Presence of an in situ component is associated with reduced biological aggressiveness of size-matched invasive breast cancer

Abstract

Background: The metastatic propensity of invasive ductal carcinoma (IDC) of the breast correlates with axillary node involvement and with expression of the proliferation antigen Ki-67, whereas ductal carcinoma in situ (DCIS) is non-metastasising. To clarify whether concomitant DCIS affects IDC prognosis, we compared Ki-67 expression and node status of size-matched IDC subgroups either with DCIS (IDC-DCIS) or without DCIS (pure IDC).

Methods: We analysed data from 1355 breast cancer patients. End points were defined by the association of IDC (with or without DCIS) with grade, nodal status, Ki-67, and ER/HER2.

Results: Size-matched IDC-DCIS was more likely than pure IDC to be screen detected (P=0.03), to occur in pre-menopausal women (P=0.002), and to be either ER-positive (P=0.002) or HER2-positive (P<0.0005), but less likely to be treated with breast-conserving surgery (P=0.004). Grade and Ki-67 were lower in IDC-DCIS than in pure IDC (P=0.02), and declined as the DCIS enlarged (P<0.01). Node involvement and lymphovascular invasion in IDC-DCIS increased with the size ratio of IDC to DCIS (P<0.01). A 60-month cancer-specific survival favoured IDC-DCIS over size-matched pure IDC (97.4 vs 96.0%).

Conclusion: IDC co-existing with DCIS is characterised by lower proliferation and metastatic potential than size-matched pure IDC, especially if the ratio of DCIS to IDC size is high. We submit that IDC-DCIS is biologically distinct from pure IDC, and propose an incremental molecular pathogenesis of IDC-DCIS evolution involving an intermediate DCIS precursor that remains dependent for replication on upstream mitogens.

Figure 1

Percentage of invasive ductal carcinoma (IDC) with and without ductal carcinoma in situ (DCIS) with different Ki-67 levels. The higher the Ki-67 level, the larger the proportion of pure IDC, and vice versa for IDC-DCIS. Black bars, pure IDC; white bars, IDC-DCIS.

Figure 2

Hypothetical carcinogenesis model for invasive ductal carcinoma–ductal carcinoma in situ (IDC-DCIS) vs pure IDC. In this model, IDC-DCIS – intrinsically less aggressive as reflected by lower Ki-67 expression and less nodal involvement – develops stepwise from normal breast epithelium via DCIS, through acquiring minor sequential genetic dysfunctions each time, whereas pure IDC develops de novo due to major genetic event(s).