Affiliations of authors: Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA (LAH, AMC); Department of Health Studies, University of Chicago; Chicago, IL (JJD); National Surgical Adjuvant Breast and Bowel Project (NSABP) Biostatistical Center (JJD, SRL) and Department of Biostatistics (SRL), University of Pittsburgh, Pittsburgh, PA; MSW Consulting, Bloomfield Hills, MI (MS); NSABP Operations Center, Allegheny General Hospital, Pittsburgh, PA (TBJ)
Correspondence to: Laurel A. Habel, PhD, 2000 Broadway, Division of Research, Kaiser Permanente Medical Care Program, Oakland, CA 94612 (e-mail: lah{at}dor.kaiser.org)
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ABSTRACT |
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The association of percent density with breast cancer risk appears to be linear, and it has been estimated that for every 1% increase in percent density, there will be a 2% increase in the relative risk of breast cancer (3). Mammographic density has been consistently observed to be inversely associated with both age and weight or obesity (13). In addition, mammographic density has been reported to increase after initiation of postmenopausal hormone therapy (713) and to decrease after initiation of tamoxifen (1417).
Compared with women with invasive breast cancer, breast cancer mortality rates are low for women with a recent history of DCIS (1820). However, compared with women in the general population, DCIS patients treated with breast-conserving surgery are at substantially increased risk of subsequent cancer in the involved (ipsilateral) breast and, to a lesser extent, in the unaffected (contralateral) breast (2123). Occult malignant cells are often left behind after breast-conserving surgery for DCIS (24,25), and the extent to which the ipsilateral breast is occupied by radiologically dense tissue at diagnosis may reflect the activity of hormones and other factors capable of stimulating the growth and proliferation of these cells. Highly dense breasts also may make it more difficult to mammographically visualize the extent of a DCIS tumor, increasing the chance of incomplete excision. Furthermore, it is possible that disease surveillance (e.g., mammography, clinical breast examination) after treatment for the primary DCIS tumor is less accurate among women with highly dense breasts.
Although numerous studies have examined the association between mammographic density and risk of first primary breast cancer, to our knowledge, density has not been evaluated as a possible predictor of subsequent breast cancer after either invasive breast cancer or DCIS. The aim of this study was to examine whether mammographic density at diagnosis of DCIS is associated with risk of subsequent breast cancer in a group of women who participated in a randomized clinical trial evaluating radiotherapy after excision for DCIS. We estimated the relative risk of any subsequent breast cancer. Separate relative risks were also estimated for subsequent invasive breast cancer and for subsequent ipsilateral breast cancer.
The study population consisted of participants in the National Surgical Adjuvant Breast and Bowel Project (NSABP) Protocol B-17, a randomized clinical trial evaluating radiotherapy after breast-conserving surgery for DCIS. Briefly, women with localized DCIS detected by physical examination or mammography were enrolled between October 1, 1985, and December 31, 1990. After surgery, 818 women were randomly assigned to either breast irradiation (total of 50 Gy; 10 Gy per week) or to no radiation therapy. Trial participants had follow-up physical examinations every 6 months and mammographic examinations annually. Subsequent tumors in the ipsilateral and contralateral breast and regional sites were confirmed by biopsy. A distant-site recurrence was verified by clinical, radiographic, or pathologic findings. Analyses in this study include information reported to the NSABP Biostatistical Center through March 31, 2001 (median follow-up time = 11 years). Further details of the study design and primary findings have been described elsewhere (19,2628). Participating sites obtained institutional review board approval for the B-17 trial, and all patients provided written informed consent. The current study was also approved by the Kaiser Permanente Northern California Institutional Review Board.
Information obtained at the time of enrollment included patient age, menopausal status, height, weight, and use of postmenopausal hormone therapy. At trial entry, tumors were assessed for pathologic features such as nuclear grade and histologic subtype by pathologists at participating institutions. Tumors from 623 women also underwent subsequent central pathologic review by the NSABP Headquarters pathologist for assessment of the following features: nuclear grade, focality, comedo necrosis, cancerization, stroma, lymphoid infiltrate, tumor size, surgical margin status, and histologic subtype (19,29).
In addition to assessments done by local radiologists at trial entry, a central review of mammograms of the involved breast taken at initial DCIS diagnosis was performed by the NSABP Headquarters radiologist on 739 of the trial participants (27). The review included assessment of tumor size and, when no tumor mass was visible, of the presence and appearance of microcalcifications, without knowledge of (blinded to) clinical and pathologic tumor size or any other patient or tumor characteristics.
