Endocrine therapy

Transfection of normal breast cancer cells with the HER2 gene has been shown to result in acquisition of estrogen-independent growth which is insensitive to tamoxifen.80,81 A number of clinical studies, using various endpoints, have reported an association between HER2 positivity and resistance to endocrine therapy.82-84 Some reports have described specific resistance to tamoxifen in HER2-overex-pressing tumors.8284 The recently reported 20-year update of the Naples GUN Trial82

found that HER2 overexpression not only predicted resistance to tamoxifen, but that HER2-positive patients had a worse outcome on tamoxifen therapy compared to those who were untreated.

Several studies have also shown a reduction in response rates to endocrine therapy. Metastatic breast cancer which overexpressed HER2, measured by high plasma levels of the extracellular domain, demonstrated a substantial reduction in response rate to endocrine therapy.85 Cheung et al86 have examined marker levels [CA 15.3, CEA, ESR and serum HER2] in 15 patients receiving docetaxel-based regimes from two multicenter trials. Measurement of serum HER2 showed a correlation with tissue HER2 (Herceptest) in the primary tumor (p <0.003); and, more importantly, among those patients with positive tissue staining, sequential changes in serum HER2 paralleled initial response.

Other studies have failed to find an association or even a trend between HER2 status and response to endocrine therapy.87-89 Elledge et al89 examined the response to tamoxifen in 205 tumors with estrogen receptor (ER)-positive disease. In HER2-positive compared to HER2-negative patients, they found no significant evidence for a poorer response, time to treatment failure, or survival. In another study, the relationship between HER2 overexpression and response to tamoxifen was examined in the adjuvant setting in 741 (650 ER-positive, 91 ERnegative/progesterone receptor (PR) positive) of the total 1572 patients in the CALGB 8541 Trial who had HER2 measured.87 Tamoxifen significantly improved response, DFS and OS irrespective of HER2 status. However, it is important to appreciate that tamoxifen was not randomized within this trial and that all patients had received one of three regimens of doxoru-bicin, and response to this was related to HER2 status. Thus, this data on tamoxifen resistance has some limitations in interpretation.

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