A number of studies have aimed to identify factors that predict the presence of invasive disease in patients diagnosed with DCIS (7
), but few have included HER2 in their analyses. Although DCIS phenotypes similar to those seen in invasive disease have been previously identified (9
), the clinical implications of these phenotypes in early disease have, likewise, infrequently been considered. Interestingly, in our series, multivariate logistic regression suggested that HER2 overexpression is a more powerful predictor for the presence of invasion than are size or high nuclear grade; factors associated with invasion in other series (7
). Moreover, tumors with HER2-overexpressing phenotypes were more likely to harbor invasive foci than were luminal A tumors.
Preclinical work associating HER2 signaling with tumor cell migration (10
) and the expression of proangiogenic factors (11
) and cyclooxygenase-2 (12
) suggests a potentially significant role in inducing invasion or the elaboration of a stroma that supports tumor growth. Despite these findings, it has been previously suggested that the increased rate of HER2 overexpression in DCIS compared with invasive breast cancer reflects less aggressive biology of HER2 overexpressing DCIS (13
). Moreover, the low frequency of HER2 expression in advanced disease has been cited as evidence that HER2 down-regulation is an epiphenomenon of disease progression (14
). An alternative explanation for the more frequent expression of HER2 in early disease, however, emerges from this study. HER2 expression may be characteristic of tumors at a discreet stage of pathogenesis and may represent a transient phenomenon. Specifically, HER2 may be up-regulated as in situ
tumors progress to invasive disease and down-regulated again in more advanced tumors. The close association between HER2-overexpressing phenotypes and early invasive lesions seen in this study supports this latter explanation as does the occasional discordance in HER2 expression between in situ
and associated invasive foci that has been observed in other studies (15
If validated through additional study, the implications of this study are broad and highlight the power of diagnostic studies that identify pathogenic molecular mechanisms. The clustering of invasive foci in patients with HER2-overexpressing tumors suggests a disease pattern hinted at in other studies; specifically, HER2 expression may reflect an important pathway through which DCIS lesions may progress toward invasion. Although efforts to target early carcinomas that over-express HER2 with novel therapies are in an early phase of development, such strategies may ultimately allow for the prevention of many aggressive malignancies. Conversely, investigators must be cognizant that a substantial percentage of patients with HER2 overexpressing DCIS harbor invasive disease and must carefully weigh the potential benefits of a novel treatment approach against the risk of delaying conventional therapy in this group. As the molecular mechanisms underlying disease pathogenesis are more clearly delineated, novel molecular markers with prognostic value will play a more prominent role in guiding therapeutic approaches.