[6033] HER-2/neu expression/amplification is not stable during tumor progression. A single institution study with intrapatient comparisons years 1999 through to 2007.
Wilking U, Skoog L, Elmberger G, Hatschek T, Lidbrink E, Bergh J Karolinska Institute, Stockholm, Sweden
Background: HER-2/neu (HER2) expression/amplification has been considered to be intrapatient stable in primary breast cancer vs corresponding metastatic lesions. Treatment decisions, in many institutions, only rely on status in primary tumors. Few studies have been published on this subject. Single small studies reveal a high rate of concordance, while others reveal change in HER2 status (one study had 9 of 24 patients with no HER-2 amplification in the primary tumor changed genotype in circulating tumor cells, Meng et al PNAS 2004). At Radiumhemmet, Karolinska in Stockholm we have, whenever possible, morphologically verified all new metastases since 1999 using ultrasound-, CT- or X-ray guided or manually guided cytological aspirates. In addition to morphology, we aim to analyze receptors, HER-2 and proliferation MIB-1 on aspirates.
Materials and methods: Retrospective analysis of intra patient HER-2 over expression/amplification on routinely analyzed primary cancers and corresponding metastatic lesions during the time period 1999 to 2007. Data from the Pathology laboratory at the Karolinska University Hospital and the population based registry at the Regional Cancer Registry in Stockholm were used for patient identification. Most immunihistochical/immunocytochemical (IHC) with 2+ or 3+ samples (using several antibodies with cell line controls) were fluorescent in situ hybridization (FISH) verified. IHC 3+ and/or FISH amplification (av. >2 copies per cell) was considered HER2 positive.
Results: A total of 1067 breast cancers recurrences from the Stockholm hospitals were reported to the Regional Cancer Registry, 401 patients had a fine needle aspirate including a HER-2 analysis of recurrence/metastasis. 141 patients had HER-2 analyzed in both primary tumor (133 IHC, 8 FISH, 81 combined analyses) and the corresponding metastatic lesion (73 IHC, 67 FISH and 33 combined analyses). We identified 44 (31%) HER2 positive primary tumors and 44 (31%) HER2 positive metastases, respectively, in the 141 double tested tumors. 16 patients (11%) had a change in HER2 expression. 10 changed from negative to positive, and 6 changed from positive to negative (6/44 and 10/97, respectively altered their HER2 status). The metastatic sites of these patients were: loco-regional 3, liver 6, skeletal/ bone-marrow 2, lung 1, skin 4.
Discussion:
Our study shows that there are discrepancies between primary tumor and corresponding metastasis in HER-2 expression/amplification, within the same patient. If this is related to the heterogeneity of both the primary tumor and the metastasis, or if it is a true change in tumor cells is not yet clear. We also need to establish eventual inter metastatic heterogeneity in HER-2 expression. Our findings may, to some extent, explain why some patients with 
HER2 negative
cancers respond, and vice versa. Cytological confirmation of radiological lesions adds diagnostic precision and is in our hands a very safe procedure which has important impact on patient management, in this case the use of trastuzumab.
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