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.
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Abstract |
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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
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Introduction |
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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
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Methods |
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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 434) 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.79 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:
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 15 illustrate the appearance of the five Tabar categories.
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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
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Results |
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Discussion |
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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.1,3,1214 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 6 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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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.
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Acknowledgments |
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References |
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