Comparison of HER2 amplification status among breast cancer subgroups offers new insights in pathways of breast cancer progression

Abstract

Although the prognostic and predictive significance of human epidermal growth factor receptor 2 (HER2) in invasive breast cancer is well established, its role in ductal carcinoma in situ (DCIS) remains unclear. Reports on combined evaluation of both HER2 protein expression and HER2 amplification status in pure DCIS and DCIS adjacent to invasive ductal carcinoma (i.e., admixed DCIS) are scarce. In this study, immunohistochemistry and fluorescence in situ hybridization (FISH) were used to assess HER2 status in 72 cases of pure DCIS, 73 cases of DCIS admixed with invasive ductal carcinoma (IDC), and 60 cases of pure IDC. HER2 copy number-based amplification was present in 49% of pure DCIS, 16% of admixed DCIS, 18% of admixed IDC, and 8% of pure IDC. Amplified pure DCIS with clusters of HER2 signals showed a significantly lower HER2 copy number than amplified admixed DCIS with clusters. Whereas pure DCIS and admixed DCIS presented significant differences, the in situ and invasive component of admixed tumors showed striking similarities regarding mean HER2 and chromosome 17 centromere (CEP17) copy number, grade, and estrogen and progesterone receptor expression. The discrepant prevalence of HER2 amplification among breast cancer subgroups indirectly suggests that HER2 may not play a crucial role in the transition of in situ to invasive breast cancer. The similarities in HER2 amplification status between the in situ and invasive component of admixed tumors hint at a common biological pathway for both components. Our data support the theory that pure DCIS, pure IDC, and admixed lesions have a common progenitor, but can progress as separate lineages.

HER2 protein overexpression in non‐amplified ductal carcinoma in situ: quality issue or transcription mechanisms gone awry?

“…may seem to be paradoxical, and might raise questions regarding technical quality issues and misinterpretation of IHC results. However, we can corroborate their findings, as we previously reported similar results obtained with HER2 IHC and fluorescence ISH (FISH) in a cohort of pure DCIS and DCIS admixed with invasive breast cancer . In our series, seven of 41 pure DCISs (17%) and seven of 19 admixed DCISs (37%) with a genuinely positive 3+ IHC score presented without HER2 copy number‐based amplification .…”

“…However, we can corroborate their findings, as we previously reported similar results obtained with HER2 IHC and fluorescence ISH (FISH) in a cohort of pure DCIS and DCIS admixed with invasive breast cancer . In our series, seven of 41 pure DCISs (17%) and seven of 19 admixed DCISs (37%) with a genuinely positive 3+ IHC score presented without HER2 copy number‐based amplification . As all of these IHC and FISH tests were performed in an ISO15189‐accredited laboratory, and as independent researchers such as Hui et al .…”

“…Both the study of Hui et al . and our own observations show that discordant ISH and IHC results in DCIS occur quite frequently …”

Some diffuse large B cell lymphomas (DLBCLs) present with clone‐dependent TTF‐1 positivity

“…Information on immunoglobulin (Ig)H rearrangement (as determined by FISH for IGH/BCL2 dual fusion t14;18 and q32;q21) was available for 65 of 105 cases (62%). All tests were performed in an ISO15189‐accredited laboratory (Ghent University Hospital), as described previously . Two mouse monoclonal anti‐TTF‐1 antibodies were used: SPT24 (Novocastra™ Leica Biosystems Newcastle Ltd, Newcastle upon Tyne, UK) and 8G7G3/1 (Dako Cytomation, Glostrup, Denmark).…”

A retrospective alternative for active surveillance trials for ductal carcinoma in situ of the breast

“…HER2 amplification and its concurrent protein overexpression might act as a driver for intraductal clonal proliferation, instead of being a driver of cancer cell invasion. This hypothesis may explain the observations of Zhou et al ., and it may also explain the paradoxical observation of HER2 overexpression being much more common in DCIS than in invasive carcinoma . Nevertheless, a nested case–control study identified HER2 as a marker for progression to invasive carcinoma, and therefore additional investigations remain warranted to clarify the role of this intriguing receptor …”