Original ArticleConcordance between HER-2 and steroid hormone receptor expression between primary breast cancer, sentinel node metastases, and isolated tumor cells
Introduction
Sentinel node (SN) biopsy has largely replaced axillary lymph node dissection in lymphatic staging of early breast cancer. This technique allows a thorough examination of only a few lymph nodes, as well as the application of serial sectioning of excised lymphatic tissue followed by immunohistochemistry (IHC). As a consequence, small cancerous deposits are frequently detected, and a new dimension of regional lymph node metastases has been identified, micrometastases and isolated tumor cells (ITCs) [1]. The clinical significance of micrometastases and ITCs is currently unclear, and studies addressing their prognostic impact are controversial. It has been speculated that some ITCs may constitute tissue dislocated after a tissue needle biopsy or tissue handling rather than being true metastatic deposits [2], [3].
Overexpression of the HER-2 (c-erb B2) tyrosine kinase in breast cancer is usually associated with aggressive tumor features and poor outcome [4]. The outcome of HER-2-positive breast cancer has now improved considerably due to trastuzumab and other HER-2-targeting therapies [5], [6], [7]. The HER-2 status is usually analyzed from the primary breast tumor, which raises the question of whether the HER-2-status of the primary tumor reliably reflects that of cancer metastases. In general, the concordance of the HER-2 status between the primary tumor and ipsilateral axillary lymph node metastases is high, ranging from 78% to 90% [8], [9], [10], [11]. Similarly, a high concordance in the estrogen receptor (ER) and progesterone receptor (PR) status, ranging from 79% to 90%, has been reported between primary tumors and axillary lymph node metastases [12], [13], [14], [15], [16], [17], [18]. However, the majority of the LN metastases examined in previous studies are macrometastases obtained from axillary lymph node dissection specimens, and the concordance between the primary tumor HER-2 and steroid hormone receptor expression levels and those of lymph node micrometastases and ITCs is not known.
The aim of the present study was to compare the HER-2, ER, and PR status of the primary breast tumors with that of SN micrometastases and ITCs to elucidate the biological significance of lymph node micrometastases and ITCs.
Section snippets
Patients and methods
A total of 1652 breast cancer patients underwent an SN biopsy between February 2001 and July 2005 at the Breast Surgery Unit of Helsinki University Central Hospital, Finland. The study patients were selected from a prospectively collected database, established for investigating the SN biopsy technique.
The HER-2 CISH-positive study group
Altogether 39 SN-positive patients were selected, all with primary tumors with HER-2 amplification in chromogenic in situ hybridization (CISH). All cases with micrometastases (n=6) or ITCs (n=9)
Immunohistochemistry
The status for ER was analyzed both in the PT and the SN metastases by routine IHC using clone Ncl-Er-6F11 with a dilution of 1:50 (Novocastra Laboratories Ltd., Newcastle upon Tyne, United Kingdom). PR was analyzed by clone PGR 636, dilution 1:100 by DAKO (Cytomation, Glostrup, Denmark), in the primary tumor and the SN metastasis. Positive staining in IHC was defined as at least over 10% nuclear staining for ER and PR. The proliferation index Ki-67 was analyzed in the PT with clone MIB-1 by
The concordance in HER-2 amplification status between PT and SN metastases
In the HER-2 CISH-positive PTs, altogether 26 (90%) of the analyzed 29 metastases showed a low or a high level of HER-2 gene amplification in CISH. Three cases were negative. All these three discordant cases were macrometastases. The amplification level of HER-2 in the SN metastases is presented in Fig. 1.
In the 23 macrometastases, the amplification level was fully identical when compared with the PT in 16 (70%) cases, lower in 4 (17%) cases, and negative in 3 (13%) cases. None of the
Discussion
To the best of our knowledge, this is the first study to evaluate the concordance of the HER-2 status between primary breast cancer and SN micrometastases or ITCs. Among the HER-2-positive PTs, all the SN micrometastases and ITCs studied were also HER-2-positive. The high HER-2 gene amplification level in the three ITC-cases suggests that ITCs may represent metastatic cells with a potential for aggressive behavior. We are aware of the fact that the number of cases examined in this study is very
Conclusions
The concordance in HER-2, ER, and PR was high between the PTs and their SN metastases, as well as even micrometastases and ITCs. However, this concordance may be remarkably lower, when analyzed simultaneously for all three predictive factors. The high HER-2 gene amplification level in the three analyzed ITC-cases could imply that ITCs may represent metastatic cells with a potential for aggressive behavior.
Conflicts of interest
None declared.
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