Mammographic density was assessed on B-17 trial participants whose mammograms of the ipsilateral breast had been reviewed centrally and were still available. Mammogram films (or film copies) stored at facilities associated with the NSABP Biostatistical Center were retrieved and sent to a technician with expertise in density assessment (M. Salane). Films were first visually evaluated and scored for assessment quality (good, fair, poor, not assessable). Ipsilateral mammogram films were available and assessable for density measurements on 504 women, with only needle localization films available for 96 of these. Of these 504 patients, 475 had films scored as good or fair quality, 16 were scored as poor quality, and 13 were missing a quality score. The exclusion of 83 patients (with good- or fair-quality films that were needle localizations and may not have imaged the entire area of the breast) left 392 patients with mammograms for primary analyses.
The density expert, who was blinded to study endpoints, categorized parenchymal pattern and measured the total area of the breast and the total area of radiologic density on the craniocaudal view of the diagnostic mammograms (30). When the craniocaudal view was unavailable, the mediolateral oblique view was assessed (n = 47). Parenchymal pattern was based on criteria defined by Wolfe et al. (30). The N1 pattern includes breasts composed primarily of fat. The P1 pattern includes breasts composed mainly of fat with prominent ducts occupying up to 25% of the breast; the P2 breast has prominent ducts occupying more than 25% of the breast. The DY breast is characterized by poorly defined sheet-like regions of densities admixed with areas of fat; no ducts are visible. The DCIS tumor was included in the measurements of the approximately 15% of patients with a visible tumor mass. A compensating polar planimeter was used to measure the total breast area (in cm2) and the area of density (in cm2). Percent mammographic density was calculated as the area of density divided by the area of the breast. To calculate intra-observer reproducibility, 10% of all films were re-blinded and sent for re-review. The within-person Spearman correlation coefficient of percent density was .9 and the mean difference in percent density assessments was 2% (95% confidence interval [CI] = 1% to 5%). For parenchymal pattern assessments, kappa = .7.
We examined whether availability and quality of mammograms were related to age, race, treatment with radiotherapy, and other factors that were found to be associated with subsequent cancer in this population. We also examined the relationship between percent mammographic density and patient characteristics, treatment, and tumor factors among women with assessable mammograms. Finally, we compared parenchymal pattern, area of density, and percent mammographic density for assessable films of any quality to these measures for films of good or fair quality only.
Differences in frequency distributions of selected patient/disease characteristics by mammographic density were evaluated using two approaches. Both approaches test a null hypothesis of equality of the distributions of mammographic density across the groups defined by a given patient characteristic against an alternative hypothesis in which the distributions are ordered with respect to density. The JonckheereTerpstra test was used in cases in which the patient/disease characteristic was also ordered (age, tumor size, and body mass index [BMI]), and the exact KruskalWallis test was applied for characteristics that were not ordered (31).
Endpoints of interest included a) time to any breast cancer event (DCIS or invasive disease in the ipsilateral breast, regional or distant recurrence, and DCIS or invasive contralateral breast tumors); b) time to any invasive breast cancer event (ipsilateral, contralateral, and regional or distant metastases); c) time to any ipsilateral breast tumor (DCIS or invasive); and d) time to any contralateral breast tumor (DCIS or invasive). All endpoints were defined with respect to the first event following trial entry and did not include breast cancer events that occurred after the first subsequent cancer. Cox regression modeling was used to estimate cause-specific relative risks for these events in relation to mammographic density, while controlling for confounding variables (32). The validity of the proportional hazards assumption was tested by fitting a model with a covariate indicating the existence of a time-dependent hazard ratio for density and testing the significance of the coefficient for this covariate (33). Cumulative incidence curves, stratified by categories of percent density, were generated (34). Percent mammographic density was examined as both a continuous variable and when categorized as 0%24%, 25%49%, 50%74%, and 75% [these cutpoints are similar to those used in other studies (4)]. We also examined total area of mammographic density, treated as both a continuous variable and when categorized into quintiles. Parenchymal pattern was considered as four categories (N1, P1, P2, DY) or as two categories when collapsed (N1/P1 and P2/DY). Potential confounders included patient characteristicsage (continuous and categorized as <45, 4554,
55 years), menopausal status (premenopausal, perimenopausal, postmenopausal), race (white, black, other), weight (continuous and categorized into quintiles), BMI (weight in kilograms/ height in meters squared; continuous and categorized as <20, 2024, 2529, 3034,
35), and postmenopausal hormone therapy (never, former, current) (all at diagnosis of index DCIS); treatment factorsradiotherapy (yes, no), status of surgical margins (free, involved/unknown); tumor featuressize, histologic subtype (solid, cribriform, mixed), grade (good, poor), and presence of comedo necrosis (absent or slight, moderate or marked, or unknown); and primary mammographic findings of the initial DCISvisible tumor and appearance of microcalcifications (clustered, scattered, all other, or unknown). Addition of age, treatment with radiotherapy, or mammographic findings (one at a time) to models with only density variables lowered relative risk estimates by 10% or more, but the addition of BMI, menopausal status, comedo necrosis, and status of surgical margin increased the relative risk estimates by 10% or more. Given the small number of events, especially in the upper density category, those variables that changed relative risks by greater than 20% (age and BMI) were included in the final Cox regression models (35). Radiotherapy was also included because of its established association with local recurrence.
