Introduction: Biologic markers that predict development of invasive breast cancer (IBC) in patients diagnosed with ductal carcinoma in situ (DCIS) are needed to improve personalized therapy. In this study, we examined the incidence of early IBC in DCIS subgroups defined by immunophenotype. Methods: Clinical and histologic materials of 143 patients with radiographically suggesting DCIS without obvious evidence of IBC were reviewed. All patients underwent initial biopsy followed by short-term subsequent resection. The presence of IBC, histopathologic features of DCIS and IBC, when present, and their estrogen receptor (ER), progesterone receptor (PR), and HER2 phenotypes were evaluated. Results: Early IBC was identified on initial biopsy in 6 (4%) and subsequent resection in 24 (17%) patients. HER2 positivity in DCIS was the dominant factor associated with IBC. There was also a significant association between ER/PR/HER2+ DCIS and the presence of IBC. The ER/PR/HER2+ DCIS appeared to be the most unstable precursor, because of the highest invasion rate and frequent association with a discordant phenotype. Conclusions: HER2 positivity and ER/PR/HER2 phenotype may be used to identify DCIS patients at higher risk of harboring or potentially developing IBC. Strategies targeting HER2 in DCIS may be of potential benefit in preventing IBC in patients with DCIS. © 2011 Wiley-Liss, Inc.