The clinical and biological significance of HER2 over-expression in breast ductal carcinoma in situ: a large study from a single institution

Islam M Miligy,Ian O Ellis,Emad A Rakha,Andrew H S Lee,Kylie L Gorringe,Andrew R Green,Michael S Toss

doi:10.1038/s41416-019-0436-3

Abstract

BackgroundPrevious studies have reported up to 50% of ductal carcinoma in situ (DCIS), is HER2 positive, but the frequency of HER2-positive invasive breast cancer (IBC) is lower. The aim of this study is to characterise HER2 status in DCIS and assess its prognostic value.MethodsHER2 status was evaluated in a large series of DCIS (n = 868), including pure DCIS and DCIS associated with IBC, prepared as tissue microarrays (TMAs). HER2 status was assessed using immunohistochemistry (IHC) and chromogenic in situ hybridisation (CISH).ResultsIn pure DCIS, HER2 protein was over-expressed in 9% of DCIS (3+), whereas 15% were HER2 equivocal (2+). Using CISH, the final HER2 status was positive in 20%. In mixed DCIS, HER2 amplification of the DCIS component was detected in 15% with amplification in the invasive component of only 12%. HER2-positive DCIS was associated with features of aggressiveness (p < 0.0001) and more frequent local recurrence (p = 0.03). On multivariate analysis, combined HER2+/Ki67+ profile was an independent predictor of local recurrence (p = 0.006).ConclusionsThe frequency of HER2 positivity in DCIS is comparable to IBC- and HER2-positive DCIS is associated with features of poor prognosis. The majority of HER2 over-expression in DCIS is driven by gene amplification.

Highlights

Previous studies have reported up to 50% of ductal carcinoma in situ (DCIS), is HER2 positive, but the frequency of HER2-positive invasive breast cancer (IBC) is lower
A total of 651 cases of pure DCIS patients (Supplementary Table 2) and 217 cases mixed with invasive carcinoma were suitable for analysis
In cases with an IHC score of 2+, the inter-observer agreement is poor, and the predictive value is unsatisfactory for clinical use. This led to the recommendation of additional testing measuring HER2 gene copy number status using an in situ hybridisation technique such as FISH or chromogenic in situ hybridisation (CISH) to avoid inaccurate prognostication and inappropriate treatment.[32,33]

Summary

Introduction

Previous studies have reported up to 50% of ductal carcinoma in situ (DCIS), is HER2 positive, but the frequency of HER2-positive invasive breast cancer (IBC) is lower. HER2-positive DCIS was associated with features of aggressiveness (p < 0.0001) and more frequent local recurrence (p = 0.03). CONCLUSIONS: The frequency of HER2 positivity in DCIS is comparable to IBC- and HER2-positive DCIS is associated with features of poor prognosis. Lumpectomy with or without adjuvant radiotherapy.[6] Factors such as young patient age, large tumour size,[7] positive margins, comedo necrosis and high-nuclear grade[8] are associated with a higher risk of recurrence with some emerging data suggesting that ERBB2-amplified (HER2) DCIS could present a higher risk of recurrence.[9] The Van Nuys

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