In DCIS, HER2 Status May Predict Development of Invasive Breast Cancer

May 28, 2009 Cases of ductal carcinoma in situ (DCIS) that overexpress the protein HER2/neu are much more likely to develop into invasive breast cancer than DCIS without the overexpression, according to a new study.

Analyzing biopsies of 106 women diagnosed with DCIS, researchers from the University of Pennsylvania found that 37% of the women had DCIS that overexpressed HER2 and that the likelihood a woman with DCIS had early invasive disease was 6.4-fold higher when a tumor overexpressed HER2.

The study appears in the May issue of Cancer Epidemiology, Biomarkers & Prevention.

"Not all DCIS is the same," said study senior author Brian Czerniecki, MD, PhD, codirector of the Rena Rowan Breast Center at the University of Pennsylvania in Philadelphia, in a press statement.

He explained that the patients in the study were not followed over time, but instead were analyzed at a single point in time after a diagnosis of DCIS.

"We merely asked, in a group of patients with clinical presentation of DCIS, how often and what predicts whether you see early invasive cancer develop," Dr. Czerniecki told Medscape Oncology.

Dr. Czerniecki illustrated 1 potential affect of the findings: "From a practical standpoint, if you know that a patient has a greater chance of invasive cancer when you're doing a lumpectomy or mastectomy, then you might want to do a sentinel node biopsy, because there is a greater chance the cancer has spread to the lymph nodes," he said.

However, the study needs to be validated by additional investigation, write Dr. Czerniecki and his coauthors.

Nevertheless, the authors suggest that targeting of HER2 in an early disease setting may forestall or prevent disease progression. "If HER2 is associated with invasion or plays a role in the development of invasive disease, then maybe targeting it early can keep people from moving from DCIS to invasive cancer," said Dr. Czerniecki.

Study Details

In this study of women who were diagnosed with DCIS between 2003 and 2007 at the University of Pennsylvania, the mean patient age was 53.4 years. Their biopsy specimens were diagnosed either by core needle biopsy or by needle localization biopsy, and were subjected to immunohistochemical staining for HER2, estrogen-receptor (ER), and progesterone-receptor (PR) expression.

Lesions were characterized as luminal A (ER positive or PR positive, HER2 negative), luminal B (ER positive or PR positive, HER2 positive), HER2 positive (ER negative and PR negative, HER2 positive), or basal-like (ER egative, PR negative, and HER2 negative).

Luminal A was the most common tumor phenotype and accounted for the most lesions (59%), and basal-like accounted for the fewest (3%).

The HER2-positive phenotypes HER2 positive and luminal B accounted for 21% and 17% of lesions, respectively.

Invasive disease was seen in HER2-positive DCIS in 8 of 23 cases (35%) and in luminal B DCIS in 7 of 17 cases (41%).

The DCIS specimens were also characterized by nuclear grade (high, intermediate, or low), assessed for the presence of comedo necrosis, and measured for tumor size.

Univariate analysis revealed significant associations between invasion and high nuclear grade, HER2 overexpression, and tumor size of more than 3 cm. However, of these associations, only tumors with HER2 overexpression remained significant upon multivariate analysis. DCIS lesions that overexpressed HER2 were more than 6 times as likely to be associated with invasive disease than were DCIS lesions in which HER2 overexpression was not present (odds ratio, 6.4; P = .01), write the authors.

HER2 expression may reflect an important pathway through which DCIS lesions may progress toward invasion.

The study is not the first to identify factors that predict the presence of invasive disease in patients diagnosed with DCIS, but few studies have looked at HER2 status. Nevertheless, among those that did, the findings echoed the current study's, suggest the authors. "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," they write.

HER2 Expression May Be Fleeting

The authors note that there is a low frequency of HER2 expression in advanced disease and a higher frequency in early disease.

Given the results of their study, the authors speculate about the possible reason for these differing frequencies. "HER2 expression may be characteristic of tumors at a discreet stage of pathogenesis and may represent a transient phenomenon. Specifically, HER2 may be upregulated as in situ tumors progress to invasive disease and downregulated again in more advanced tumors," they write.

HER-2/neu overexpression as a predictor for the transition from in situ to invasive breast cancer.

Roses RE      Cancer Epidemiol Biomarkers Prev. 2009 May;18(5):1386-9. Epub 2009 Apr 21.

Department of Surgery, University of Pennsylvania, Philadelphia, PA, USA.


The clinical implications of HER-2/neu (HER2) expression in ductal carcinoma in situ (DCIS) lesions have yet to be clearly elucidated; this despite the more frequent expression of HER2 in high-grade DCIS lesions compared with invasive cancers. We hypothesized that HER2 overexpression in DCIS is associated with more rapid progression to invasive disease. Immunohistochemical staining for estrogen receptor, progesterone receptor, and HER2 was done on DCIS specimens. Univariate analysis and a multivariate logistic regression were done to determine whether estrogen receptor, progesterone receptor, or HER2 status, comedo necrosis, nuclear grade, lesion size, or patient age predicted the presence of associated invasive disease in patients with DCIS. Invasive foci were found in association with HER2 overexpressing DCIS at a higher frequency than with DCIS that did not overexpress HER2. Although high nuclear grade, large lesion size, and HER2 overexpression were all associated with the presence of invasive disease on univariate analysis, HER2 was the only significant predictor for the presence of invasive disease after multivariate adjustment (odds ratio, 6.4; P = 0.01). These data indicate that HER2 overexpression in DCIS lesions predicts the presence of invasive foci in patients with DCIS and suggest that targeting of HER2 in an early disease setting may forestall or prevent disease progression.