Analysis of data from this large population-based case–control study provides convincing evidence that breast cancer risk factors differ by clinically important tumour features, including histopathological type, grade, size, and nodal status. Thus, exposures that influence the risk of developing breast cancer might also affect the biology and clinical behaviour of the tumours that arise. These findings parallel data suggesting that molecular profiles of breast cancers are generally fixed at inception and represent important determinants of clinical behavior (Lacroix et al, 2004
). Accordingly, understanding relationships between risk factors for breast cancer and tumour characteristics could have implications for screening and prevention.
Similar to a previous case–control study (Wohlfahrt et al, 1999
), we found that delayed age at first full-term birth was associated with increased risk of tumours that were large or node positive, whereas multiparity was associated with reduced risk for small tumours. Furthermore, analyses using a novel statistical method, which considered all tumour characteristics simultaneously, indicated that late age at first full-term birth and multiparity were more strongly related to larger tumour size than nodal invasion. Thus, these reproductive factors might act primarily to enhance tumour growth rate or delay detection. Either explanation would favour implementing improved prevention efforts for these women. Although the mechanisms responsible for the associations of delayed age at first birth with poor prognostic features are unknown, continuous exposure to cyclic hormones uninterrupted by the dramatic differentiation and remodelling effects of pregnancy on breast tissue might play an important role. In contrast to some previous reports (LiVolsi et al, 1982
; Ewertz and Duffy, 1988
; Stalsberg et al, 1989
), we and others (Morrison, 1976
; Wohlfahrt et al, 1999
) did not find that late age at first full-term birth was more strongly associated with lobular as compared with ductal carcinoma, NOS.
As previously reported, we found that HRT use was more strongly related to lobular (Gapstur et al, 1999
; Li et al, 2000
; Chen et al, 2002
; Daling et al, 2002
; Newcomb et al, 2002
; Li et al, 2003
; Newcomer et al, 2003
) and tubular (Manjer et al, 2001
) carcinomas than to other histopathologic types. In addition, we observed a stronger association between HRT use and risk for grade 1 ductal carcinomas, NOS, and tubulo-lobular carcinomas. This observation is consistent with the hypothesis that low-grade ductal or tubular and lobular carcinomas are aetiologically related and may represent the morphologic extremes of tumours (with the former being the most highly differentiated and the later the most undifferentiated extremes) that share a common carcinogenic pathway (Fisher et al, 1977
; Eusebi et al, 1979
; Green et al, 1997
This report and others have found that combined HRT use is also associated with low grade or small tumours (Collaborative Group on Hormonal Factors in Breast Cancer, 1997
; Gapstur et al, 1999
; Li et al, 2000
; Manjer et al, 2001
). Consideration of all tumour characteristics simultaneously in our analyses indicated that HRT use is primarily associated with tumour grade and to a lesser extent, with tumour size, whereas associations with histopathologic type or nodal status were not significant. It is possible that these findings reflect a detection bias associated with increased screening among HRT users; however, we found similar associations among screened and unscreened women (data not shown). In addition, it is known that HRT increases breast density, which decreases the sensitivity of mammography, and that mammography is insensitive in detecting lobular carcinomas. From a public health perspective, it is reassuring that the excess breast cancer risk associated with HRT use is related mainly to tumours with good prognostic features.
Findings from this case–control study provide support for an association between obesity and later stage at diagnosis, as it has been reported in most previous studies, mostly case-series (Daniell, 1988
; Ingram et al, 1989
; Verreault et al, 1989
; Reeves et al, 1996
; Jones et al, 1997
; Hall et al, 1999
; Cui et al, 2002
), with a few exceptions (Donegan et al, 1978
; Howson et al, 1986
). In addition, consideration of all tumour characteristics simultaneously, suggested that obesity is primarily associated with larger tumour size rather than nodal status, particularly among postmenopausal women. Case–control analyses indicated that the association between obesity and larger tumour size in pre-menopausal women reflects a protection of obesity against small but not larger tumours, as it has been previously reported (Hall et al, 1999
). This finding could reflect failed detection of smaller tumours by self or medical examination since tumours are more difficult to palpate in obese women. Among postmenopausal women only, high BMI was also associated with a small increase in risk for large tumours, which is consistent with growth enhancement due to higher levels of circulating hormones among obese than non-obese postmenopausal women. Previous studies have suggested that BMI is associated with hormone receptor-positive tumours which could confound the observed association with tumour size (Althuis et al, 2004
). However, in our data, associations between BMI and tumour size were independent of hormone receptor status.
It has been suggested that tumours with poor prognostic features (i.e. high grade, large size, node positive, ER negative) differ aetiologically (Mueller, 1988
; Anderson et al, 2004b
; Li et al, 2005
). Our data support this notion, challenging the view that tumour aggressiveness results entirely from stochastic molecular events that occur over time (Hellman and Harris, 2000
). It is unclear whether risk factors directly affect prognosis, indirectly affect outcomes by influencing tumour characteristics at presentation or are unrelated to the clinical course.
Strengths of our study include large sample size, high participation rates, and standardised histopathologic assessment by an independent pathology review. In addition, we considered different tumour characteristics simultaneously using a novel statistical method (Chatterjee, 2004
) which allowed us to evaluate the independent association of these characteristics, and adjust for hormone receptor status of the tumour. Although this study population had higher percentage of tumours with adverse prognostic features than those observed in other Western populations, most known breast cancer risk factors were present in similar magnitude as previously reported, indicating that our findings should be generalisable to other populations.
In summary, this population-based study provides evidence that breast cancer risk factors are associated with clinically important tumour characteristics, suggesting that aetiological factors may affect the biological behaviour of breast cancers. In addition, these data suggest that postmenopausal women who are nulliparous have later ages at first birth and are obese might benefit from more frequent screening.