopsy of unknown outcome. Two hundred forty-one potential case patients were ineligible because they were out-of-state residents (eight patients), were non-English speaking (21 patients), had a history of breast cancer/biopsy of unknown outcome (181 patients), or were older than age 79 years (31 patients). We received consent from the physicians of 91% of the eligible case patients to contact the case patients. Of those whom we contacted, 83% participated in the study. Seventy-four control subjects were ineligible because they were out-of-state residents (three subjects), were non-English speaking (18 subjects), had a history of breast cancer/biopsy of unknown outcome (51 subjects), or were older than age 79 years (two subjects). Among control subjects, the initial household-screening response rate when approached by Northeast Research was 85.7%. Of those whom we contacted, 81% agreed to be interviewed. The final study population included 1068 case patients and 999 control subjects, with overall estimated response rates of 76% and 70% for case patients and control subjects, respectively.
The pathology reports of all case patients were reviewed by the study pathologist (D. Carter). Case patients were grouped according their pathologic diagnosis as either DCIS (n = 875) or LCIS (n=123) patients. Case patients with mixed or other pathologic conditions (i.e., both DCIS and LCIS, invasive cancer, or no identifiable disease) (n = 70) were excluded from these analyses. Information on breast cancer risk factors and screening was truncated at the date of diagnosis for case patients and the date of interview for control subjects (hereafter referred to as the "reference date"). Data on screening variables included information on routine checkups, clinical breast examinations, breast self-examinations, Pap smears, and mammograms. For each of the screening methods, respondents were asked to provide their age at first screening. For the determination of the usual screening behavior of study subjects, respondents were asked to provide the date of their most recent screening and the frequency of each screening in the 5-year time period 1 year before the reference date. This information was used to construct two mammography-screening variables: 1) the existence of at least one mammographic examination in the 5-year period 1 year before the reference date and 2) the number of mammographic examinations in the 5-year period 1 year before the reference date (coded as 0, 1, or 2). Study subjects were also asked how any breast lesions were found (i.e., by mammography or other means).
Statistical Analysis
The initial portion of the statistical analysis included descriptive statistics. Student's t tests and chi-square tests were used to examine the association between the risk of breast carcinoma in situ and independent covariates. To assess the relative risk of breast carcinoma in situ associated with risk factors, we used conditional logistic regression to provide maximum likelihood estimates of the odds ratios (ORs) (adjusted and unadjusted) with 95% confidence intervals (CIs). All statistical analyses were performed with PC-SAS version 6.11 (17). Relative risk estimates were adjusted for age, college education (yes/no), history of at least one screening mammogram in the 5-year period 1 year before the reference date, body mass index (i.e., weight in kilograms divided by height in meters, squared), and ethnicity (white/other) and were mutually adjusted for other statistically significant risk factors in the logistic model. All reported P values were two-sided.
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RESULTS |
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Because of the association between casecontrol status and mammography, all ORs were adjusted for mammogram history (categorized as having had at least one mammographic examination in the 5-year period 1 year before the reference date). Additional adjustment for other breast cancer-screening procedures did not statistically significantly alter the ORs and were not included in the final model. The logistic regression analyses were also performed retaining the original frequencymatched study design (5-year age strata); the results obtained were essentially unchanged from those presented in Table 4.
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DISCUSSION |
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Other variables associated with invasive breast cancer risk include those with endogenous or exogenous hormonal components. The risk of DCIS was also associated with several hormone-related factors. Similar to previous reports, DCIS case patients were more likely than control subjects to be older at first full-term pregnancy (4,6,911) and at menopause (4) and to have fewer full-term pregnancies (3,911). We also found a reduction in DCIS risk associated with older age at menarche, although this effect was of borderline statistical significance. There was no association between oral contraceptive or HRT use and the risk of breast carcinoma in situ. To our knowledge, this is the first estimate of the relative risk associated with oral contraceptive use. Although the association between HRT use and breast carcinoma in situ has been explored previously, the sample sizes were small and the results were inconsistent, with several (4,30,31) but not all (32) of the previous studies reporting an increased risk. It is possible that some of this effect may be the result of increased breast cancer screening among HRT users compared with nonusers because all of the studies mentioned made some attempt to adjust for screening history. To further explore the relationship between exogenous hormones and the development of breast carcinoma in situ, detailed analyses will be presented elsewhere to define the role of age, duration, frequency, composition, and potency of hormone use on this relationship.
Previous studies have associated alcohol consumption (3335), but not active smoking (3638), with an increased risk of invasive breast cancer. We found no association between either alcohol consumption or cigarette smoking and the risk of breast carcinoma in situ. To our knowledge, this is the first examination of the effect of these two variables on the risk of breast carcinoma in situ. Further analyses will study whether subsets of these variables are associated with any change in breast carcinoma in situ risk.
A history of breast biopsy is strongly associated with a diagnosis of DCIS or LCIS in our study and in other studies (3,4,6,9,10). The association between benign breast disease and risk of invasive breast cancer is well known. The association reported here between a diagnosis of breast carcinoma in situ and a benign breast disease biopsy is likely due to a combination of factors, including the likelihood that some benign breast disease is associated with the eventual development of breast carcinoma in situ. However, this observed association is also likely a function of increased surveillance and thus early detection. It is not possible at present to quantify the extent to which each of these possibilities plays a role in this association.
There were a number of statistically significant associations between screening patterns and risk factors for breast cancer in situ. At least within the state of Connecticut, women with either a family history of breast cancer or a previous breast biopsy appear to be participating in more intensive screening programs than those without such a family history. Ethnicity was also statistically significantly associated with screening frequency, with white women twice as likely as nonwhite women to report having had a screening mammogram but less likely to report having practiced breast self-examination. This is of note, given the increased rates of diagnoses of breast carcinoma in situ associated with mammography use but not with breast self-examinations. The risk factor most strongly associated (fourfold) with screening in our data was the use of HRT. Women with this risk factor were almost twice as likely as women with a family history of breast cancer among a first-degree relative to receive a mammographic examination. This finding suggests that, unless screening history is controlled for, results of studies reporting a relationship between HRT use and the risk of DCIS may be confounded by screening variables.
Although the strong association between mammography use and the diagnosis of breast carcinoma in situ makes collection of these data important in any study of the topic, it is necessary to consider a number of potential biases in reporting mammographic history. In particular, women with breast carcinoma in situ may be more likely to report increased numbers and/or a greater frequency of screening because of guilt related to their diagnosis. Researchers should be careful to attempt to collect information on usual screening behavior for both case patients and control subjects and to avoid the collection of information only on the screening mammogram that led to the diagnosis of breast carcinoma in situ for case patients because, once diagnosed, all case patients will have a recent mammographic examination as part of their work-up. Furthermore, to minimize any differences in the recall of screening data, researchers should interview case patients relatively soon after diagnosis.
This study provides evidence that many of the risk factors for DCIS are similar in nature and magnitude to those for invasive breast cancer, suggesting the possibility that some in situ lesions may be a part of the pathway leading to invasive disease. These data represent the largest examination to date of the epidemiology of breast carcinoma in situ across all categories of age and histology. Furthermore, because information on screening was included in all analyses, the estimates of risk presented here should be relatively free of any screening bias, which is particularly important in the analysis of noninvasive tumors that are more likely to be diagnosed at an early stage during screening procedures, such as mammographic examinations.
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NOTES |
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We thank Sheila Griffin and Marjorie Jasmin (both of the Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, CT) for their work as interviewers on the study.
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Manuscript received March 27, 2001; revised September 21, 2001; accepted October 4, 2001.
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