Mammographic parenchymal patterns and risk of breast cancer at and after a prevalence screen in Singaporean women

RW Jakesa, SW Duffyb, FC Ngc, F Gaoa,d and EH Nge

a NMRC Clinical Trials & Epidemiology Research Unit, Singapore.
b MRC Biostatistics Unit, Cambridge, UK.
c Singapore General Hospital, Singapore.
d National Cancer Centre, Singapore.
e Mount Elizabeth Medical Centre, Singapore.

Reprint requests to: Rupert Jakes, Department of Community Medicine, Institute of Public Health, University Forvie Site, Robinson Way, Cambridge CB2 2SR, UK.


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background The objective of this study was to assess the effect of mammographic parenchymal patterns on risk of breast cancer detected at first screen or in the period following a negative screen.

Methods The study utilizes a nested case-control design with 132 breast cancer patients detected at first screen (from a total of 29 193 screened) and 42 breast cancer patients detected in the period following the first screen. These patients were matched to 348 screened-negative controls. The mammograms were classified according to Tabar's classification for parenchymal pattern and statistical analysis was done by conditional logistic regression.

Results The risk of breast cancer for women with Tabar pattern IV was significantly high when compared to the remaining patterns (odds ratio 2.59). Risk factors for Tabar pattern IV coincided largely with established risk factors for breast cancer.

Conclusion The study confirms the increased risk of breast cancer associated with Tabar pattern IV (approximately Wolfe pattern P2), in an Asian population. This pattern is associated with nulliparity and high educational status and is strongly associated with grade 3 cancers.

Keywords Breast cancer, mammography, parenchymal patterns, Asian women, case control study

Accepted 27 July 1999


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
It has long been observed that after controlling for age, the more dense mammographic parenchymal patterns are associated with a higher risk of breast cancer.1 Additionally, the denser patterns may also predispose to poorer sensitivity of mammographic screening for breast cancer. Thus, it has been suggested that in screening for breast cancer, the mammographic density of the breast may be used to determine aspects of the screening regime.2 For example, women whose mammograms display a more dense pattern may be recalled more frequently or subject to additional mammographic views.

If indeed the denser patterns constitute both a risk factor for breast cancer and an obstacle to sensitivity of breast cancer screening, one might expect that women with a dense pattern might be more prone to developing clinically symptomatic disease in the interval between screens. There is some evidence from the service screening in East Anglia, England that this is the case.3 In addition, there is evidence that the more aggressive, poorly differentiated tumours more commonly occur in mammographically dense breasts.4

It is of considerable importance to confirm the association of parenchymal pattern and mode of detection (screen or post-negative screen) as there has been no clear demonstration whether the practice, already used in some programmes,2 of designing the screening regime in response to the mammographic pattern, is actually effective. The Singapore trial of mammographic screening provides a useful resource in which to evaluate this hypothesis further.5


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
We describe two nested case-control6 studies that were performed simultaneously; eligible subjects were those who participated in the Singapore Breast Screening Project (SBSP).5 The SBSP is a population-based study that compares the prevalence of breast cancer in women aged 45–69 years randomized to either a single screen with two-view mammography without physical examination, followed by observation over 2 years, or simply to observation over 2 years. In all 29 193 women were screened by mammography in the SBSP and subjects in the current study were drawn from this total. The current study comprises one of post-negative-screen cancers (referred to as interval cancers, for purposes of brevity. Note there was no second screen associated with the SBSP) compared to controls who were negatively screened at the first time of screening but who did not develop interval cancer. The second is of first (and only) screen-detected cancers compared to controls who were negatively screened.

