HER-2 gene amplification can be acquired as breast cancer progresses

Abstract

Amplification and overexpression of the HER-2 oncogene in breast cancer is felt to be stable over the course of disease and concordant between primary tumor and metastases. Therefore, patients with HER-2-negative primary tumors rarely will receive anti-Her-2 antibody (trastuzumab, Herceptin) therapy. A very sensitive blood test was used to capture circulating tumor cells (CTCs) and evaluate their HER-2 gene status by fluorescence in situ hybridization. The HER-2 status of the primary tumor and corresponding CTCs in 31 patients showed 97% agreement, with no false positives. In 10 patients with HER-2-positive tumors, the HER-2͞chromosome enumerator probe 17 ratio in each tumor was about twice that of the corresponding CTCs (mean 6.64 ؎ 2.72 vs. 2.8 ؎ 0.6). Hence, the ratio of the CTCs is a reliable surrogate marker for the expected high ratio in the primary tumor. Her-2 protein expression of 10 CTCs was sufficient to make a definitive diagnosis of the HER-2 gene status of the whole population of CTCs in 19 patients with recurrent breast cancer. Nine of 24 breast cancer patients whose primary tumor was HER-2-negative each acquired HER-2 gene amplification in their CTCs during cancer progression, i.e., 37.5% (95% confidence interval of 18.8 -59.4%). Four of the 9 patients were treated with Herceptin-containing therapy. One had a complete response and 2 had a partial response.

uPAR and HER-2 gene status in individual breast cancer cells from blood and tissues

“…Consistent with our prior results (19), five formerly HER-2 Ϫ cases acquired HER-2 ϩ CTCs upon recurrence or progression. Their patterns of HER-2 distribution were similar to those whose primary tumor was HER-2 ϩ .…”

“…Conventional pathological analysis and touch prep assays showed complete concordance with HER-2 and uPAR gene status in 21 and 7 consecutive patients, respectively, thereby validating the use of TPs for this purpose (P ϭ 0.0001). Similar results were obtained with HER-2 gene status of CTCs and pathological analysis of primary tumors provided acquisition (i.e., clonal selection͞ expansion) of HER-2 gene amplification in CTCs associated with cancer progression was taken into consideration (19). Expression of HER-2 protein in 52 cases using either their primary tumors or CTCs showed a minimum of 96% concordance with HER-2 gene amplification determined by the pathologist.…”

“…The higher the HER-2 ratio, the more likely it was to have coamplification and to have higher levels of uPAR amplification. The concordance of gene amplification patterns between primary tumor and CTCs obtained much later in the course of disease (taking into account acquisition of HER-2 gene amplification) also supports the validity of using CTCs in monitoring the genetic status of tumors (19). The likelihood of HER-2 and uPAR gene overexpression occurring in the same primary breast cancer by conventional pathological analysis has been reported (31) and is consistent with coamplification.…”

Detection of occult HER2 mRNA-positive tumor cells in the peripheral blood of patients with operable breast cancer: evaluation of their prognostic relevance

“…Previous studies have demonstrated that cytokeratin/HER2 double-positive clustered peripheral blood cells have a high potential for locomotion suggesting that they might be precursor cells responsible for the development of DTCs [12]; furthermore, HER2-positive CTCs have a growth and survival advantage [12]. In addition, it has been shown that HER2 gene amplification can be acquired during breast cancer progression [26]. This hypothesis is further supported by the recently reported 14% discordance of HER2 overexpression between the primary tumor and the corresponding metastases in patients with breast cancer [27].…”

HER2 status of bone marrow micrometastasis and their corresponding primary tumours in a pilot study of 27 cases: a possible tool for anti-HER2 therapy management?

“…Another recently published study also showed that HER2 amplification was more frequently observed in circulating cells than in primary tumours and therefore concluded that HER2 amplification could be acquired during the metastatic process (Meng et al, 2004). The HER2 amplicon corresponds to a 280-kb minimal region of amplification at the HER2 locus of chromosome 17q arm, in breast cancer.…”