We also examined whether the association between mammographic density and breast cancer risk was modified by treatment with radiotherapy or menopausal status at index DCIS by examining interaction effects in the Cox models. In addition, we examined whether associations changed when we excluded patients with a visible tumor mass or if associations differed by time period after index DCIS.
The distributions of age, race, treatment with radiotherapy, and tumor features were similar between women with and without assessable mammograms and between women with and without mammograms of good or fair quality. In addition, there was little difference in the distribution of density measures for assessable films of any quality when compared with measures for films of good or fair quality (not shown). Because inclusion of needle localization and films of otherwise poor quality attenuated risk estimates, women with these films were excluded from our primary analysis cohort.
In this group of patients, mostly 50 years old or older, approximately 6.6% had breasts categorized as highly dense (75% dense). Percent density decreased with increasing age and BMI (Table 1). Density was not statistically significantly associated with treatment-related factors (i.e., radiotherapy, status of surgical margins). Features of the index DCIS tumor did not differ statistically significantly by percent density category.
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There was no statistically significant increase in risk of subsequent breast cancer with increasing density, as measured by Wolfes parenchymal patterns, or with increasing total area of density (data for both not shown). However, the percentage of the breast occupied by dense tissue was associated with subsequent breast cancer risk. Unadjusted relative risks showed increased risk of any breast cancer event (RR = 2.7, 95% CI = 1.4 to 5.3), invasive breast cancer event (RR = 2.6, 95% CI = 1.1 to 6.2), and any ipsilateral tumor event (RR = 2.7, 95% CI = 1.1 to 6.3) for women with breast density of 75% or greater compared with those with breast density of less than 25% (Table 2). Cumulative incidence of any breast cancer stratified by percent density reflected the risk for women with highly dense breasts (Fig. 1).
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In general, risk of subsequent breast cancer was not markedly different for women in the lower three categories of percent density, and there was no statistical evidence of a linear increasing trend across ordinal categories of density (data for both not shown). Explorations of percent density on a continuous scale also suggested increased risk only for those with high breast density (not shown). Relative risks were not materially modified when we restricted the follow-up period to begin at 2 or more years after the initial DCIS diagnosis or when analyses were restricted to patients without a visible tumor mass (not shown). Relative risks were also not modified by treatment with radiotherapy or by menopausal status (not shown). However, they were attenuated when we included all patients whose films were assessable for density, including films of poor quality and needle localizations. For example, unadjusted relative risks associated with percent density were 2.2, 2.2, and 2.0 for any breast cancer, invasive breast cancer, and ipsilateral breast cancer, respectively (versus 2.7, 2.6, and 2.7, as noted above, when poor-quality films and needle localizations were excluded).
This is the first study, to our knowledge, to report on the potential relationship between mammographic density and risk of breast cancer after a diagnosis of DCIS. Our results provide initial evidence that the risk of subsequent breast cancers may be increased among DCIS patients with highly dense breasts. This association did not appear to be limited to certain time periods after DCIS diagnosis or to patients with or without a mammographically visible tumor mass.
Our study has several limitations. Mammograms were not available on all trial participants, although women with and without available or assessable mammograms appeared to be similar with respect to several factors, including age, treatment with radiotherapy, and features of the initial DCIS tumor. In addition, approximately 20% of films were of poor quality for density assessments. However, although analyses that included data from poor-quality mammograms showed an attenuated effect of percent density on breast cancer risk, our findings still suggest increased risk for women with highly dense breasts. Density assessments have been found to be variable in many studies that have not used trained radiologists or technicians (37), and we therefore used an expert technician whose measurements are highly reproducible and have been validated in several studies (4,30,38,39). Although the distribution of DCIS patients across density categories was similar to that reported for healthy women of a similar age range (4), the number of patients with subsequent breast cancer events in some of the density categories was small, resulting in unstable risk estimates.
There is a growing interest in using mammographic density as a possible intermediate marker of breast cancer risk in dietary interventions (40,41) and in trials of chemopreventive or therapeutic agents, such as tamoxifen (1417,42). Our results suggest that mammographic density assessment at diagnosis also may aid in risk assessment for women with DCIS, although additional studies are needed to confirm our findings. These studies will need to be large enough to accumulate the necessary events for adequate power to identify high-risk subgroups and may require mammogram films of better quality (original films or good-quality copies; standard views, and not needle localizations) than we encountered in this retrospective study. In addition, information should be collected on potentially confounding variables, such as age, treatment (radiotherapy and/or tamoxifen, status of surgical margins), BMI, use of postmenopausal hormone therapy at diagnosis, and tumor characteristics.
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Manuscript received June 16, 2003; revised June 25, 2004; accepted July 13, 2004.
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