With 174 cases, two matched controls per case gives 80% power to detect a doubling of risk associated with a risk factor with 10% prevalence.3 In the first study, cases were all interval cancers occurring after negative screening (these cases are collected proactively by the Singapore Breast Cancer Registry). Median time to interval cancer was 20 (range 4–34) months. For each interval cancer, two controls were randomly selected and matched for age (one within one year younger and one within one year older) at the time of screening, and who did not develop an interval cancer within at least the same time since first negative screen of their corresponding interval cancer. For the second study, cases were all cancers detected at first screen; three subjects who had bilateral disease were not used. For each screen-detected cancer, two controls were selected, matched for age at screen (one within one year younger and one within one year older), who were screened negative. All cases and controls attended the first screen.

Note that here we are not using the case-control design to evaluate screening as such.7–9 We are using it to investigate specific hypotheses with respect to parenchymal patterns and mode of presentation.

Parenchymal patterns, according to Tabar's classification system,10 were determined by one radiologist (NFC) who studied both cranio-caudal and medial-lateral-oblique views, in the Department of Radiology, Singapore General Hospital. To blind the radiologist to case-control status, determination of the parenchymal pattern was made using the mammogram of a single breast; for cases the breast contralateral to that in which the cancer was diagnosed and in controls the same side as the corresponding case. Further, all identification markings on each x-ray were masked while it was in the possession of the radiologist.

Tabar's classification consists of five categories, as follows:

I Mammogram composed of scalloped contours with some lucent areas of fatty replacement, and 1 mm evenly distributed nodular densities.
II Mammogram composed almost entirely of lucent areas of fatty replacement, and 1 mm evenly distributed nodular densities.
III Prominent ducts in the retroareolar area.
IV Extensive nodular and linear densities, with nodular size larger than normal lobules.
V Homogeneous, ground glass-like appearance with no perceptible features.

Pattern I represents the classic appearance of the premenopausal breast. Pattern II represents the normal postmenopausal breast with glandular tissue replaced by fatty tissue. Pattern III indicates more periductal elastosis. Pattern IV probably represents proliferation. Pattern V represents extensive fibrosis, which may be, but is not necessarily, associated with any malignant or proliferative process.

Gram et al. show a relationship of patterns IV and V with known breast cancer risk factors, and suggest that these patterns may be associated with increased risk of disease.10 Figures 1–5GoGoGoGoGo illustrate the appearance of the five Tabar categories.



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Figure 1 Pattern I

 


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Figure 2 Pattern II

 


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Figure 3 Pattern III

 


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Figure 4 Pattern IV

 


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Figure 5 Pattern V

 
Demographic data, including known risk factors for breast cancer, were gathered at the time of first screen, as part of the screening project. The data were analysed by conditional logistic regression which yielded odds ratios (OR) and 95% confidence intervals (CI) for breast cancer with respect to parenchymal patterns. These estimates were produced separately for screen-detected and interval cancers, and according to grade of invasive cancer.

In addition to risk by mode of diagnosis, we also estimated effects on risk of breast cancer by malignancy grade, a histological measure of a tumour's aggressive potential, categorized as 1 (good prognosis), 2 (intermediate prognosis) and 3 (poor prognosis).

For further comparison, Tabar I, II, III and V were combined to form a ‘low-risk’ group and Tabar IV reclassified ‘high-risk’, with respect to breast cancer. Unadjusted OR for known risk factors and potential confounders, (including age at menarche, parity, number of children, age at first birth, breastfeeding, use of both oral contraceptive (OC) and hormone replacement therapy (HRT), and menopausal status), were calculated. OR, adjusted for ‘high-risk’ parenchymal patterns (and vice versa), were also calculated and tested for interaction between the two for these covariates.

Logistic regression methods were used to estimate the effect of potential risk factors, and confounders, on being a ‘high-risk’ parenchymal pattern (Tabar IV). Here OR were calculated for controls only.

The calculations to produce all the tables were performed using Stata Statistical Package.11


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Frequencies describing demographic features, risk factors and possible confounding variables are given, by disease status, in Table 1Go. There are 174 cases and 348 controls (132 of the cancers were detected at first screen and the remaining 42 in the period following first screen). The age range of the group is 46–67 years of which most are postmenopausal. The majority of subjects are radiologically classified as Tabar patterns I and II (74%).


