Serum HER-2/neu Conversion and Breast Cancer Progression
Serum HER-2/neu Conversion and Breast Cancer Progression
Abstract & Commentary
William B. Ershler, MD, INOVA Fairfax Hospital Cancer Center, Fairfax, VA; Director, Institute for Advanced Studies in Aging, Washington, DC, is Editor for Clinical Oncology Alert.
Synopsis: Detection of increased levels of HER-2/neu was observed in approximately 25% of patients at the time of progression after primary hormonal therapy. Although the initial response rate or time to progression was not different in those who expressed increased levels vs. those who did not, overall survival was worse for converted (ie, went from negative to positive with regard to HER-2/neu serum levels) was worse.
Source: Lipton A, et al. Serum HER-2/neu conversion to positive at the time of disease progression in patients with breast carcinoma on hormone therapy. Cancer. 2005;104:257-263.
There is a curious in vitro phenomenon that when human breast carcinoma cells are exposed to tamoxifen over several months, tamoxifen resistance develops.1,2 These cells express increased levels of certain kinases as well as increased levels of HER-2/neu. To test the clinical significance of this observation the question was asked whether patients who were HER-2/neu negative prior to treatment (in this case, locally advanced or metastatic breast cancer patients, hormone receptor positive, treated with either tamoxifen or letrozole) began to express increased quantities of HER-2/neu upon progression of disease.
Serum samples just prior to treatment or at the time of progression were analyzed by immunoassay for HER-2/neu in 240 patients. Of these, 26% converted from negative to positive in the HER-2/neu assay. The response rate with regard to initial treatment (either tamoxifen or letrozole) and the time to disease progression were not affected by serum HER-2/neu conversion. However, the survival of patients who converted to positive was significantly shorter than for those who remained negative for HER-2/neu at the time of progression. A multivariate analysis revealed that conversion to positive in the serum HER-2/neu assay was an independent prognostic variable for survival.
COMMENTARY
Clinicians generally have a good sense of prognosis derived from factors such as performance status, extent of tumor and organ involvement, and the introduction of a laboratory marker might be considered of only limited value. Perhaps, if these findings are confirmed and the assay becomes clinically available, those that convert from negative to positive in their expression of serum HER-2/neu would be considered to have more aggressive disease and be treated with greater intensity. However, a significant amount of laboratory and clinical investigation would be required before this becomes anything more than an investigational tool.
The intrigue in this work, however, relates to the implications of the marker (serum HER-2/neu) with regard to cancer cell biology. The in vitro development of tamoxifen resistance was associated with increased levels of both epidermal growth factor receptor (EGFR) and HER-2/neu, and it has been speculated that the dysregulation of this growth factor pathway is causally related to tamoxifen resistance. The question whether the detection of a change in serum HER-2/neu is of biological relevance is one that is calling for prompt attention. One way to address this might be to analyze fresh tumor biopsy specimens in a small cohort of patients at presentation and at the time of tumor recurrence or progression. If, as might be expected, serum levels correlate with new or increased expression of HER-2/neu, the assay might take on new clinical significance, and patient treatment for those individuals might be appropriately targeted
References
1. Osborne CK, Fuqua SA. Mechanisms of tamoxifen resistance. Breast Cancer Res Treat. 1994;32:49-55.
2. Encarnacion CA, et al. Measurement of steroid hormone receptors in breast cancer patients on tamoxifen. Breast Cancer Res Treat. 1993;26:237-246.
3. Nicholson RI, Gee JM. Oestrogen and growth factor cross-talk and endocrine insensitivity and acquired resistance in breast cancer. Br J Cancer. 2000;82: 501-513.
Detection of increased levels of HER-2/neu was observed in approximately 25% of patients at the time of progression after primary hormonal therapy. Although the initial response rate or time to progression was not different in those who expressed increased levels vs. those who did not, overall survival was worse for converted (ie, went from negative to positive with regard to HER-2/neu serum levels) was worse.Subscribe Now for Access
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