Incidence rates of ILC have been increasing steadily in the USA and Geneva, and likely in other parts of the world, while IDC rates have remained essentially constant. Based on its underlying pathology, ILC presents unique clinical challenges since it is more difficult to detect by both clinical breast exam and mammography. It is associated with better survival rates, and since the majority of ILCs are most are amenable to treatment with anti-hormonal agents such as tamoxifen. However, until recently, the epidemiology of ILC has been poorly defined. Epidemiologic investigations aimed at understanding the increases in ILC incidence rates have consistently identified that CHRT use is more strongly associated with ILC risk rather than it is with IDC risk. CHRT may partly account for the increases in ILC rates observed based on these findings and the parallel rise in CHRT use and ILC incidence rates. CHRT also appears to act as a cancer promoter given that current use, but not former use, is positively associated with

ILC risk. P and PRs appear to play key roles in this process since ERT is not associated with risk of either ER+ or PR+ tumors, while CHRT is associated with an increased risk of ERa+/PR+ tumors but notERa+/PR" tumors. P is also known to stimulate the proliferation of lobules, but not ducts, particular through PR-B. Moreover, P's proliferative effects primarily target lobular rather than ductal tissue in the breast. Thus, one would expect that P would be more likely to promote neoplastic growth in lobular, but not in ductal, tissue, particularly through interactions with PR-B. However, the specific mechanisms by which P is involved in oncogenic pathways leading to the development of ILC remain poorly understood. The fact that progestins are commonly used by women world-wide, particularly as forms of contraception or HRT, further stress the importance of advancing our understanding of the roles that P plays in the etiology of BC.

The studies described here indicate that beyond their histologic differences, ILC and IDC appear to have different etiologies. Thus, it is important to take into account the heterogeneity of diseases such as breast cancer when assessing their risk factors. The failure to do so may result in important associations being missed, as illustrated by the results of studies showing a differential effect of CHRT use on risk of ILC and IDC. A greater understanding of risk factors for different histologic types of BC may aid in the development of improved management and treatment approaches for women with BC.

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