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Table 1 Descriptive data on cases and controls
 
Table 2Go provides OR for breast cancer, according to mammographic classification, reported separately for cancers detected at first screen or following a negative first screen. Results are shown unadjusted and adjusted for age at menarche, age at first birth and breastfeeding history. For all cancers combined and for interval cancers only, being pattern II significantly reduces the risk of having breast cancer when compared to pattern I (OR 0.42 and 0.15, respectively). For all cancers combined and for screen-detected cancers only, risk of breast cancer is significantly raised in those with pattern IV when compared to pattern I (OR 2.30 and 3.49, respectively).


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Table 2 Effect of Tabar's pattern on risk of breast cancer, by mode of detection
 
When risks for mammographic patterns are calculated for invasive cancers only the reduction in risk remains for pattern II (OR 0.48) and the increase in risk remains for pattern IV (OR 2.27). These risks are given in Table 3Go unadjusted and adjusted as in Table 2Go. When OR for grades 1 and 2 combined and grade 3 are considered separately the risks mimic those when all invasives are combined. The effects for patterns II and IV appear to be accentuated although the numbers of cases are small.


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Table 3 Effect of Tabar's pattern on risk of invasive (non-DCIS) breast cancer, by grade of cancer
 
Table 4Go shows OR for known risk factors for breast cancer and other confounders. At this point Tabar patterns I, II, III, and V are combined to form a ‘low-risk’ group for comparison with a ‘high-risk’ group (Tabar IV). The unadjusted odds ratio for breast cancer for those in Tabar IV is 2.59 (95% CI : 1.31–5.13). This finding is seen consistently, and significantly, when individually adjusting for all other risk factors and confounding variables. Being parous proves to be protective for breast cancer (OR 0.36, 95% CI : 0.20–0.65) and this remains so after adjusting for Tabar pattern IV. Protective effects on breast cancer, with highly significant trends for increasing number of deliveries, are observed both unadjusted and adjusted for Tabar IV. Ever having breast fed again proves to be protective against disease by a factor of about a half. Being married or divorced, when compared to singles seems to significantly reduce the risk of breast cancer although the effect disappears when adjusting for parity status (OR not shown).


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Table 4 Odds ratios (OR) for breast cancer for covariates unadjusted, adjusted for being Tabar IV and Tabar IV adjusted for the covariate
 
Results for the odds of a subject being Tabar pattern IV among controls are reported in Table 5Go. Numbers of those with pattern IV are small so categorical variables are reclassified into binary variables. Having a positive parity status is shown to be significantly protective for being pattern IV for controls; the effect is diluted for the cases.


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Table 5 Odds ratios (OR) for being Tabar IV for covariates for controls
 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The nested case-control design is used here not to evaluate the efficacy of screening, but to estimate the effects of parenchymal patterns on risk of prevalence screen-detected and interval breast cancers. The design gives valid results for this purpose.6 The effects of other factors on risk of being in the Tabar IV category were estimated after breaking the nested matched design. They were not a primary aim of the study and, while interesting, they should be regarded as tentative.

The first point to note in the above results is the expected finding of an increased risk of breast cancer with Tabar pattern IV. Pattern IV corresponds to pattern P2 by the Wolfe classification and this is known to be associated with increased breast cancer risk.1,3,12–14 A more surprising result is the relatively low risk associated with pattern V. Although this pattern has not been shown to be associated with elevated risk, it does contain a substantial proportion of subjects in Wolfe's DY category, which has been observed to be associated with increased risk,10,12 albeit not as elevated as Tabar IV/Wolfe P2.1,3,13

One might expect to see some variation between these results which are mainly from Chinese women and those in Caucasian populations. Asian women have been observed to have smaller breasts and denser parenchyma than Caucasian women do.15,16 In this study 2% of women had breasts too small for mammographic positioning and 76% had Tabar patterns I, IV and V, which represent dense parenchyma.

In this study the Tabar pattern IV was associated with elevated risk of screen-detected cancers. For interval cancers, the picture is less clear. In the unadjusted analysis, the patterns which tend to predispose to interval cancers are I and III. After adjustment for breast cancer risk factors, patterns I, IV and V are associated with interval cancers, in comparison with pattern II (which is associated with very low risk of interval cancers). This is consistent with the fact that pattern II is the lucent fatty-replaced type which is easiest to read radiologically. Sala et al. find that both the Wolfe P2 (Tabar IV pattern) and the Wolfe DY (mixture of Tabar I and V) were more strongly associated with interval cancers than with screen-detected.3 Possible reasons for the different results include the fact that the more high-risk pattern, including Tabar IV, are much rarer in Asian populations than in Western.14 Consequently, the screening radiologists may be more aware of the dense patterns as a high-risk group. It should also be noted that there are relatively few interval cancers in this study, and consequently, the results with respect to interval cancers have a high degree of uncertainty attached.

Interestingly, in our study, the increased risk associated with Tabar pattern IV is most pronounced for the aggressive, more poorly differentiated grade 3 cancers. This is in agreement with the results of Sala et al.3 One might expect that a strong association with grade 3 cancers would also mean a strong association with interval cancers, as grade 3 tumours tend to be faster growing and therefore more likely to appear as interval cancers.17 Table 6Go shows detection mode by grade in the present study. Clearly, the expected positive association of interval cancer status and grade 3 is present. This indicates that the association of Tabar pattern IV with screen-detected and grade 3 tumours is not due to a different relationship between grade and detection mode in this population. The association of pattern IV with grade 3 cancers suggests that diagnostic attention to this pattern may be beneficial in terms of advancing the diagnosis of these particular cancers, which have a higher potential fatality.


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Table 6 Malignancy grade of breast cancer by detection mode
 
The results of the analysis of the association between Tabar pattern IV and some of the risk factors are interesting (Table 5Go). The significant association with nulliparity and the suggestive association with age at first birth and no history of breastfeeding are consistent with the results of other studies10,18 and with established effects of breast cancer risk.19 The negative association with HRT is unexpected.20 We examined the effect of Tabar IV on breast cancer risk in those with and without a history of HRT use and found OR of 2.22 and 6.30 in those without and with such a history, respectively. The finding was not significant (P = 0.3), but the result is at least suggestive. The prevalence of a history of HRT use in this population was relatively low (13–14%). It should also be noted that there is potential confounding with age at menopause, the HRT users being more likely to have early menopause.

It is also of interest that there was no association of OC use with either breast cancer risk or the Tabar IV category in this study. A very large overview found an association of OC use with a transient increase in risk of breast cancer.21 The effect was modest in absolute terms, and it may be that our study was not large enough to have the power to detect it as significant.

The association of the Tabar IV pattern with higher educational status may be a manifestation of an effect of dietary habits. This is interesting, as the Singaporean population has a diet relatively high in soya protein, which contains phyto-oestrogens and which have been associated with decreased breast cancer risk.22 A study of diet and mammographic pattern in this population is in progress. Disentangling childhood and adult dietary effects is likely to be difficult, however.

In conclusion, this study confirms the increased risk of breast cancer associated with Tabar pattern IV (approximately Wolfe pattern P2), in an Asian population (85% Chinese). This high-risk pattern is associated with nulliparity and high educational status. The pattern is strongly associated with grade 3 cancers. Further research on the complex inter-relations between pattern, risk of breast cancer by grade, detection mode and stage of disease may reveal implications for screening and diagnostic practices.


    Acknowledgments
 
We are grateful to the Singapore Breast Screening Project Working Committee for allowing us access to the data.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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